Acyl-CoA is a group of coenzymes that metabolize fatty acids. Acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several equivalents of ATP. In this way, fats are converted to ATP, the universal biochemical energy carrier.
General chemical structure of an acyl-CoA, where R is a fatty acid side chain
Fats are broken down by conversion to acyl-CoA. This conversion is one response to high energy demands such as exercise.[1] The oxidative degradation of fatty acids is a two-step process, catalyzed by acyl-CoA synthetase. Fatty acids are converted to their acyl phosphate, the precursor to acyl-CoA. The latter conversion is mediated by acyl-CoA synthase"
acyl-P + HS-CoA → acyl-S-CoA + Pi + H+
Three types of acyl-CoA synthases are employed, depending on the chain length of the fatty acid.[2] For example, the substrates for medium chain acyl-CoA synthase are 4-11 carbon fatty acids.[3] The enzyme acyl-CoA thioesterase takes of the acyl-CoA to form a free fatty acid and coenzyme A.[3]
Beta Oxidation of Acyl-CoA
The second step of fatty acid degradation is beta oxidation. Beta oxidation occurs in mitochondria.[4] After formation in the cytosol, acyl-CoA is transported into the mitochondria, the locus of beta oxidation. Transport of acyl-CoA into the mitochondria requires carnitine palmitoyltransferase 1 (CPT1), which converts acyl-CoA into acylcarnitine, which gets transported into the mitochondrial matrix.[1] Once in the matrix, acylcarnitine is converted back to acyl-CoA by CPT2.[4] Beta oxidation may begin now that Acyl-CoA is in the mitochondria.
Beta oxidation of acyl-CoA occurs in four steps.
1. Acyl-CoA dehydrogenase catalyzes dehydrogenation of the acyl-CoA, creating a double bond between the alpha and beta carbons.[5]FAD is the hydrogen acceptor, yielding FADH2.[6]
2. Enoyl-CoA hydrase catalyzes the addition of water across the newly formed double bond to make an alcohol.[4][5]
4. Thiolase cleaves between the alpha carbon and ketone to release one molecule of Acetyl-CoA and the Acyl-CoA which is now 2 carbons shorter.[5]
This four step process repeats until acyl-CoA has removed all carbons from the chain, leaving only Acetyl-CoA. During one cycle of beta oxidation, Acyl-CoA creates one molecule of Acetyl-CoA, FADH2, and NADH.[6] Acetyl-CoA is then used in the citric acid cycle while FADH2 and NADH are sent to the electron transport chain.[7] These intermediates all end up providing energy for the body as they are ultimately converted to ATP.[7]
Example of Beta Oxidation using Stearic Acid
Beta oxidation, as well as alpha-oxidation, also occurs in the peroxisome.[1] The peroxisome handles beta oxidation of fatty acids that have more than 20 carbons in their chain because the peroxisome contains very-long-chain Acyl-CoA synthetases.[8] These enzymes are better equipped to oxidize Acyl-CoA with long chains that the mitochondria cannot handle.
Example using Stearic Acid
Beta oxidation removes 2 carbons at a time, so in the oxidation of an 18 carbon fatty acid such as Stearic Acid 8 cycles will need to occur to completely break down Acyl-CoA.[8] This will produce 9 Acetyl-CoA that have 2 carbons each, 8 FADH2, and 8 NADH.
Clinical Significance
Heart muscle primarily metabolizes fat for energy and Acyl-CoA metabolism has been identified[9] as a critical molecule in early stage heart muscle pump failure.
