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Metabolism

Metabolism (/məˈtæbəlɪzəm/, from Greek: μεταβολή metabolē, "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the conversion of food to building blocks for proteins, lipids, nucleic acids, and some carbohydrates; and the elimination of metabolic wastes. These enzyme-catalyzed reactions allow organisms to grow and reproduce, maintain their structures, and respond to their environments. The word metabolism can also refer to the sum of all chemical reactions that occur in living organisms, including digestion and the transportation of substances into and between different cells, in which case the above described set of reactions within the cells is called intermediary (or intermediate) metabolism.

Simplified view of the cellular metabolism
Structure of adenosine triphosphate (ATP), a central intermediate in energy metabolism

Metabolic reactions may be categorized as catabolic – the breaking down of compounds (for example, of glucose to pyruvate by cellular respiration); or anabolic – the building up (synthesis) of compounds (such as proteins, carbohydrates, lipids, and nucleic acids). Usually, catabolism releases energy, and anabolism consumes energy.

The chemical reactions of metabolism are organized into metabolic pathways, in which one chemical is transformed through a series of steps into another chemical, each step being facilitated by a specific enzyme. Enzymes are crucial to metabolism because they allow organisms to drive desirable reactions that require energy and will not occur by themselves, by coupling them to spontaneous reactions that release energy. Enzymes act as catalysts – they allow a reaction to proceed more rapidly – and they also allow the regulation of the rate of a metabolic reaction, for example in response to changes in the cell's environment or to signals from other cells.

The metabolic system of a particular organism determines which substances it will find nutritious and which poisonous. For example, some prokaryotes use hydrogen sulfide as a nutrient, yet this gas is poisonous to animals.[1] The basal metabolic rate of an organism is the measure of the amount of energy consumed by all of these chemical reactions.

A striking feature of metabolism is the similarity of the basic metabolic pathways among vastly different species.[2] For example, the set of carboxylic acids that are best known as the intermediates in the citric acid cycle are present in all known organisms, being found in species as diverse as the unicellular bacterium Escherichia coli and huge multicellular organisms like elephants.[3] These similarities in metabolic pathways are likely due to their early appearance in evolutionary history, and their retention is likely due to their efficacy.[4][5] In various diseases, such as type II diabetes, metabolic syndrome, and cancer, normal metabolism is disrupted.[6] The metabolism of cancer cells is also different from the metabolism of normal cells, and these differences can be used to find targets for therapeutic intervention in cancer.[7]

Key biochemicals

 
Structure of a triacylglycerol lipid
 
This is a diagram depicting a large set of human metabolic pathways.[image reference needed]

Most of the structures that make up animals, plants and microbes are made from four basic classes of molecules: amino acids, carbohydrates, nucleic acid and lipids (often called fats). As these molecules are vital for life, metabolic reactions either focus on making these molecules during the construction of cells and tissues, or on breaking them down and using them to obtain energy, by their digestion. These biochemicals can be joined to make polymers such as DNA and proteins, essential macromolecules of life.[8]

Type of molecule Name of monomer forms Name of polymer forms Examples of polymer forms
Amino acids Amino acids Proteins (made of polypeptides) Fibrous proteins and globular proteins
Carbohydrates Monosaccharides Polysaccharides Starch, glycogen and cellulose
Nucleic acids Nucleotides Polynucleotides DNA and RNA

Amino acids and proteins

Proteins are made of amino acids arranged in a linear chain joined by peptide bonds. Many proteins are enzymes that catalyze the chemical reactions in metabolism. Other proteins have structural or mechanical functions, such as those that form the cytoskeleton, a system of scaffolding that maintains the cell shape.[9] Proteins are also important in cell signaling, immune responses, cell adhesion, active transport across membranes, and the cell cycle.[10] Amino acids also contribute to cellular energy metabolism by providing a carbon source for entry into the citric acid cycle (tricarboxylic acid cycle),[11] especially when a primary source of energy, such as glucose, is scarce, or when cells undergo metabolic stress.[12]

Lipids

Lipids are the most diverse group of biochemicals. Their main structural uses are as part of biological membranes both internal and external, such as the cell membrane.[10] Their chemical energy can also be used. Lipids are the polymers of fatty acids[citation needed] that contain a long, non-polar hydrocarbon chain with a small polar region containing oxygen. Lipids are usually defined as hydrophobic or amphipathic biological molecules but will dissolve in organic solvents such as ethanol, benzene or chloroform.[13] The fats are a large group of compounds that contain fatty acids and glycerol; a glycerol molecule attached to three fatty acids by ester linkages is called a triacylglyceride.[14] Several variations on this basic structure exist, including backbones such as sphingosine in sphingomyelin, and hydrophilic groups such as phosphate as in phospholipids. Steroids such as sterol are another major class of lipids.[15]

Carbohydrates

 
Glucose can exist in both a straight-chain and ring form.

Carbohydrates are aldehydes or ketones, with many hydroxyl groups attached, that can exist as straight chains or rings. Carbohydrates are the most abundant biological molecules, and fill numerous roles, such as the storage and transport of energy (starch, glycogen) and structural components (cellulose in plants, chitin in animals).[10] The basic carbohydrate units are called monosaccharides and include galactose, fructose, and most importantly glucose. Monosaccharides can be linked together to form polysaccharides in almost limitless ways.[16]

Nucleotides

The two nucleic acids, DNA and RNA, are polymers of nucleotides. Each nucleotide is composed of a phosphate attached to a ribose or deoxyribose sugar group which is attached to a nitrogenous base. Nucleic acids are critical for the storage and use of genetic information, and its interpretation through the processes of transcription and protein biosynthesis.[10] This information is protected by DNA repair mechanisms and propagated through DNA replication. Many viruses have an RNA genome, such as HIV, which uses reverse transcription to create a DNA template from its viral RNA genome.[17] RNA in ribozymes such as spliceosomes and ribosomes is similar to enzymes as it can catalyze chemical reactions. Individual nucleosides are made by attaching a nucleobase to a ribose sugar. These bases are heterocyclic rings containing nitrogen, classified as purines or pyrimidines. Nucleotides also act as coenzymes in metabolic-group-transfer reactions.[18]

Coenzymes

 
Structure of the coenzyme acetyl-CoA.The transferable acetyl group is bonded to the sulfur atom at the extreme left.

Metabolism involves a vast array of chemical reactions, but most fall under a few basic types of reactions that involve the transfer of functional groups of atoms and their bonds within molecules.[19] This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions.[18] These group-transfer intermediates are called coenzymes. Each class of group-transfer reactions is carried out by a particular coenzyme, which is the substrate for a set of enzymes that produce it, and a set of enzymes that consume it. These coenzymes are therefore continuously made, consumed and then recycled.[20]

One central coenzyme is adenosine triphosphate (ATP), the universal energy currency of cells. This nucleotide is used to transfer chemical energy between different chemical reactions. There is only a small amount of ATP in cells, but as it is continuously regenerated, the human body can use about its own weight in ATP per day.[20] ATP acts as a bridge between catabolism and anabolism. Catabolism breaks down molecules, and anabolism puts them together. Catabolic reactions generate ATP, and anabolic reactions consume it. It also serves as a carrier of phosphate groups in phosphorylation reactions.[21]

A vitamin is an organic compound needed in small quantities that cannot be made in cells. In human nutrition, most vitamins function as coenzymes after modification; for example, all water-soluble vitamins are phosphorylated or are coupled to nucleotides when they are used in cells.[22] Nicotinamide adenine dinucleotide (NAD+), a derivative of vitamin B3 (niacin), is an important coenzyme that acts as a hydrogen acceptor. Hundreds of separate types of dehydrogenases remove electrons from their substrates and reduce NAD+ into NADH. This reduced form of the coenzyme is then a substrate for any of the reductases in the cell that need to transfer hydrogen atoms to their substrates.[23] Nicotinamide adenine dinucleotide exists in two related forms in the cell, NADH and NADPH. The NAD+/NADH form is more important in catabolic reactions, while NADP+/NADPH is used in anabolic reactions.[24]

 
The structure of iron-containing hemoglobin. The protein subunits are in red and blue, and the iron-containing heme groups in green. From PDB: 1GZX​.

Mineral and cofactors

Inorganic elements play critical roles in metabolism; some are abundant (e.g. sodium and potassium) while others function at minute concentrations. About 99% of a human's body weight is made up of the elements carbon, nitrogen, calcium, sodium, chlorine, potassium, hydrogen, phosphorus, oxygen and sulfur. Organic compounds (proteins, lipids and carbohydrates) contain the majority of the carbon and nitrogen; most of the oxygen and hydrogen is present as water.[25]

The abundant inorganic elements act as electrolytes. The most important ions are sodium, potassium, calcium, magnesium, chloride, phosphate and the organic ion bicarbonate. The maintenance of precise ion gradients across cell membranes maintains osmotic pressure and pH.[26] Ions are also critical for nerve and muscle function, as action potentials in these tissues are produced by the exchange of electrolytes between the extracellular fluid and the cell's fluid, the cytosol.[27] Electrolytes enter and leave cells through proteins in the cell membrane called ion channels. For example, muscle contraction depends upon the movement of calcium, sodium and potassium through ion channels in the cell membrane and T-tubules.[28]

Transition metals are usually present as trace elements in organisms, with zinc and iron being most abundant of those.[29] Metal cofactors are bound tightly to specific sites in proteins; although enzyme cofactors can be modified during catalysis, they always return to their original state by the end of the reaction catalyzed. Metal micronutrients are taken up into organisms by specific transporters and bind to storage proteins such as ferritin or metallothionein when not in use.[30][31]

