Pyrimidine metabolism
This article includes a list of general references, but it lacks sufficient corresponding inline citations. (August 2008) |
Pyrimidine biosynthesis occurs both in the body and through organic synthesis.[1]
De novo biosynthesis of pyrimidine edit
| Steps | Enzymes | Products | |
| 1 | carbamoyl phosphate synthetase II[2] | carbamoyl phosphate | This is the regulated step in the pyrimidine biosynthesis in animals. |
| 2 | aspartic transcarbamoylase (aspartate carbamoyl transferase)[2] | carbamoyl aspartic acid | The phosphate group is replaced with Aspartate. This is the regulated step in the pyrimidine biosynthesis in bacteria. |
| 3 | dihydroorotase[2] | dihydroorotate | Ring formation and Dehydration. |
| 4 | dihydroorotate dehydrogenase[3] (the only mitochondrial enzyme) | orotate | Dihydroorotate then enters the mitochondria where it is oxidized through removal of hydrogens. This is the only mitochondrial step in nucleotide rings biosynthesis. |
| 5 | orotate phosphoribosyltransferase[4] | OMP | PRPP donates a Ribose group. |
| 6 | OMP decarboxylase[4] | UMP | Decarboxylation |
| uridine-cytidine kinase 2[5] | UDP | Phosphorylation. ATP is used. | |
| nucleoside diphosphate kinase | UTP | Phosphorylation. ATP is used. | |
| CTP synthase | CTP | Glutamine and ATP are used. |
De Novo biosynthesis of a pyrimidine is catalyzed by three gene products CAD, DHODH and UMPS. The first three enzymes of the process are all coded by the same gene in CAD which consists of carbamoyl phosphate synthetase II, aspartate carbamoyltransferase and dihydroorotase. Dihydroorotate dehydrogenase (DHODH) unlike CAD and UMPS is a mono-functional enzyme and is localized in the mitochondria. UMPS is a bifunctional enzyme consisting of orotate phosphoribosyltransferase (OPRT) and orotidine monophosphate decarboxylase (OMPDC). Both, CAD and UMPS are localized around the mitochondria, in the cytosol.[6] In Fungi, a similar protein exists but lacks the dihydroorotase function: another protein catalyzes the second step.
In other organisms (Bacteria, Archaea and the other Eukaryota), the first three steps are done by three different enzymes.[7]
Pyrimidine catabolism edit
Pyrimidines are ultimately catabolized (degraded) to CO2, H2O, and urea. Cytosine can be broken down to uracil, which can be further broken down to N-carbamoyl-β-alanine, and then to beta-alanine, CO2, and ammonia by beta-ureidopropionase. Thymine is broken down into β-aminoisobutyrate which can be further broken down into intermediates eventually leading into the citric acid cycle.
β-aminoisobutyrate acts as a rough indicator for rate of DNA turnover.[8]
Regulations of pyrimidine nucleotide biosynthesis edit
Through negative feedback inhibition, the end-products UTP and UDP prevent the enzyme CAD from catalyzing the reaction in animals. Conversely, PRPP and ATP act as positive effectors that enhance the enzyme's activity.[9]
Pharmacotherapy edit
Modulating the pyrimidine metabolism pharmacologically has therapeutical uses, and could implement in cancer treatment.[10]
Pyrimidine synthesis inhibitors are used in active moderate to severe rheumatoid arthritis and psoriatic arthritis, as well as in multiple sclerosis. Examples include Leflunomide and Teriflunomide (the active metabolite of leflunomide).
Prebiotic synthesis of pyrimidine nucleotides edit
In order to understand how life arose, knowledge is required of the chemical pathways that permit formation of the key building blocks of life under plausible prebiotic conditions. The RNA world hypothesis holds that in the primordial soup there existed free-floating pyrimidine and purine ribonucleotides, the fundamental molecules that combine in series to form RNA. Complex molecules such as RNA must have emerged from relatively small molecules whose reactivity was governed by physico-chemical processes. RNA is composed of pyrimidine and purine nucleotides, both of which are necessary for reliable information transfer, and thus natural selection and Darwinian evolution. Becker et al. showed how pyrimidine nucleosides can be synthesized from small molecules and ribose, driven solely by wet-dry cycles.[11]
References edit
- ^ Alqahtani, Saad Saeed; Koltai, Tomas; Ibrahim, Muntaser E.; Bashir, Adil H. H.; Alhoufie, Sari T. S.; Ahmed, Samrein B. M.; Molfetta, Daria Di; Carvalho, Tiago M. A.; Cardone, Rosa Angela; Reshkin, Stephan Joel; Hifny, Abdelhameed; Ahmed, Mohamed E.; Alfarouk, Khalid Omer (6 July 2022). "Role of pH in Regulating Cancer Pyrimidine Synthesis". Journal of Xenobiotics. 12 (3): 158–180. doi:10.3390/jox12030014. PMC 9326563.
- ^ a b c "Entrez Gene: CAD carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase".
- ^ "Entrez Gene: DHODH dihydroorotate dehydrogenase".
- ^ a b "Entrez Gene: UMPS uridine monophosphate synthetase".
- ^ "Entrez Gene: UCK2 uridine-cytidine kinase 2".
- ^ Chitrakar I, Kim-Holzapfel DM, Zhou W, French JB (March 2017). "Higher order structures in purine and pyrimidine metabolism". Journal of Structural Biology. 197 (3): 354–364. doi:10.1016/j.jsb.2017.01.003. PMID 28115257.
- ^ Garavito MF, Narváez-Ortiz HY, Zimmermann BH (May 2015). "Pyrimidine Metabolism: Dynamic and Versatile Pathways in Pathogens and Cellular Development". Journal of Genetics and Genomics = Yi Chuan Xue Bao. 42 (5): 195–205. doi:10.1016/j.jgg.2015.04.004. PMID 26059768.
- ^ Nielsen HR, Sjolin KE, Nyholm K, Baliga BS, Wong R, Borek E (June 1974). "Beta-aminoisobutyric acid, a new probe for the metabolism of DNA and RNA in normal and tumorous tissue". Cancer Research. 34 (6): 1381–4. PMID 4363656.
- ^ Jones ME (June 1980). "Pyrimidine nucleotide biosynthesis in animals: genes, enzymes, and regulation of UMP biosynthesis". Annual Review of Biochemistry. 49 (1): 253–79. doi:10.1146/annurev.bi.49.070180.001345. PMID 6105839.
- ^ Alqahtani, Saad Saeed; Koltai, Tomas; Ibrahim, Muntaser E.; Bashir, Adil H. H.; Alhoufie, Sari T. S.; Ahmed, Samrein B. M.; Molfetta, Daria Di; Carvalho, Tiago M. A.; Cardone, Rosa Angela; Reshkin, Stephan Joel; Hifny, Abdelhameed; Ahmed, Mohamed E.; Alfarouk, Khalid Omer (6 July 2022). "Role of pH in Regulating Cancer Pyrimidine Synthesis". Journal of Xenobiotics. 12 (3): 158–180. doi:10.3390/jox12030014. PMC 9326563.
- ^ Becker S, Feldmann J, Wiedemann S, Okamura H, Schneider C, Iwan K, Crisp A, Rossa M, Amatov T, Carell T. Unified prebiotically plausible synthesis of pyrimidine and purine RNA ribonucleotides. Science. 2019 Oct 4;366(6461):76-82. doi: 10.1126/science.aax2747. PMID 31604305