Cellular acyl-CoA content correlates with insulin resistance, suggesting that it can mediate lipotoxicity in non-adipose tissues.[10] Acyl-CoA: diacylglycerol acyltransferase (DGAT) plays an important role in energy metabolism on account of key enzyme in triglyceride biosynthesis. The synthetic role of DGAT in adipose tissue such as the liver and the intestine, sites where endogenous levels of its activity and triglyceride synthesis are high and comparatively clear. Also, any changes in the activity levels might cause changes in systemic insulin sensitivity and energy homeostasis.[11]
A rare disease called multiple acyl-CoA dehydrogenase deficiency (MADD)[12] is a fatty acid metabolism disorder. Acyl-CoA is important because this enzyme helps make Acyl-CoA from free fatty acids, and this activates the fatty acid to be metabolized. This compromised fatty acid oxidation leads to many different symptoms, including severe symptoms such as cardiomyopathy and liver disease and mild symptoms such as episodic metabolic decomposition, muscle weakness and respiratory failure. MADD is a genetic disorder, caused by a mutation in the ETFA, ETFB, and ETFDH genes. MADD is known as an "autosomal recessive disorder"[12] because for one to get this disorder, one must receive this recessive gene from both parents.
^ abcTalley, Jacob T.; Mohiuddin, Shamim S. (2020), "Biochemistry, Fatty Acid Oxidation", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32310462, retrieved 2021-02-23
^Blanco, Antonio; Blanco, Gustavo (2017). "Lipid Metabolism". Medical Biochemistry. pp. 325–365. doi:10.1016/B978-0-12-803550-4.00015-X. ISBN978-0-12-803550-4.
^ abBhagavan, N.V.; Ha, Chung-Eun (2015). "Lipids I: Fatty Acids and Eicosanoids". Essentials of Medical Biochemistry. pp. 269–297. doi:10.1016/B978-0-12-416687-5.00016-6. ISBN978-0-12-416687-5.
^ abReddy, Janardan K; Hashimoto, Takashi (2001-07-01). "PEROXISOMAL β-OXIDATION AND PEROXISOME PROLIFERATOR–ACTIVATED RECEPTOR α: An Adaptive Metabolic System". Annual Review of Nutrition. 21 (1): 193–230. doi:10.1146/annurev.nutr.21.1.193. ISSN 0199-9885. PMID 11375435.
^Goldenberg, Joseph R.; Carley, Andrew N.; Ji, Ruiping; Zhang, Xiaokan; Fasano, Matt; Schulze, P. Christian; Lewandowski, E. Douglas (26 March 2019). "Preservation of Acyl-CoA Attenuates Pathological and Metabolic Cardiac Remodeling Through Selective Lipid Trafficking". Circulation. 139 (24): 2765–2777. doi:10.1161/CIRCULATIONAHA.119.039610. PMC6557671. PMID 30909726.
Lay summary in: Marti Leitch (March 26, 2019). "Scientists find metabolic target to prevent, treat heart failure at earliest stage". Ohio State News.
^Li, Lei O.; Klett, Eric L.; Coleman, Rosalind A. (March 2010). "Acyl-CoA synthesis, lipid metabolism and lipotoxicity". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1801 (3): 246–251. doi:10.1016/j.bbalip.2009.09.024. PMC2824076. PMID 19818872.
^Yu, Yi‐Hao; Ginsberg, Henry (8 July 2009). "The role of acyl‐CoA:diacylglycerol acyltransferase (DGAT) in energy metabolism". Annals of Medicine. 36 (4): 252–261. doi:10.1080/07853890410028429. PMID 15224651. S2CID 9174481.