Catabolism

Catabolism is the set of metabolic processes that break down large molecules. These include breaking down and oxidizing food molecules. The purpose of the catabolic reactions is to provide the energy and components needed by anabolic reactions which build molecules.[32] The exact nature of these catabolic reactions differ from organism to organism, and organisms can be classified based on their sources of energy, hydrogen, and carbon (their primary nutritional groups), as shown in the table below. Organic molecules are used as a source of hydrogen atoms or electrons by organotrophs, while lithotrophs use inorganic substrates. Whereas phototrophs convert sunlight to chemical energy,[33] chemotrophs depend on redox reactions that involve the transfer of electrons from reduced donor molecules such as organic molecules, hydrogen, hydrogen sulfide or ferrous ions to oxygen, nitrate or sulfate. In animals, these reactions involve complex organic molecules that are broken down to simpler molecules, such as carbon dioxide and water. Photosynthetic organisms, such as plants and cyanobacteria, use similar electron-transfer reactions to store energy absorbed from sunlight.[34]

Classification of organisms based on their metabolism [35]
Energy source sunlight photo-   -troph
molecules chemo-
Hydrogen or electron donor organic compound   organo-  
inorganic compound litho-
Carbon source organic compound   hetero-
inorganic compound auto-

The most common set of catabolic reactions in animals can be separated into three main stages. In the first stage, large organic molecules, such as proteins, polysaccharides or lipids, are digested into their smaller components outside cells. Next, these smaller molecules are taken up by cells and converted to smaller molecules, usually acetyl coenzyme A (acetyl-CoA), which releases some energy. Finally, the acetyl group on acetyl-CoA is oxidized to water and carbon dioxide in the citric acid cycle and electron transport chain, releasing more energy while reducing the coenzyme nicotinamide adenine dinucleotide (NAD+) into NADH.[32]

Digestion

Macromolecules cannot be directly processed by cells. Macromolecules must be broken into smaller units before they can be used in cell metabolism. Different classes of enzymes are used to digest these polymers. These digestive enzymes include proteases that digest proteins into amino acids, as well as glycoside hydrolases that digest polysaccharides into simple sugars known as monosaccharides.[36]

Microbes simply secrete digestive enzymes into their surroundings,[37][38] while animals only secrete these enzymes from specialized cells in their guts, including the stomach and pancreas, and in salivary glands.[39] The amino acids or sugars released by these extracellular enzymes are then pumped into cells by active transport proteins.[40][41]

 
A simplified outline of the catabolism of proteins, carbohydrates and fats[image reference needed]

Energy from organic compounds

Carbohydrate catabolism is the breakdown of carbohydrates into smaller units. Carbohydrates are usually taken into cells after they have been digested into monosaccharides.[42] Once inside, the major route of breakdown is glycolysis, where sugars such as glucose and fructose are converted into pyruvate and some ATP is generated.[43] Pyruvate is an intermediate in several metabolic pathways, but the majority is converted to acetyl-CoA through aerobic (with oxygen) glycolysis and fed into the citric acid cycle. Although some more ATP is generated in the citric acid cycle, the most important product is NADH, which is made from NAD+ as the acetyl-CoA is oxidized. This oxidation releases carbon dioxide as a waste product. In anaerobic conditions, glycolysis produces lactate, through the enzyme lactate dehydrogenase re-oxidizing NADH to NAD+ for re-use in glycolysis.[44] An alternative route for glucose breakdown is the pentose phosphate pathway, which reduces the coenzyme NADPH and produces pentose sugars such as ribose, the sugar component of nucleic acids.[citation needed]

Fats are catabolized by hydrolysis to free fatty acids and glycerol. The glycerol enters glycolysis and the fatty acids are broken down by beta oxidation to release acetyl-CoA, which then is fed into the citric acid cycle. Fatty acids release more energy upon oxidation than carbohydrates. Steroids are also broken down by some bacteria in a process similar to beta oxidation, and this breakdown process involves the release of significant amounts of acetyl-CoA, propionyl-CoA, and pyruvate, which can all be used by the cell for energy. M. tuberculosis can also grow on the lipid cholesterol as a sole source of carbon, and genes involved in the cholesterol-use pathway(s) have been validated as important during various stages of the infection lifecycle of M. tuberculosis.[45]

Amino acids are either used to synthesize proteins and other biomolecules, or oxidized to urea and carbon dioxide to produce energy.[46] The oxidation pathway starts with the removal of the amino group by a transaminase. The amino group is fed into the urea cycle, leaving a deaminated carbon skeleton in the form of a keto acid. Several of these keto acids are intermediates in the citric acid cycle, for example α-ketoglutarate formed by deamination of glutamate.[47] The glucogenic amino acids can also be converted into glucose, through gluconeogenesis (discussed below).[48]

Energy transformations

Oxidative phosphorylation

In oxidative phosphorylation, the electrons removed from organic molecules in areas such as the citric acid cycle are transferred to oxygen and the energy released is used to make ATP. This is done in eukaryotes by a series of proteins in the membranes of mitochondria called the electron transport chain. In prokaryotes, these proteins are found in the cell's inner membrane.[49] These proteins use the energy from reduced molecules like NADH to pump protons across a membrane.[50]

 
Mechanism of ATP synthase. ATP is shown in red, ADP and phosphate in pink and the rotating stalk subunit in black.

Pumping protons out of the mitochondria creates a proton concentration difference across the membrane and generates an electrochemical gradient.[51] This force drives protons back into the mitochondrion through the base of an enzyme called ATP synthase. The flow of protons makes the stalk subunit rotate, causing the active site of the synthase domain to change shape and phosphorylate adenosine diphosphate – turning it into ATP.[20]

Energy from inorganic compounds

Chemolithotrophy is a type of metabolism found in prokaryotes where energy is obtained from the oxidation of inorganic compounds. These organisms can use hydrogen,[52] reduced sulfur compounds (such as sulfide, hydrogen sulfide and thiosulfate),[1] ferrous iron (Fe(II))[53] or ammonia[54] as sources of reducing power and they gain energy from the oxidation of these compounds.[55] These microbial processes are important in global biogeochemical cycles such as acetogenesis, nitrification and denitrification and are critical for soil fertility.[56][57]

Energy from light

The energy in sunlight is captured by plants, cyanobacteria, purple bacteria, green sulfur bacteria and some protists. This process is often coupled to the conversion of carbon dioxide into organic compounds, as part of photosynthesis, which is discussed below. The energy capture and carbon fixation systems can, however, operate separately in prokaryotes, as purple bacteria and green sulfur bacteria can use sunlight as a source of energy, while switching between carbon fixation and the fermentation of organic compounds.[58][59]

In many organisms, the capture of solar energy is similar in principle to oxidative phosphorylation, as it involves the storage of energy as a proton concentration gradient. This proton motive force then drives ATP synthesis[60] The electrons needed to drive this electron transport chain come from light-gathering proteins called photosynthetic reaction centres. Reaction centers are classified into two types depending on the nature of photosynthetic pigment present, with most photosynthetic bacteria only having one type, while plants and cyanobacteria have two.[61]

In plants, algae, and cyanobacteria, photosystem II uses light energy to remove electrons from water, releasing oxygen as a waste product. The electrons then flow to the cytochrome b6f complex, which uses their energy to pump protons across the thylakoid membrane in the chloroplast.[34] These protons move back through the membrane as they drive the ATP synthase, as before. The electrons then flow through photosystem I and can then be used to reduce the coenzyme NADP+.[62] This coenzyme can enter the Calvin cycle, which is discussed below, or be recycled for further ATP generation.[citation needed]

Anabolism

Anabolism is the set of constructive metabolic processes where the energy released by catabolism is used to synthesize complex molecules. In general, the complex molecules that make up cellular structures are constructed step-by-step from smaller and simpler precursors. Anabolism involves three basic stages. First, the production of precursors such as amino acids, monosaccharides, isoprenoids and nucleotides, secondly, their activation into reactive forms using energy from ATP, and thirdly, the assembly of these precursors into complex molecules such as proteins, polysaccharides, lipids and nucleic acids.[63]

Anabolism in organisms can be different according to the source of constructed molecules in their cells. Autotrophs such as plants can construct the complex organic molecules in their cells such as polysaccharides and proteins from simple molecules like carbon dioxide and water. Heterotrophs, on the other hand, require a source of more complex substances, such as monosaccharides and amino acids, to produce these complex molecules. Organisms can be further classified by ultimate source of their energy: photoautotrophs and photoheterotrophs obtain energy from light, whereas chemoautotrophs and chemoheterotrophs obtain energy from oxidation reactions.[63]

Carbon fixation

 
Plant cells (bounded by purple walls) filled with chloroplasts (green), which are the site of photosynthesis

Photosynthesis is the synthesis of carbohydrates from sunlight and carbon dioxide (CO2). In plants, cyanobacteria and algae, oxygenic photosynthesis splits water, with oxygen produced as a waste product. This process uses the ATP and NADPH produced by the photosynthetic reaction centres, as described above, to convert CO2 into glycerate 3-phosphate, which can then be converted into glucose. This carbon-fixation reaction is carried out by the enzyme RuBisCO as part of the Calvin – Benson cycle.[64] Three types of photosynthesis occur in plants, C3 carbon fixation, C4 carbon fixation and CAM photosynthesis. These differ by the route that carbon dioxide takes to the Calvin cycle, with C3 plants fixing CO2 directly, while C4 and CAM photosynthesis incorporate the CO2 into other compounds first, as adaptations to deal with intense sunlight and dry conditions.[65]

In photosynthetic prokaryotes the mechanisms of carbon fixation are more diverse. Here, carbon dioxide can be fixed by the Calvin – Benson cycle, a reversed citric acid cycle,[66] or the carboxylation of acetyl-CoA.[67][68] Prokaryotic chemoautotrophs also fix CO2 through the Calvin–Benson cycle, but use energy from inorganic compounds to drive the reaction.[69]

Carbohydrates and glycans

In carbohydrate anabolism, simple organic acids can be converted into monosaccharides such as glucose and then used to assemble polysaccharides such as starch. The generation of glucose from compounds like pyruvate, lactate, glycerol, glycerate 3-phosphate and amino acids is called gluconeogenesis. Gluconeogenesis converts pyruvate to glucose-6-phosphate through a series of intermediates, many of which are shared with glycolysis.[43] However, this pathway is not simply glycolysis run in reverse, as several steps are catalyzed by non-glycolytic enzymes. This is important as it allows the formation and breakdown of glucose to be regulated separately, and prevents both pathways from running simultaneously in a futile cycle.[70][71]

Although fat is a common way of storing energy, in vertebrates such as humans the fatty acids in these stores cannot be converted to glucose through gluconeogenesis as these organisms cannot convert acetyl-CoA into pyruvate; plants do, but animals do not, have the necessary enzymatic machinery.[72] As a result, after long-term starvation, vertebrates need to produce ketone bodies from fatty acids to replace glucose in tissues such as the brain that cannot metabolize fatty acids.[73] In other organisms such as plants and bacteria, this metabolic problem is solved using the glyoxylate cycle, which bypasses the decarboxylation step in the citric acid cycle and allows the transformation of acetyl-CoA to oxaloacetate, where it can be used for the production of glucose.[72][74] Other than fat, glucose is stored in most tissues, as an energy resource available within the tissue through glycogenesis which was usually being used to maintained glucose level in blood.[75]

Polysaccharides and glycans are made by the sequential addition of monosaccharides by glycosyltransferase from a reactive sugar-phosphate donor such as uridine diphosphate glucose (UDP-Glc) to an acceptor hydroxyl group on the growing polysaccharide. As any of the hydroxyl groups on the ring of the substrate can be acceptors, the polysaccharides produced can have straight or branched structures.[76] The polysaccharides produced can have structural or metabolic functions themselves, or be transferred to lipids and proteins by enzymes called oligosaccharyltransferases.[77][78]

Fatty acids, isoprenoids and sterol

 
Simplified version of the steroid synthesis pathway with the intermediates isopentenyl pyrophosphate (IPP), dimethylallyl pyrophosphate (DMAPP), geranyl pyrophosphate (GPP) and squalene shown. Some intermediates are omitted for clarity.

Fatty acids are made by fatty acid synthases that polymerize and then reduce acetyl-CoA units. The acyl chains in the fatty acids are extended by a cycle of reactions that add the acyl group, reduce it to an alcohol, dehydrate it to an alkene group and then reduce it again to an alkane group. The enzymes of fatty acid biosynthesis are divided into two groups: in animals and fungi, all these fatty acid synthase reactions are carried out by a single multifunctional type I protein,[79] while in plant plastids and bacteria separate type II enzymes perform each step in the pathway.[80][81]

Terpenes and isoprenoids are a large class of lipids that include the carotenoids and form the largest class of plant natural products.[82] These compounds are made by the assembly and modification of isoprene units donated from the reactive precursors isopentenyl pyrophosphate and dimethylallyl pyrophosphate.[83] These precursors can be made in different ways. In animals and archaea, the mevalonate pathway produces these compounds from acetyl-CoA,[84] while in plants and bacteria the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates.[83][85] One important reaction that uses these activated isoprene donors is sterol biosynthesis. Here, the isoprene units are joined to make squalene and then folded up and formed into a set of rings to make lanosterol.[86] Lanosterol can then be converted into other sterols such as cholesterol and ergosterol.[86][87]

Proteins

Organisms vary in their ability to synthesize the 20 common amino acids. Most bacteria and plants can synthesize all twenty, but mammals can only synthesize eleven nonessential amino acids, so nine essential amino acids must be obtained from food.[10] Some simple parasites, such as the bacteria Mycoplasma pneumoniae, lack all amino acid synthesis and take their amino acids directly from their hosts.[88] All amino acids are synthesized from intermediates in glycolysis, the citric acid cycle, or the pentose phosphate pathway. Nitrogen is provided by glutamate and glutamine. Nonessensial amino acid synthesis depends on the formation of the appropriate alpha-keto acid, which is then transaminated to form an amino acid.[89]

Amino acids are made into proteins by being joined in a chain of peptide bonds. Each different protein has a unique sequence of amino acid residues: this is its primary structure. Just as the letters of the alphabet can be combined to form an almost endless variety of words, amino acids can be linked in varying sequences to form a huge variety of proteins. Proteins are made from amino acids that have been activated by attachment to a transfer RNA molecule through an ester bond. This aminoacyl-tRNA precursor is produced in an ATP-dependent reaction carried out by an aminoacyl tRNA synthetase.[90] This aminoacyl-tRNA is then a substrate for the ribosome, which joins the amino acid onto the elongating protein chain, using the sequence information in a messenger RNA.[91]

Nucleotide synthesis and salvage

Nucleotides are made from amino acids, carbon dioxide and formic acid in pathways that require large amounts of metabolic energy.[92] Consequently, most organisms have efficient systems to salvage preformed nucleotides.[92][93] Purines are synthesized as nucleosides (bases attached to ribose).[94] Both adenine and guanine are made from the precursor nucleoside inosine monophosphate, which is synthesized using atoms from the amino acids glycine, glutamine, and aspartic acid, as well as formate transferred from the coenzyme tetrahydrofolate. Pyrimidines, on the other hand, are synthesized from the base orotate, which is formed from glutamine and aspartate.[95]

Xenobiotics and redox metabolism

All organisms are constantly exposed to compounds that they cannot use as foods and that would be harmful if they accumulated in cells, as they have no metabolic function. These potentially damaging compounds are called xenobiotics.[96] Xenobiotics such as synthetic drugs, natural poisons and antibiotics are detoxified by a set of xenobiotic-metabolizing enzymes. In humans, these include cytochrome P450 oxidases,[97] UDP-glucuronosyltransferases,[98] and glutathione S-transferases.[99] This system of enzymes acts in three stages to firstly oxidize the xenobiotic (phase I) and then conjugate water-soluble groups onto the molecule (phase II). The modified water-soluble xenobiotic can then be pumped out of cells and in multicellular organisms may be further metabolized before being excreted (phase III). In ecology, these reactions are particularly important in microbial biodegradation of pollutants and the bioremediation of contaminated land and oil spills.[100] Many of these microbial reactions are shared with multicellular organisms, but due to the incredible diversity of types of microbes these organisms are able to deal with a far wider range of xenobiotics than multicellular organisms, and can degrade even persistent organic pollutants such as organochloride compounds.[101]

A related problem for aerobic organisms is oxidative stress.[102] Here, processes including oxidative phosphorylation and the formation of disulfide bonds during protein folding produce reactive oxygen species such as hydrogen peroxide.[103] These damaging oxidants are removed by antioxidant metabolites such as glutathione and enzymes such as catalases and peroxidases.[104][105]

Thermodynamics of living organisms

Living organisms must obey the laws of thermodynamics, which describe the transfer of heat and work. The second law of thermodynamics states that in any isolated system, the amount of entropy (disorder) cannot decrease. Although living organisms' amazing complexity appears to contradict this law, life is possible as all organisms are open systems that exchange matter and energy with their surroundings. Living systems are not in equilibrium, but instead are dissipative systems that maintain their state of high complexity by causing a larger increase in the entropy of their environments.[106] The metabolism of a cell achieves this by coupling the spontaneous processes of catabolism to the non-spontaneous processes of anabolism. In thermodynamic terms, metabolism maintains order by creating disorder.[107]

Regulation and control

As the environments of most organisms are constantly changing, the reactions of metabolism must be finely regulated to maintain a constant set of conditions within cells, a condition called homeostasis.[108][109] Metabolic regulation also allows organisms to respond to signals and interact actively with their environments.[110] Two closely linked concepts are important for understanding how metabolic pathways are controlled. Firstly, the regulation of an enzyme in a pathway is how its activity is increased and decreased in response to signals. Secondly, the control exerted by this enzyme is the effect that these changes in its activity have on the overall rate of the pathway (the flux through the pathway).[111] For example, an enzyme may show large changes in activity (i.e. it is highly regulated) but if these changes have little effect on the flux of a metabolic pathway, then this enzyme is not involved in the control of the pathway.[112]

 
Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1), which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).[image reference needed]

There are multiple levels of metabolic regulation. In intrinsic regulation, the metabolic pathway self-regulates to respond to changes in the levels of substrates or products; for example, a decrease in the amount of product can increase the flux through the pathway to compensate.[111] This type of regulation often involves allosteric regulation of the activities of multiple enzymes in the pathway.[113] Extrinsic control involves a cell in a multicellular organism changing its metabolism in response to signals from other cells. These signals are usually in the form of water-soluble messengers such as hormones and growth factors and are detected by specific receptors on the cell surface.[114] These signals are then transmitted inside the cell by second messenger systems that often involved the phosphorylation of proteins.[115]

A very well understood example of extrinsic control is the regulation of glucose metabolism by the hormone insulin.[116] Insulin is produced in response to rises in blood glucose levels. Binding of the hormone to insulin receptors on cells then activates a cascade of protein kinases that cause the cells to take up glucose and convert it into storage molecules such as fatty acids and glycogen.[117] The metabolism of glycogen is controlled by activity of phosphorylase, the enzyme that breaks down glycogen, and glycogen synthase, the enzyme that makes it. These enzymes are regulated in a reciprocal fashion, with phosphorylation inhibiting glycogen synthase, but activating phosphorylase. Insulin causes glycogen synthesis by activating protein phosphatases and producing a decrease in the phosphorylation of these enzymes.[118]

Evolution

 
Evolutionary tree showing the common ancestry of organisms from all three domains of life. Bacteria are colored blue, eukaryotes red, and archaea green. Relative positions of some of the phyla included are shown around the tree.