^ abRashmi, S.; Gayathri, N.; Kumar, M. Veerendra; Sumanth, S.; Subasree, R.; Pooja, M. (1 January 2017). "Multiple Acyl CoA dehydrogenase deficiency: Uncommon yet treatable disorder". Neurology India. 65 (1): 177–8. doi:10.4103/0028-3886.198186 (inactive 31 December 2022). PMID 28084266.{{cite journal}}: CS1 maint: DOI inactive as of December 2022 (link)
acyl, group, coenzymes, that, metabolize, fatty, acids, susceptible, beta, oxidation, forming, ultimately, acetyl, acetyl, enters, citric, acid, cycle, eventually, forming, several, equivalents, this, fats, converted, universal, biochemical, energy, carrier, g. Acyl CoA is a group of coenzymes that metabolize fatty acids Acyl CoA s are susceptible to beta oxidation forming ultimately acetyl CoA The acetyl CoA enters the citric acid cycle eventually forming several equivalents of ATP In this way fats are converted to ATP the universal biochemical energy carrier General chemical structure of an acyl CoA where R is a fatty acid side chain Contents 1 Functions 1 1 Fatty acid activation 1 2 Beta Oxidation of Acyl CoA 1 2 1 Example using Stearic Acid 2 Clinical Significance 3 See also 4 References 5 External linksFunctions EditFatty acid activation Edit Fats are broken down by conversion to acyl CoA This conversion is one response to high energy demands such as exercise 1 The oxidative degradation of fatty acids is a two step process catalyzed by acyl CoA synthetase Fatty acids are converted to their acyl phosphate the precursor to acyl CoA The latter conversion is mediated by acyl CoA synthase acyl P HS CoA acyl S CoA Pi H Three types of acyl CoA synthases are employed depending on the chain length of the fatty acid 2 For example the substrates for medium chain acyl CoA synthase are 4 11 carbon fatty acids 3 The enzyme acyl CoA thioesterase takes of the acyl CoA to form a free fatty acid and coenzyme A 3 Beta Oxidation of Acyl CoA Edit The second step of fatty acid degradation is beta oxidation Beta oxidation occurs in mitochondria 4 After formation in the cytosol acyl CoA is transported into the mitochondria the locus of beta oxidation Transport of acyl CoA into the mitochondria requires carnitine palmitoyltransferase 1 CPT1 which converts acyl CoA into acylcarnitine which gets transported into the mitochondrial matrix 1 Once in the matrix acylcarnitine is converted back to acyl CoA by CPT2 4 Beta oxidation may begin now that Acyl CoA is in the mitochondria Beta oxidation of acyl CoA occurs in four steps 1 Acyl CoA dehydrogenase catalyzes dehydrogenation of the acyl CoA creating a double bond between the alpha and beta carbons 5 FAD is the hydrogen acceptor yielding FADH2 6 2 Enoyl CoA hydrase catalyzes the addition of water across the newly formed double bond to make an alcohol 4 5 3 3 hydroxyacyl CoA dehydrogenase oxidizes the alcohol group to a ketone 4 NADH is produced from NAD 5 4 Thiolase cleaves between the alpha carbon and ketone to release one molecule of Acetyl CoA and the Acyl CoA which is now 2 carbons shorter 5 This four step process repeats until acyl CoA has removed all carbons from the chain leaving only Acetyl CoA During one cycle of beta oxidation Acyl CoA creates one molecule of Acetyl CoA FADH2 and NADH 6 Acetyl CoA is then used in the citric acid cycle while FADH2 and NADH are sent to the electron transport chain 7 These intermediates all end up providing energy for the body as they are ultimately converted to ATP 7 Example of Beta Oxidation using Stearic Acid Beta oxidation as well as alpha oxidation also occurs in the peroxisome 1 The peroxisome handles beta oxidation of fatty acids that have more than 20 carbons in their chain because the peroxisome contains very long chain Acyl CoA synthetases 8 These enzymes are better equipped to oxidize Acyl CoA with long chains that the mitochondria cannot handle Example using Stearic Acid Edit Beta oxidation removes 2 carbons at a time so in the oxidation of an 18 carbon fatty acid such as Stearic Acid 8 cycles will need to occur to completely break down Acyl CoA 8 This will produce 9 Acetyl CoA that have 2 carbons each 8 FADH2 and 8 NADH Clinical Significance EditHeart muscle primarily