The central pathways of metabolism described above, such as glycolysis and the citric acid cycle, are present in all three domains of living things and were present in the last universal common ancestor.[3][119] This universal ancestral cell was prokaryotic and probably a methanogen that had extensive amino acid, nucleotide, carbohydrate and lipid metabolism.[120][121] The retention of these ancient pathways during later evolution may be the result of these reactions having been an optimal solution to their particular metabolic problems, with pathways such as glycolysis and the citric acid cycle producing their end products highly efficiently and in a minimal number of steps.[4][5] The first pathways of enzyme-based metabolism may have been parts of purine nucleotide metabolism, while previous metabolic pathways were a part of the ancient RNA world.[122]

Many models have been proposed to describe the mechanisms by which novel metabolic pathways evolve. These include the sequential addition of novel enzymes to a short ancestral pathway, the duplication and then divergence of entire pathways as well as the recruitment of pre-existing enzymes and their assembly into a novel reaction pathway.[123] The relative importance of these mechanisms is unclear, but genomic studies have shown that enzymes in a pathway are likely to have a shared ancestry, suggesting that many pathways have evolved in a step-by-step fashion with novel functions created from pre-existing steps in the pathway.[124] An alternative model comes from studies that trace the evolution of proteins' structures in metabolic networks, this has suggested that enzymes are pervasively recruited, borrowing enzymes to perform similar functions in different metabolic pathways (evident in the MANET database)[125] These recruitment processes result in an evolutionary enzymatic mosaic.[126] A third possibility is that some parts of metabolism might exist as "modules" that can be reused in different pathways and perform similar functions on different molecules.[127]

As well as the evolution of new metabolic pathways, evolution can also cause the loss of metabolic functions. For example, in some parasites metabolic processes that are not essential for survival are lost and preformed amino acids, nucleotides and carbohydrates may instead be scavenged from the host.[128] Similar reduced metabolic capabilities are seen in endosymbiotic organisms.[129]

Investigation and manipulation

 
Metabolic network of the Arabidopsis thaliana citric acid cycle. Enzymes and metabolites are shown as red squares and the interactions between them as black lines.

Classically, metabolism is studied by a reductionist approach that focuses on a single metabolic pathway. Particularly valuable is the use of radioactive tracers at the whole-organism, tissue and cellular levels, which define the paths from precursors to final products by identifying radioactively labelled intermediates and products.[130] The enzymes that catalyze these chemical reactions can then be purified and their kinetics and responses to inhibitors investigated. A parallel approach is to identify the small molecules in a cell or tissue; the complete set of these molecules is called the metabolome. Overall, these studies give a good view of the structure and function of simple metabolic pathways, but are inadequate when applied to more complex systems such as the metabolism of a complete cell.[131]

An idea of the complexity of the metabolic networks in cells that contain thousands of different enzymes is given by the figure showing the interactions between just 43 proteins and 40 metabolites to the right: the sequences of genomes provide lists containing anything up to 26.500 genes.[132] However, it is now possible to use this genomic data to reconstruct complete networks of biochemical reactions and produce more holistic mathematical models that may explain and predict their behavior.[133] These models are especially powerful when used to integrate the pathway and metabolite data obtained through classical methods with data on gene expression from proteomic and DNA microarray studies.[134] Using these techniques, a model of human metabolism has now been produced, which will guide future drug discovery and biochemical research.[135] These models are now used in network analysis, to classify human diseases into groups that share common proteins or metabolites.[136][137]

Bacterial metabolic networks are a striking example of bow-tie[138][139][140] organization, an architecture able to input a wide range of nutrients and produce a large variety of products and complex macromolecules using a relatively few intermediate common currencies.

A major technological application of this information is metabolic engineering. Here, organisms such as yeast, plants or bacteria are genetically modified to make them more useful in biotechnology and aid the production of drugs such as antibiotics or industrial chemicals such as 1,3-propanediol and shikimic acid.[141][142][143] These genetic modifications usually aim to reduce the amount of energy used to produce the product, increase yields and reduce the production of wastes.[144]

History

The term metabolism is derived from French "métabolisme" or Ancient Greek μεταβολή – "Metabole" for "a change" which derived from μεταβάλλ –"Metaballein" means "To change"[145]

 
Aristotle's metabolism as an open flow model

Greek philosophy

Aristotle's The Parts of Animals sets out enough details of his views on metabolism for an open flow model to be made. He believed that at each stage of the process, materials from food were transformed, with heat being released as the classical element of fire, and residual materials being excreted as urine, bile, or faeces.[146]

Ibn al-Nafis described metabolism in his 1260 AD work titled Al-Risalah al-Kamiliyyah fil Siera al-Nabawiyyah (The Treatise of Kamil on the Prophet's Biography) which included the following phrase "Both the body and its parts are in a continuous state of dissolution and nourishment, so they are inevitably undergoing permanent change."[147]

Application of the scientific method and Modern metabolic theories

The history of the scientific study of metabolism spans several centuries and has moved from examining whole animals in early studies, to examining individual metabolic reactions in modern biochemistry. The first controlled experiments in human metabolism were published by Santorio Santorio in 1614 in his book Ars de statica medicina.[148] He described how he weighed himself before and after eating, sleep, working, sex, fasting, drinking, and excreting. He found that most of the food he took in was lost through what he called "insensible perspiration".

 
Santorio Santorio in his steelyard balance, from Ars de statica medicina, first published 1614

In these early studies, the mechanisms of these metabolic processes had not been identified and a vital force was thought to animate living tissue.[149] In the 19th century, when studying the fermentation of sugar to alcohol by yeast, Louis Pasteur concluded that fermentation was catalyzed by substances within the yeast cells he called "ferments". He wrote that "alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells."[150] This discovery, along with the publication by Friedrich Wöhler in 1828 of a paper on the chemical synthesis of urea,[151] and is notable for being the first organic compound prepared from wholly inorganic precursors. This proved that the organic compounds and chemical reactions found in cells were no different in principle than any other part of chemistry.

It was the discovery of enzymes at the beginning of the 20th century by Eduard Buchner that separated the study of the chemical reactions of metabolism from the biological study of cells, and marked the beginnings of biochemistry.[152] The mass of biochemical knowledge grew rapidly throughout the early 20th century. One of the most prolific of these modern biochemists was Hans Krebs who made huge contributions to the study of metabolism.[153] He discovered the urea cycle and later, working with Hans Kornberg, the citric acid cycle and the glyoxylate cycle.[154][155][74] Modern biochemical research has been greatly aided by the development of new techniques such as chromatography, X-ray diffraction, NMR spectroscopy, radioisotopic labelling, electron microscopy and molecular dynamics simulations. These techniques have allowed the discovery and detailed analysis of the many molecules and metabolic pathways in cells.[citation needed]

See also

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Further reading

Introductory

  • Rose S, Mileusnic R (1999). The Chemistry of Life. Penguin Press Science. ISBN 0-14-027273-9.
  • Schneider EC, Sagan D (2005). Into the Cool: Energy Flow, Thermodynamics, and Life. University of Chicago Press. ISBN 0-226-73936-8.
  • Lane N (2004). Oxygen: The Molecule that Made the World. USA: Oxford University Press. ISBN 0-19-860783-0.

Advanced

  • Price N, Stevens L (1999). Fundamentals of Enzymology: Cell and Molecular Biology of Catalytic Proteins. Oxford University Press. ISBN 0-19-850229-X.
  • Berg J, Tymoczko J, Stryer L (2002). Biochemistry. W. H. Freeman and Company. ISBN 0-7167-4955-6.
  • Cox M, Nelson DL (2004). Lehninger Principles of Biochemistry. Palgrave Macmillan. ISBN 0-7167-4339-6.
  • Brock TD, Madigan MR, Martinko J, Parker J (2002). Brock's Biology of Microorganisms. Benjamin Cummings. ISBN 0-13-066271-2.
  • Da Silva JJ, Williams RJ (1991). The Biological Chemistry of the Elements: The Inorganic Chemistry of Life. Clarendon Press. ISBN 0-19-855598-9.
  • Nicholls DG, Ferguson SJ (2002). Bioenergetics. Academic Press Inc. ISBN 0-12-518121-3.
  • Wood HG (February 1991). "Life with CO or CO2 and H2 as a source of carbon and energy". FASEB Journal. 5 (2): 156–63. doi:10.1096/fasebj.5.2.1900793. PMID 1900793. S2CID 45967404.

External links

General information

  • (archived 8 March 2005)
  • Sparknotes SAT biochemistry Overview of biochemistry. School level.
  • MIT Biology Hypertextbook Undergraduate-level guide to molecular biology.

Human metabolism

  • Topics in Medical Biochemistry Guide to human metabolic pathways. School level.
  • THE Medical Biochemistry Page Comprehensive resource on human metabolism.

Databases

  • Flow Chart of Metabolic Pathways at ExPASy
  • IUBMB-Nicholson Metabolic Pathways Chart
  • SuperCYP: Database for Drug-Cytochrome-Metabolism 3 November 2011 at the Wayback Machine

Metabolic pathways

metabolism, cellular, metabolism, redirects, here, journal, cell, journal, clinical, experimental, architectural, movement, architecture, from, greek, μεταβολή, metabolē, change, life, sustaining, chemical, reactions, organisms, three, main, functions, metabol. Cellular metabolism redirects here For the journal see Cell Metabolism For the journal Metabolism see Metabolism Clinical and Experimental For the architectural movement see Metabolism architecture Metabolism m e ˈ t ae b e l ɪ z e m from Greek metabolh metabole change is the set of life sustaining chemical reactions in organisms The three main functions of metabolism are the conversion of the energy in food to energy available to run cellular processes the conversion of food to building blocks for proteins lipids nucleic acids and some carbohydrates and the elimination of metabolic wastes These enzyme catalyzed reactions allow organisms to grow and reproduce maintain their structures and respond to their environments The word metabolism can also refer to the sum of all chemical reactions that occur in living organisms including digestion and the transportation of substances into and between different cells in which case the above described set of reactions within the cells is called intermediary or intermediate metabolism Simplified view of the cellular metabolism Structure of adenosine triphosphate ATP a central intermediate in energy metabolism Metabolic reactions may be categorized as catabolic the breaking down of compounds for example of glucose to pyruvate by cellular respiration or anabolic the building up synthesis of compounds such as proteins carbohydrates lipids and nucleic acids Usually catabolism releases energy and anabolism consumes energy The chemical reactions of metabolism are organized into metabolic pathways in which one chemical is transformed through a series of steps into another chemical each step being facilitated by a specific enzyme Enzymes are crucial to metabolism because they allow organisms to drive desirable reactions that require energy and will not occur by themselves by coupling them to spontaneous reactions that release energy Enzymes act as catalysts they allow a reaction to proceed more rapidly and they also allow the regulation of the rate of a metabolic reaction for example in response to changes in the cell s environment or to signals from other cells The metabolic system of a particular organism determines which substances it will find nutritious and which poisonous For example some prokaryotes use hydrogen sulfide as a nutrient yet this gas is poisonous to animals 1 The basal metabolic rate of an organism is the measure of the amount of energy consumed by all of these chemical reactions A striking feature of metabolism is the similarity of the basic metabolic pathways among vastly different species 2 For example the set of carboxylic acids that are best known as the intermediates in the citric acid cycle are present in all known organisms being found in species as diverse as the unicellular bacterium Escherichia coli and huge multicellular organisms like elephants 3 These similarities in metabolic pathways are likely due to their early appearance in evolutionary history and their retention is likely due to their efficacy 4 5 In various diseases such as type II diabetes metabolic syndrome and cancer normal metabolism is disrupted 6 The metabolism of cancer cells is also different from the metabolism of normal cells and these differences can be used to find targets for therapeutic intervention in cancer 7 Contents 1 Key biochemicals 1 1 Amino acids and proteins 1 2 Lipids 1 3 Carbohydrates 1 4 Nucleotides 1 5 Coenzymes 1 6 Mineral and cofactors 2 Catabolism 2 1 Digestion 2 2 Energy from organic compounds 3 Energy transformations 3 1 Oxidative phosphorylation 3 2 Energy from inorganic compounds 3 3 Energy from light 4 Anabolism 4 1 Carbon fixation 4 2 Carbohydrates and glycans 4 3 Fatty acids isoprenoids and sterol 4 4 Proteins 4 5 Nucleotide synthesis and salvage 5 Xenobiotics and redox metabolism 6 Thermodynamics of living organisms 7 Regulation and control 8 Evolution 9 Investigation and manipulation 10 History 10 1 Greek philosophy 10 2 Application of the scientific method and Modern metabolic theories 11 See also 12 References 13 Further reading 14 External linksKey biochemicals EditFurther information Biomolecule Cell biology and Biochemistry Structure of a triacylglycerol lipid This is a diagram depicting a large set of human metabolic pathways image reference needed Most of the structures that make up animals plants and microbes are made from four basic classes of molecules amino acids carbohydrates nucleic acid and lipids often called fats As these molecules are vital for life metabolic reactions either focus on making these molecules during the construction of cells and tissues or on breaking them down and using them to obtain energy by their digestion These biochemicals can be joined to make polymers such as DNA and proteins essential macromolecules of life 8 Type of molecule Name of monomer forms Name of polymer forms Examples of polymer formsAmino acids Amino acids Proteins made of polypeptides Fibrous proteins and globular proteinsCarbohydrates Monosaccharides Polysaccharides Starch glycogen and celluloseNucleic acids Nucleotides Polynucleotides DNA and RNAAmino acids and proteins Edit Main article Protein Proteins are made of amino acids arranged in a linear chain joined by peptide bonds Many proteins are enzymes that catalyze the chemical reactions in metabolism Other proteins have structural or mechanical functions such as those that form the cytoskeleton a system of scaffolding that maintains the cell shape 9 Proteins are also important in cell signaling immune responses cell adhesion active transport across membranes and the cell cycle 10 Amino acids also contribute to cellular energy metabolism by providing a carbon source for entry into the citric acid cycle tricarboxylic acid cycle 11 especially when a primary source of energy such as glucose is scarce or when cells undergo metabolic stress 12 Lipids Edit Main article Biolipid Lipids are the most diverse group of biochemicals Their main structural uses are as part of biological membranes both internal and external such as the cell membrane 10 Their chemical energy can also be used Lipids are the polymers of fatty acids citation needed that contain a long non polar hydrocarbon chain with a small polar region containing oxygen Lipids are usually defined as hydrophobic or amphipathic biological molecules but will dissolve in organic solvents such as ethanol benzene or chloroform 13 The fats are a large group of compounds that contain fatty acids and glycerol a glycerol molecule attached to three fatty acids by ester linkages is called a triacylglyceride 14 Several variations on this basic structure exist including backbones such as sphingosine in sphingomyelin and hydrophilic groups such as phosphate as in phospholipids Steroids such as sterol are another major class of lipids 15 Carbohydrates Edit Glucose can exist in both a straight chain and ring form Main article Carbohydrate Carbohydrates are aldehydes or ketones with many hydroxyl groups attached that can exist as straight chains or rings Carbohydrates are the most abundant biological molecules and fill numerous roles such as the storage and transport of energy starch glycogen and structural components cellulose in plants chitin in animals 10 The basic carbohydrate units are called monosaccharides and include galactose fructose and most importantly glucose Monosaccharides can be linked together to form polysaccharides in almost limitless ways 16 Nucleotides Edit Main article Nucleotide The two nucleic acids DNA and RNA are polymers of nucleotides Each nucleotide is composed of a phosphate attached to a ribose or deoxyribose sugar group which is attached to a nitrogenous base Nucleic acids are critical for the storage and use of genetic information and its interpretation through the processes of transcription and protein biosynthesis 10 This information is protected by DNA repair mechanisms and propagated through DNA replication Many viruses have an RNA genome such as HIV which uses reverse transcription to create a DNA template from its viral RNA genome 17 RNA in ribozymes such as spliceosomes and ribosomes is similar to enzymes as it can catalyze chemical reactions Individual nucleosides are made by attaching a nucleobase to a ribose sugar These bases are heterocyclic rings containing nitrogen classified as purines or pyrimidines Nucleotides also act as coenzymes in metabolic group transfer reactions 18 Coenzymes Edit Structure of the coenzyme acetyl CoA The transferable acetyl group is bonded to the sulfur atom at the extreme left Main article Coenzyme Metabolism involves a vast array of chemical reactions but most fall under a few basic types of reactions that involve the transfer of functional groups of atoms and their bonds within molecules 19 This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions 18 These group transfer intermediates are called coenzymes Each class of group transfer reactions is carried out by a particular coenzyme which is the substrate for a set of enzymes that produce it and a set of enzymes that consume it These coenzymes are therefore continuously made consumed and then recycled 20 One central coenzyme is adenosine triphosphate ATP the universal energy currency of cells This nucleotide is used to transfer chemical energy between different chemical reactions There is only a small amount of ATP in cells but as it is continuously regenerated the human body can use about its own weight in ATP per day 20 ATP acts as a bridge between catabolism and anabolism Catabolism breaks down molecules and anabolism puts them together Catabolic reactions generate ATP and anabolic reactions consume it It also serves as a carrier of phosphate groups in phosphorylation reactions 21 A vitamin is an organic compound needed in small quantities that cannot be made in cells In human nutrition most vitamins function as coenzymes after modification for example all water soluble vitamins are phosphorylated or are coupled to nucleotides when they are used in cells 22 Nicotinamide adenine dinucleotide NAD a derivative of vitamin B3 niacin is an important coenzyme that acts as a hydrogen acceptor Hundreds of separate types of dehydrogenases remove electrons from their substrates and reduce NAD into NADH This reduced form of the coenzyme is then a substrate for any of the reductases in the cell that need to transfer hydrogen atoms to their substrates 23 Nicotinamide adenine dinucleotide exists in two related forms in the cell NADH and NADPH The NAD NADH form is more important in catabolic reactions while NADP NADPH is used in anabolic reactions 24 The structure of iron containing hemoglobin The protein subunits are in red and blue and the iron containing heme groups in green From PDB 1GZX Mineral and cofactors Edit Further information Bioinorganic chemistry Inorganic elements play critical roles in metabolism some are abundant e g sodium and potassium while others function at minute concentrations About 99 of a human s body weight is made up of the elements carbon nitrogen calcium sodium chlorine potassium hydrogen phosphorus oxygen and sulfur Organic compounds proteins lipids and carbohydrates contain the majority of the carbon and nitrogen most of the oxygen and hydrogen is present as water 25 The abundant inorganic elements act as electrolytes The most important ions are sodium potassium calcium magnesium chloride phosphate and the organic ion bicarbonate The maintenance of precise ion gradients across cell membranes maintains osmotic pressure and pH 26 Ions are also