metabolizes fat for energy and Acyl CoA metabolism has been identified 9 as a critical molecule in early stage heart muscle pump failure Cellular acyl CoA content correlates with insulin resistance suggesting that it can mediate lipotoxicity in non adipose tissues 10 Acyl CoA diacylglycerol acyltransferase DGAT plays an important role in energy metabolism on account of key enzyme in triglyceride biosynthesis The synthetic role of DGAT in adipose tissue such as the liver and the intestine sites where endogenous levels of its activity and triglyceride synthesis are high and comparatively clear Also any changes in the activity levels might cause changes in systemic insulin sensitivity and energy homeostasis 11 A rare disease called multiple acyl CoA dehydrogenase deficiency MADD 12 is a fatty acid metabolism disorder Acyl CoA is important because this enzyme helps make Acyl CoA from free fatty acids and this activates the fatty acid to be metabolized This compromised fatty acid oxidation leads to many different symptoms including severe symptoms such as cardiomyopathy and liver disease and mild symptoms such as episodic metabolic decomposition muscle weakness and respiratory failure MADD is a genetic disorder caused by a mutation in the ETFA ETFB and ETFDH genes MADD is known as an autosomal recessive disorder 12 because for one to get this disorder one must receive this recessive gene from both parents See also EditAcetyl CoA Beta oxidation Coenzyme A Acyl CoA dehydrogenase Fatty acid metabolismReferences Edit a b c Talley Jacob T Mohiuddin Shamim S 2020 Biochemistry Fatty Acid Oxidation StatPearls Treasure Island FL StatPearls Publishing PMID 32310462 retrieved 2021 02 23 Blanco Antonio Blanco Gustavo 2017 Lipid Metabolism Medical Biochemistry pp 325 365 doi 10 1016 B978 0 12 803550 4 00015 X ISBN 978 0 12 803550 4 a b Bhagavan N V Ha Chung Eun 2015 Lipids I Fatty Acids and Eicosanoids Essentials of Medical Biochemistry pp 269 297 doi 10 1016 B978 0 12 416687 5 00016 6 ISBN 978 0 12 416687 5 a b c d Fatty acid beta oxidation Abcam www abcam com Retrieved 2021 02 23 a b c d 6 11 Fatty Acid Oxidation Biology LibreTexts 2016 02 26 Retrieved 2021 02 23 a b Beta Oxidation Biology Dictionary 2017 06 03 Retrieved 2021 02 23 a b 6 32 Fatty Acid Oxidation Beta oxidation Nutrition Flexbook courses lumenlearning com Retrieved 2021 02 23 a b Reddy Janardan K Hashimoto Takashi 2001 07 01 PEROXISOMAL b OXIDATION AND PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR a An Adaptive Metabolic System Annual Review of Nutrition 21 1 193 230 doi 10 1146 annurev nutr 21 1 193 ISSN 0199 9885 PMID 11375435 Goldenberg Joseph R Carley Andrew N Ji Ruiping Zhang Xiaokan Fasano Matt Schulze P Christian Lewandowski E Douglas 26 March 2019 Preservation of Acyl CoA Attenuates Pathological and Metabolic Cardiac Remodeling Through Selective Lipid Trafficking Circulation 139 24 2765 2777 doi 10 1161 CIRCULATIONAHA 119 039610 PMC 6557671 PMID 30909726 Lay summary in Marti Leitch March 26 2019 Scientists find metabolic target to prevent treat heart failure at earliest stage Ohio State News Li Lei O Klett Eric L Coleman Rosalind A March 2010 Acyl CoA synthesis lipid metabolism and lipotoxicity Biochimica et Biophysica Acta BBA Molecular and Cell Biology of Lipids 1801 3 246 251 doi 10 1016 j bbalip 2009 09 024 PMC 2824076 PMID 19818872 Yu Yi Hao Ginsberg Henry 8 July 2009 The role of acyl CoA diacylglycerol acyltransferase DGAT in energy metabolism Annals of Medicine 36 4 252 261 doi 10 1080 07853890410028429 PMID 15224651 S2CID 9174481 a b Rashmi S Gayathri N Kumar M Veerendra Sumanth S Subasree R Pooja M 1 January 2017 Multiple Acyl CoA dehydrogenase deficiency Uncommon yet treatable disorder Neurology India 65 1 177 8 doi 10 4103 0028 3886 198186 inactive 31 December 2022 PMID 28084266 a href Template Cite journal html title Template Cite journal cite journal a CS1 maint DOI inactive as of December 2022 link External links EditAcyl Coenzyme A at the US National Library of Medicine Medical Subject Headings MeSH Retrieved from https en wikipedia org w index php title Acyl CoA amp oldid 1130882636, wikipedia, wiki, book, books, library,