critical for nerve and muscle function as action potentials in these tissues are produced by the exchange of electrolytes between the extracellular fluid and the cell s fluid the cytosol 27 Electrolytes enter and leave cells through proteins in the cell membrane called ion channels For example muscle contraction depends upon the movement of calcium sodium and potassium through ion channels in the cell membrane and T tubules 28 Transition metals are usually present as trace elements in organisms with zinc and iron being most abundant of those 29 Metal cofactors are bound tightly to specific sites in proteins although enzyme cofactors can be modified during catalysis they always return to their original state by the end of the reaction catalyzed Metal micronutrients are taken up into organisms by specific transporters and bind to storage proteins such as ferritin or metallothionein when not in use 30 31 Catabolism EditMain article Catabolism Catabolism is the set of metabolic processes that break down large molecules These include breaking down and oxidizing food molecules The purpose of the catabolic reactions is to provide the energy and components needed by anabolic reactions which build molecules 32 The exact nature of these catabolic reactions differ from organism to organism and organisms can be classified based on their sources of energy hydrogen and carbon their primary nutritional groups as shown in the table below Organic molecules are used as a source of hydrogen atoms or electrons by organotrophs while lithotrophs use inorganic substrates Whereas phototrophs convert sunlight to chemical energy 33 chemotrophs depend on redox reactions that involve the transfer of electrons from reduced donor molecules such as organic molecules hydrogen hydrogen sulfide or ferrous ions to oxygen nitrate or sulfate In animals these reactions involve complex organic molecules that are broken down to simpler molecules such as carbon dioxide and water Photosynthetic organisms such as plants and cyanobacteria use similar electron transfer reactions to store energy absorbed from sunlight 34 Classification of organisms based on their metabolism 35 Energy source sunlight photo trophmolecules chemo Hydrogen or electron donor organic compound organo inorganic compound litho Carbon source organic compound hetero inorganic compound auto The most common set of catabolic reactions in animals can be separated into three main stages In the first stage large organic molecules such as proteins polysaccharides or lipids are digested into their smaller components outside cells Next these smaller molecules are taken up by cells and converted to smaller molecules usually acetyl coenzyme A acetyl CoA which releases some energy Finally the acetyl group on acetyl CoA is oxidized to water and carbon dioxide in the citric acid cycle and electron transport chain releasing more energy while reducing the coenzyme nicotinamide adenine dinucleotide NAD into NADH 32 Digestion Edit Further information Digestion and Gastrointestinal tract Macromolecules cannot be directly processed by cells Macromolecules must be broken into smaller units before they can be used in cell metabolism Different classes of enzymes are used to digest these polymers These digestive enzymes include proteases that digest proteins into amino acids as well as glycoside hydrolases that digest polysaccharides into simple sugars known as monosaccharides 36 Microbes simply secrete digestive enzymes into their surroundings 37 38 while animals only secrete these enzymes from specialized cells in their guts including the stomach and pancreas and in salivary glands 39 The amino acids or sugars released by these extracellular enzymes are then pumped into cells by active transport proteins 40 41 A simplified outline of the catabolism of proteins carbohydrates and fats image reference needed Energy from organic compounds Edit Further information Cellular respiration Fermentation biochemistry Carbohydrate catabolism Fat catabolism and Protein catabolism Carbohydrate catabolism is the breakdown of carbohydrates into smaller units Carbohydrates are usually taken into cells after they have been digested into monosaccharides 42 Once inside the major route of breakdown is glycolysis where sugars such as glucose and fructose are converted into pyruvate and some ATP is generated 43 Pyruvate is an intermediate in several metabolic pathways but the majority is converted to acetyl CoA through aerobic with oxygen glycolysis and fed into the citric acid cycle Although some more ATP is generated in the citric acid cycle the most important product is NADH which is made from NAD as the acetyl CoA is oxidized This oxidation releases carbon dioxide as a waste product In anaerobic conditions glycolysis produces lactate through the enzyme lactate dehydrogenase re oxidizing NADH to NAD for re use in glycolysis 44 An alternative route for glucose breakdown is the pentose phosphate pathway which reduces the coenzyme NADPH and produces pentose sugars such as ribose the sugar component of nucleic acids citation needed Fats are catabolized by hydrolysis to free fatty acids and glycerol The glycerol enters glycolysis and the fatty acids are broken down by beta oxidation to release acetyl CoA which then is fed into the citric acid cycle Fatty acids release more energy upon oxidation than carbohydrates Steroids are also broken down by some bacteria in a process similar to beta oxidation and this breakdown process involves the release of significant amounts of acetyl CoA propionyl CoA and pyruvate which can all be used by the cell for energy M tuberculosis can also grow on the lipid cholesterol as a sole source of carbon and genes involved in the cholesterol use pathway s have been validated as important during various stages of the infection lifecycle of M tuberculosis 45 Amino acids are either used to synthesize proteins and other biomolecules or oxidized to urea and carbon dioxide to produce energy 46 The oxidation pathway starts with the removal of the amino group by a transaminase The amino group is fed into the urea cycle leaving a deaminated carbon skeleton in the form of a keto acid Several of these keto acids are intermediates in the citric acid cycle for example a ketoglutarate formed by deamination of glutamate 47 The glucogenic amino acids can also be converted into glucose through gluconeogenesis discussed below 48 Energy transformations EditOxidative phosphorylation Edit Further information Oxidative phosphorylation Chemiosmosis and Mitochondrion In oxidative phosphorylation the electrons removed from organic molecules in areas such as the citric acid cycle are transferred to oxygen and the energy released is used to make ATP This is done in eukaryotes by a series of proteins in the membranes of mitochondria called the electron transport chain In prokaryotes these proteins are found in the cell s inner membrane 49 These proteins use the energy from reduced molecules like NADH to pump protons across a membrane 50 Mechanism of ATP synthase ATP is shown in red ADP and phosphate in pink and the rotating stalk subunit in black Pumping protons out of the mitochondria creates a proton concentration difference across the membrane and generates an electrochemical gradient 51 This force drives protons back into the mitochondrion through the base of an enzyme called ATP synthase The flow of protons makes the stalk subunit rotate causing the active site of the synthase domain to change shape and phosphorylate adenosine diphosphate turning it into ATP 20 Energy from inorganic compounds Edit Further information Microbial metabolism and Nitrogen cycle Chemolithotrophy is a type of metabolism found in prokaryotes where energy is obtained from the oxidation of inorganic compounds These organisms can use hydrogen 52 reduced sulfur compounds such as sulfide hydrogen sulfide and thiosulfate 1 ferrous iron Fe II 53 or ammonia 54 as sources of reducing power and they gain energy from the oxidation of these compounds 55 These microbial processes are important in global biogeochemical cycles such as acetogenesis nitrification and denitrification and are critical for soil fertility 56 57 Energy from light Edit Further information Phototroph Photophosphorylation and Chloroplast The energy in sunlight is captured by plants cyanobacteria purple bacteria green sulfur bacteria and some protists This process is often coupled to the conversion of carbon dioxide into organic compounds as part of photosynthesis which is discussed below The energy capture and carbon fixation systems can however operate separately in prokaryotes as purple bacteria and green sulfur bacteria can use sunlight as a source of energy while switching between carbon fixation and the fermentation of organic compounds 58 59 In many organisms the capture of solar energy is similar in principle to oxidative phosphorylation as it involves the storage of energy as a proton concentration gradient This proton motive force then drives ATP synthesis 60 The electrons needed to drive this electron transport chain come from light gathering proteins called photosynthetic reaction centres Reaction centers are classified into two types depending on the nature of photosynthetic pigment present with most photosynthetic bacteria only having one type while plants and cyanobacteria have two 61 In plants algae and cyanobacteria photosystem II uses light energy to remove electrons from water releasing oxygen as a waste product The electrons then flow to the cytochrome b6f complex which uses their energy to pump protons across the thylakoid membrane in the chloroplast 34 These protons move back through the membrane as they drive the ATP synthase as before The electrons then flow through photosystem I and can then be used to reduce the coenzyme NADP 62 This coenzyme can enter the Calvin cycle which is discussed below or be recycled for further ATP generation citation needed Anabolism EditFurther information Anabolism Anabolism is the set of constructive metabolic processes where the energy released by catabolism is used to synthesize complex molecules In general the complex molecules that make up cellular structures are constructed step by step from smaller and simpler precursors Anabolism involves three basic stages First the production of precursors such as amino acids monosaccharides isoprenoids and nucleotides secondly their activation into reactive forms using energy from ATP and thirdly the assembly of these precursors into complex molecules such as proteins polysaccharides lipids and nucleic acids 63 Anabolism in organisms can be different according to the source of constructed molecules in their cells Autotrophs such as plants can construct the complex organic molecules in their cells such as polysaccharides and proteins from simple molecules like carbon dioxide and water Heterotrophs on the other hand require a source of more complex substances such as monosaccharides and amino acids to produce these complex molecules Organisms can be further classified by ultimate source of their energy photoautotrophs and photoheterotrophs obtain energy from light whereas chemoautotrophs and chemoheterotrophs obtain energy from oxidation reactions 63 Carbon fixation Edit Further information Photosynthesis Carbon fixation and Chemosynthesis Plant cells bounded by purple walls filled with chloroplasts green which are the site of photosynthesis Photosynthesis is the synthesis of carbohydrates from sunlight and carbon dioxide CO2 In plants cyanobacteria and algae oxygenic photosynthesis splits water with oxygen produced as a waste product This process uses the ATP and NADPH produced by the photosynthetic reaction centres as described above to convert CO2 into glycerate 3 phosphate which can then be converted into glucose This carbon fixation reaction is carried out by the enzyme RuBisCO as part of the Calvin Benson cycle 64 Three types of photosynthesis occur in plants C3 carbon fixation C4 carbon fixation and CAM photosynthesis These differ by the route that carbon dioxide takes to the Calvin cycle with C3 plants fixing CO2 directly while C4 and CAM photosynthesis incorporate the CO2 into other compounds first as adaptations to deal with intense sunlight and dry conditions 65 In photosynthetic prokaryotes the mechanisms of carbon fixation are more diverse Here carbon dioxide can be fixed by the Calvin Benson cycle a reversed citric acid cycle 66 or the carboxylation of acetyl CoA 67 68 Prokaryotic chemoautotrophs also fix CO2 through the Calvin Benson cycle but use energy from inorganic compounds to drive the reaction 69 Carbohydrates and glycans Edit Further information Gluconeogenesis Glyoxylate cycle Glycogenesis and Glycosylation In carbohydrate anabolism simple organic acids can be converted into monosaccharides such as glucose and then used to assemble polysaccharides such as starch The generation of glucose from compounds like pyruvate lactate glycerol glycerate 3 phosphate and amino acids is called gluconeogenesis Gluconeogenesis converts pyruvate to glucose 6 phosphate through a series of intermediates many of which are shared with glycolysis 43 However this pathway is not simply glycolysis run in reverse as several steps are catalyzed by non glycolytic enzymes This is important as it allows the formation and breakdown of glucose to be regulated separately and prevents both pathways from running simultaneously in a futile cycle 70 71 Although fat is a common way of storing energy in vertebrates such as humans the fatty acids in these stores cannot be converted to glucose through gluconeogenesis as these organisms cannot convert acetyl CoA into pyruvate plants do but animals do not have the necessary enzymatic machinery 72 As a result after long term starvation vertebrates need to produce ketone bodies from fatty acids to replace glucose in tissues such as the brain that cannot metabolize fatty acids 73 In other organisms such as plants and bacteria this metabolic problem is solved using the glyoxylate cycle which bypasses the decarboxylation step in the citric acid cycle and allows the transformation of acetyl CoA to oxaloacetate where it can be used for the production of glucose 72 74 Other than fat glucose is stored in most tissues as an energy resource available within the tissue through glycogenesis which was usually being used to maintained glucose level in blood 75 Polysaccharides and glycans are made by the sequential addition of monosaccharides by glycosyltransferase from a reactive sugar phosphate donor such as uridine diphosphate glucose UDP Glc to an acceptor hydroxyl group on the growing polysaccharide As any of the hydroxyl groups on the ring of the substrate can be acceptors the polysaccharides produced can have straight or branched structures 76 The polysaccharides produced can have structural or metabolic functions themselves or be transferred to lipids and proteins by enzymes called oligosaccharyltransferases 77 78 Fatty acids isoprenoids and sterol Edit Further information Fatty acid synthesis and Steroid metabolism Simplified version of the steroid synthesis pathway with the intermediates isopentenyl pyrophosphate IPP dimethylallyl pyrophosphate DMAPP geranyl pyrophosphate GPP and squalene shown Some intermediates are omitted for clarity Fatty acids are made by fatty acid synthases that polymerize and then reduce acetyl CoA units The acyl chains in the fatty acids are extended by a cycle of reactions that add the acyl group reduce it to an alcohol dehydrate it to an alkene group and then reduce it again to an alkane group The enzymes of fatty acid biosynthesis are divided into two groups in animals and fungi all these fatty acid synthase reactions are carried out by a single multifunctional type I protein 79 while in plant plastids and bacteria separate type II enzymes perform each step in the pathway 80 81 Terpenes and isoprenoids are a large class of lipids that include the carotenoids and form the largest class of plant natural products 82 These compounds are made by the assembly and modification of isoprene units donated from the reactive precursors isopentenyl pyrophosphate and dimethylallyl pyrophosphate 83 These precursors can be made in different ways In animals and archaea the mevalonate pathway produces these compounds from acetyl CoA 84 while in plants and bacteria the non mevalonate pathway uses pyruvate and glyceraldehyde 3 phosphate as substrates 83 85 One important reaction that uses these activated isoprene donors is sterol biosynthesis Here the isoprene units are joined to make squalene and then folded up and formed into a set of rings to make lanosterol 86 Lanosterol can then be converted into other sterols such as cholesterol and ergosterol 86 87 Proteins Edit Further information Protein biosynthesis and Amino acid synthesis Organisms vary in their ability to synthesize the 20 common amino acids Most bacteria and plants can synthesize all twenty but mammals can only synthesize eleven nonessential amino acids so nine essential amino acids must be obtained from food 10 Some simple parasites such as the bacteria Mycoplasma pneumoniae lack all amino acid synthesis and take their amino acids directly from their hosts 88 All amino acids are synthesized from intermediates in glycolysis the citric acid cycle or the pentose phosphate pathway Nitrogen is provided by glutamate and glutamine Nonessensial amino acid synthesis depends on the formation of the appropriate alpha keto acid which is then transaminated to form an amino acid 89 Amino acids are made into proteins by being joined in a chain of peptide bonds Each different protein has a unique sequence of amino acid residues this is its primary structure Just as the letters of the alphabet can be combined to form an almost endless variety of words amino acids can be linked in varying sequences to form a huge variety of proteins Proteins are made from amino acids that have been activated by attachment to a transfer RNA molecule through an ester bond This aminoacyl tRNA precursor is produced in an ATP dependent reaction carried out by an aminoacyl tRNA synthetase 90 This aminoacyl tRNA is then a substrate for the ribosome which joins the amino acid onto the elongating protein chain using the sequence information in a messenger RNA 91 Nucleotide synthesis and salvage Edit Further information Nucleotide salvage Pyrimidine biosynthesis and Purine Metabolism Nucleotides are made from amino acids carbon dioxide and formic acid in pathways that require large amounts of metabolic energy 92 Consequently most organisms have efficient systems to salvage preformed nucleotides 92 93 Purines are synthesized as nucleosides bases attached to ribose 94 Both adenine and guanine are made from the precursor nucleoside inosine monophosphate which is synthesized using atoms from the amino acids glycine glutamine and aspartic acid as well as formate transferred from the coenzyme tetrahydrofolate Pyrimidines on the other hand are synthesized from the base orotate which is formed from glutamine and aspartate 95 Xenobiotics and redox metabolism EditFurther information Xenobiotic metabolism Drug metabolism Alcohol metabolism and Antioxidant All organisms are constantly exposed to compounds that they cannot use as foods and that would be harmful if they accumulated in cells as they have no metabolic function These potentially damaging compounds are called xenobiotics 96 Xenobiotics such as synthetic drugs natural poisons and antibiotics are detoxified by a set of xenobiotic metabolizing enzymes In humans these include cytochrome P450 oxidases 97 UDP glucuronosyltransferases 98 and glutathione S transferases 99 This system of enzymes acts in three stages to firstly oxidize the xenobiotic phase I and then conjugate water soluble groups onto the molecule phase II The modified water soluble xenobiotic can then be pumped out of cells and in multicellular organisms may be further metabolized before being excreted phase III In ecology these reactions are particularly important in microbial biodegradation of pollutants and the bioremediation of contaminated land and oil spills 100 Many of these microbial reactions are shared with multicellular organisms but due to the incredible diversity of types of microbes these organisms are able to deal with a far wider range of xenobiotics than multicellular organisms and can degrade even persistent organic pollutants such as organochloride compounds 101 A related problem for aerobic organisms is oxidative stress 102 Here processes including oxidative phosphorylation and the formation of disulfide bonds during protein folding produce reactive oxygen species such as hydrogen peroxide 103 These damaging oxidants are removed by antioxidant metabolites such as glutathione and enzymes such as catalases and peroxidases 104 105 Thermodynamics of living organisms EditFurther information Biological thermodynamics Living organisms must obey the laws of thermodynamics which describe the transfer of heat and work The second law of thermodynamics states that in any isolated system the amount of entropy disorder cannot decrease Although living organisms amazing complexity appears to contradict this law life is possible as all organisms are open systems that exchange matter and energy with their surroundings Living systems are not in equilibrium but instead are dissipative systems that maintain their state of high complexity by causing a larger increase in the entropy of their environments 106 The metabolism of a cell achieves this by coupling the spontaneous processes of catabolism to the non spontaneous processes of anabolism In thermodynamic terms metabolism maintains order by creating disorder 107 Regulation and control EditFurther information Metabolic pathway Metabolic control analysis Hormone Regulatory enzymes and Cell signaling As the environments of most organisms are constantly changing the reactions of metabolism must be finely regulated to maintain a constant set of conditions within cells a condition called homeostasis 108 109 Metabolic regulation also allows organisms to respond to signals and interact actively with their environments 110 Two closely linked concepts are important for understanding how metabolic pathways are controlled Firstly the regulation of an enzyme in a pathway is how its activity is increased and decreased in response to signals Secondly the control exerted by this enzyme is the effect that these changes in its activity have on the overall rate of the pathway the flux through the pathway 111 For example an enzyme may show large changes in activity i e it is highly regulated but if these changes have little effect on the flux of a metabolic pathway then this enzyme is not involved in the control of the pathway 112 Effect of insulin on glucose uptake and metabolism Insulin binds to its receptor 1 which in turn starts many protein activation cascades 2 These include translocation of Glut 4 transporter to the plasma membrane and influx of glucose 3 glycogen synthesis 4 glycolysis 5 and fatty acid synthesis 6 image reference needed There are multiple levels of metabolic regulation In intrinsic regulation the metabolic pathway self regulates to respond to changes in the levels of substrates or products for example a decrease in the amount of product can increase the flux through the pathway to compensate 111 This type of regulation often involves allosteric regulation of the activities of multiple enzymes in the pathway 113 Extrinsic control involves a cell in a multicellular organism changing its metabolism in response to signals from other cells These signals are usually in the form of water soluble messengers such as hormones and growth factors and are detected by specific receptors on the cell surface 114 These signals are then transmitted inside the cell by second messenger systems that often involved the phosphorylation of proteins 115 A very well understood example of extrinsic control is the regulation of glucose metabolism by the hormone insulin 116 Insulin is produced in response to rises in blood glucose levels Binding of the hormone to insulin receptors on cells then activates a cascade of protein kinases that cause the cells to take up glucose and convert it into storage molecules such as fatty acids and glycogen 117 The metabolism of glycogen is controlled by activity of phosphorylase the enzyme that breaks down glycogen and glycogen synthase the enzyme that makes it These enzymes are regulated in a reciprocal fashion with phosphorylation inhibiting glycogen synthase but activating phosphorylase Insulin causes glycogen synthesis by activating protein phosphatases and producing a decrease in the phosphorylation of these enzymes 118 Evolution EditFurther information Molecular evolution and Phylogenetics Evolutionary tree showing the common ancestry of organisms from all three domains of life Bacteria are colored blue eukaryotes red and archaea green Relative positions of some of the phyla included are shown around the tree The central pathways of metabolism described above such as glycolysis and the citric acid cycle are present in all three domains of living things and were present in the last universal common ancestor 3 119 This universal ancestral cell was prokaryotic and probably a methanogen that had extensive amino acid nucleotide carbohydrate and lipid metabolism 120 121 The retention of these ancient pathways during later evolution may be the result of these reactions having been an optimal solution to their particular metabolic problems with pathways such as glycolysis and the citric acid cycle producing their end products highly efficiently and in a minimal number of steps 4 5 The first pathways of enzyme based metabolism may have been parts of purine nucleotide metabolism while previous metabolic pathways were a part of the ancient RNA world 122 Many models have been proposed to describe the mechanisms by which novel metabolic pathways evolve These include the sequential addition of novel enzymes to a short ancestral pathway the duplication and then divergence of entire pathways as well as the recruitment of pre existing enzymes and their assembly into a novel reaction pathway 123 The relative importance of these mechanisms is unclear but genomic studies have shown that enzymes in a pathway are likely to have a shared ancestry suggesting that many pathways have evolved in a step by step fashion with novel functions created from pre existing steps in the pathway 124 An alternative model comes from studies that trace the evolution of proteins structures in metabolic networks this has suggested that enzymes are pervasively recruited borrowing enzymes to perform similar functions in different metabolic pathways evident in the MANET database 125 These recruitment processes result in an evolutionary enzymatic mosaic 126 A third possibility is that some parts of metabolism might exist as modules that can be reused in different pathways and perform similar functions on different molecules 127 As well as the evolution of new metabolic pathways evolution can also cause the loss of metabolic functions For example in some parasites metabolic processes that are not essential for survival are lost and preformed amino acids nucleotides and carbohydrates may instead be scavenged from the host 128 Similar reduced metabolic capabilities are seen in endosymbiotic organisms 129 Investigation and manipulation EditFurther information Protein methods Proteomics Metabolomics and Metabolic network modelling Metabolic network of the Arabidopsis thaliana citric acid cycle Enzymes and metabolites are shown as red squares and the interactions between them as black lines Classically metabolism is studied by a reductionist approach that focuses on a single metabolic pathway Particularly valuable is the use of radioactive tracers at the whole organism tissue and cellular levels which define the paths from precursors to final products by identifying radioactively labelled intermediates and products 130 The enzymes that catalyze these chemical reactions can then be purified and their kinetics and responses to inhibitors investigated A parallel approach is to identify the small molecules in a cell or tissue the complete set of these molecules is called the metabolome Overall these studies give a good view of the structure and function of simple metabolic pathways but are inadequate when applied to more complex systems such as the metabolism of a complete cell 131 An idea of the complexity of the metabolic networks in cells that contain thousands of different enzymes is given by the figure showing the interactions between just 43 proteins and 40 metabolites to the right the sequences of genomes provide lists containing anything up to 26 500 genes 132 However it is now possible to use this genomic data to reconstruct complete networks of biochemical reactions and produce more holistic mathematical models that may explain and predict their behavior 133 These models are especially powerful when used to integrate the pathway and metabolite data obtained through classical methods with data on gene expression from proteomic and DNA microarray studies 134 Using these techniques a model of human metabolism has now been produced which will guide future drug discovery and biochemical research 135 These models are now used in network analysis to classify human diseases into groups that share common proteins or metabolites 136 137 Bacterial metabolic networks are a striking example of bow tie 138 139 140 organization an architecture able to input a wide range of nutrients and produce a large variety of products and complex macromolecules using a relatively few intermediate common currencies A major technological application of this information is metabolic engineering Here organisms such as yeast plants or bacteria are genetically modified to make them more useful in biotechnology and aid the production of drugs such as antibiotics or industrial chemicals such as 1 3 propanediol and shikimic acid 141 142 143 These genetic modifications usually aim to reduce the amount of energy used to produce the product increase yields and reduce the production of wastes 144 History EditFurther information History of biochemistry and History of molecular biology The term metabolism is derived from French metabolisme or Ancient Greek metabolh Metabole for a change which derived from metaball Metaballein means To change 145 Aristotle s metabolism as an open flow model Greek philosophy Edit Aristotle s The Parts of Animals sets out enough details of his views on metabolism for an open flow model to be made He believed that at each stage of the process materials from food were transformed with heat being released as the classical element of fire and residual materials being excreted as urine bile or faeces 146 Ibn al Nafis described metabolism in his 1260 AD work titled Al Risalah al Kamiliyyah fil Siera al Nabawiyyah The Treatise of Kamil on the Prophet s Biography which included the following phrase Both the body and its parts are in a continuous state of dissolution and nourishment so they are inevitably undergoing permanent change 147 Application of the scientific method and Modern metabolic theories Edit The history of the scientific study of metabolism spans several centuries and has moved from examining whole animals in early studies to examining individual metabolic reactions in modern biochemistry The first controlled experiments in human metabolism were published by Santorio Santorio in 1614 in his book Ars de statica medicina 148 He described how he weighed himself before and after eating sleep working sex fasting drinking and excreting He found that most of the food he took in was lost through what he called insensible perspiration Santorio Santorio in his steelyard balance from Ars de statica medicina first published 1614 In these early studies the mechanisms of these metabolic processes had not been identified and a vital force was thought to animate living tissue 149 In the 19th century when studying the fermentation of sugar to alcohol by yeast Louis Pasteur concluded that fermentation was catalyzed by substances within the yeast cells he called ferments He wrote that alcoholic fermentation is an act correlated with the life and organization of the yeast cells not with the death or putrefaction of the cells 150 This discovery along with the publication by Friedrich Wohler in 1828 of a paper on the chemical synthesis of urea 151 and is notable for being the first organic compound prepared from wholly inorganic precursors This proved that the organic compounds and chemical reactions found in cells were no different in principle than any other part of chemistry It was the discovery of enzymes at the beginning of the 20th century by Eduard Buchner that separated the study of the chemical reactions of metabolism from the biological study of cells and marked the beginnings of biochemistry 152 The mass of biochemical knowledge grew rapidly throughout the early 20th century One of the most prolific of these modern biochemists was Hans Krebs who made huge contributions to the study of metabolism 153 He discovered the urea cycle and later working with Hans Kornberg the citric acid cycle and the glyoxylate cycle 154 155 74 Modern biochemical research has been greatly aided by the development of new techniques such as chromatography X ray diffraction NMR spectroscopy radioisotopic labelling electron microscopy and molecular dynamics simulations These techniques have allowed the discovery and detailed analysis of the many molecules and metabolic pathways in cells citation needed See also EditAnthropogenic metabolism Antimetabolite Chemical that inhibits the use of a metabolite Calorimetry Determining heat transfer in a system by measuring its other properties Isothermal microcalorimetry Measuring versus elapsed time the net rate of heat flow Inborn errors of metabolism Class of genetic diseases Iron sulfur world hypothesis Hypothetical scenario for the origin of life a metabolism first theory of the origin of life Metabolic 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Biochemistry W H Freeman and Company ISBN 0 7167 4955 6 Cox M Nelson DL 2004 Lehninger Principles of Biochemistry Palgrave Macmillan ISBN 0 7167 4339 6 Brock TD Madigan MR Martinko J Parker J 2002 Brock s Biology of Microorganisms Benjamin Cummings ISBN 0 13 066271 2 Da Silva JJ Williams RJ 1991 The Biological Chemistry of the Elements The Inorganic Chemistry of Life Clarendon Press ISBN 0 19 855598 9 Nicholls DG Ferguson SJ 2002 Bioenergetics Academic Press Inc ISBN 0 12 518121 3 Wood HG February 1991 Life with CO or CO2 and H2 as a source of carbon and energy FASEB Journal 5 2 156 63 doi 10 1096 fasebj 5 2 1900793 PMID 1900793 S2CID 45967404 External links Edit Wikiversity has learning resources about Topic Biochemistry Wikibooks has more on the topic of Metabolism Look up metabolism in Wiktionary the free dictionary Wikimedia Commons has media related to Metabolism General information The Biochemistry of Metabolism archived 8 March 2005 Sparknotes SAT biochemistry Overview of biochemistry School level MIT Biology Hypertextbook Undergraduate level guide to molecular biology Human metabolism Topics in Medical Biochemistry Guide to human metabolic pathways School level THE Medical Biochemistry Page Comprehensive resource on human metabolism Databases Flow Chart of Metabolic Pathways at ExPASy IUBMB Nicholson Metabolic Pathways Chart SuperCYP Database for Drug Cytochrome Metabolism Archived 3 November 2011 at the Wayback MachineMetabolic pathways Metabolism reference Pathway Archived 23 February 2009 at the Wayback Machine The Nitrogen cycle and Nitrogen fixation at the Wayback Machine archive index Retrieved from https en wikipedia org w index php title Metabolism amp oldid 1134204784, wikipedia, wiki, book, books, library,

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