View source for Biology:Pyrimidine metabolism

{{short description|Set of biological pathways}}
'''Pyrimidine biosynthesis''' occurs both in the body and through organic synthesis.<ref>{{cite journal |last1=Alqahtani |first1=Saad Saeed |last2=Koltai |first2=Tomas |last3=Ibrahim |first3=Muntaser E. |last4=Bashir |first4=Adil H. H. |last5=Alhoufie |first5=Sari T. S. |last6=Ahmed |first6=Samrein B. M. |last7=Molfetta |first7=Daria Di |last8=Carvalho |first8=Tiago M. A. |last9=Cardone |first9=Rosa Angela |last10=Reshkin |first10=Stephan Joel |last11=Hifny |first11=Abdelhameed |last12=Ahmed |first12=Mohamed E. |last13=Alfarouk |first13=Khalid Omer |title=Role of pH in Regulating Cancer Pyrimidine Synthesis |journal=Journal of Xenobiotics |date=6 July 2022 |volume=12 |issue=3 |pages=158–180 |doi=10.3390/jox12030014|doi-access=free |pmc=9326563 }}</ref>

==''De novo'' biosynthesis of pyrimidine ==
{| class="wikitable"
 |Steps
|Enzymes
|Products 
|
|-
|1
|carbamoyl phosphate synthetase II<ref name="ncbi">{{cite web | title = Entrez Gene: CAD carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=790}}</ref>||[[Chemistry:Carbamoyl phosphate|carbamoyl phosphate]]|| This is the regulated step in the pyrimidine biosynthesis in animals.
 |-
|2
| aspartic transcarbamoylase (aspartate carbamoyl transferase)<ref name="ncbi" />||[[Chemistry:Carbamoyl aspartic acid|carbamoyl aspartic acid]]|| The phosphate group is replaced with Aspartate. This is the regulated step in the pyrimidine biosynthesis in bacteria.
 |-
|3
|[[Biology:Dihydroorotase|dihydroorotase]]<ref name="ncbi" />||dihydroorotate|| Ring formation and Dehydration.
 |-
|4
|[[Biology:Dihydroorotate dehydrogenase|dihydroorotate dehydrogenase]]<ref>{{cite web | title = Entrez Gene: DHODH dihydroorotate dehydrogenase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1723}}</ref> (the only mitochondrial enzyme) ||orotate|| Dihydroorotate then enters the [[Biology:Mitochondria|mitochondria]] where it is oxidized through removal of hydrogens. This is the only mitochondrial step in nucleotide rings biosynthesis. 
 |-
|5
|[[Biology:Orotate phosphoribosyltransferase|orotate phosphoribosyltransferase]]<ref name="ncbi_a">{{cite web | title = Entrez Gene: UMPS uridine monophosphate synthetase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7372}}</ref>||OMP||PRPP donates a Ribose group.
 |-
|6
|OMP decarboxylase<ref name="ncbi_a" />||[[Chemistry:Uridine monophosphate|UMP]]|| Decarboxylation
 |-
|
|uridine-cytidine kinase 2<ref>{{cite web | title = Entrez Gene: UCK2 uridine-cytidine kinase 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7371}}</ref>||[[Chemistry:Uridine diphosphate|UDP]]|| Phosphorylation. ATP is used.
 |-
|
|nucleoside diphosphate kinase||UTP|| Phosphorylation. ATP is used.
 |-
|
|CTP synthase||CTP||[[Chemistry:Glutamine|Glutamine]] and ATP are used.
|}

''De Novo'' biosynthesis of a [[Chemistry:Pyrimidine|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 [[Biology:CAD (protein)|CAD]] which consists of [[Biology:Carbamoyl phosphate synthase II|carbamoyl phosphate synthetase II]], [[Biology:Aspartate carbamoyltransferase|aspartate carbamoyltransferase]] and [[Biology:Dihydroorotase|dihydroorotase]]. [[Biology:Dihydroorotate dehydrogenase|Dihydroorotate dehydrogenase (DHODH)]] unlike [[Biology:CAD (protein)|CAD]] and [[Biology:Uridine monophosphate synthetase|UMPS]] is a mono-functional enzyme and is localized in the mitochondria. UMPS is a bifunctional enzyme consisting of [[Biology:Orotate phosphoribosyltransferase|orotate phosphoribosyltransferase (OPRT)]] and [[Biology:Orotidine 5'-phosphate decarboxylase|orotidine monophosphate decarboxylase (OMPDC)]]. Both, CAD and UMPS are localized around the mitochondria, in the cytosol.<ref>{{cite journal | vauthors = Chitrakar I, Kim-Holzapfel DM, Zhou W, French JB | title = Higher order structures in purine and pyrimidine metabolism | journal = Journal of Structural Biology | volume = 197 | issue = 3 | pages = 354–364 | date = March 2017 | pmid = 28115257 | doi = 10.1016/j.jsb.2017.01.003 }}</ref> In [[Biology:Fungi|Fungi]], a similar protein exists but lacks the dihydroorotase function: another protein catalyzes the second step.

In other organisms ([[Biology:Bacteria|Bacteria]], [[Biology:Archaea|Archaea]] and the other Eukaryota), the first three steps are done by three different enzymes.<ref>{{cite journal | vauthors = Garavito MF, Narváez-Ortiz HY, Zimmermann BH | title = Pyrimidine Metabolism: Dynamic and Versatile Pathways in Pathogens and Cellular Development | journal = Journal of Genetics and Genomics = Yi Chuan Xue Bao | volume = 42 | issue = 5 | pages = 195–205 | date = May 2015 | pmid = 26059768 | doi = 10.1016/j.jgg.2015.04.004 }}</ref>

== Pyrimidine catabolism ==

[[Chemistry:Pyrimidine|Pyrimidines]] are ultimately [[Biology:Catabolism|catabolized]] (degraded) to [[Chemistry:Carbon dioxide|CO<sub>2</sub>]], [[Chemistry:Water (molecule)|H<sub>2</sub>O]], and [[Chemistry:Urea|urea]]. [[Chemistry:Cytosine|Cytosine]] can be broken down to [[Chemistry:Uracil|uracil]], which can be further broken down to [[Chemistry:3-Ureidopropionic acid|N-carbamoyl-β-alanine]], and then to beta-alanine, CO<sub>2</sub>, and [[Chemistry:Ammonia|ammonia]] by [[Biology:Beta-ureidopropionase|beta-ureidopropionase]]. [[Chemistry:Thymine|Thymine]] is broken down into β-aminoisobutyrate which can be further broken down into intermediates eventually leading into the [[Biology:Citric acid cycle|citric acid cycle]].

[[Chemistry:3-Aminoisobutyric acid|β-aminoisobutyrate]] acts as a rough indicator for rate of [[Biology:DNA|DNA]] turnover.<ref>{{cite journal | vauthors = Nielsen HR, Sjolin KE, Nyholm K, Baliga BS, Wong R, Borek E | title = Beta-aminoisobutyric acid, a new probe for the metabolism of DNA and RNA in normal and tumorous tissue | journal = Cancer Research | volume = 34 | issue = 6 | pages = 1381–4 | date = June 1974 | pmid = 4363656 }}</ref>

=== Regulations of pyrimidine nucleotide biosynthesis ===
Through negative feedback inhibition, the end-products '''UTP''' ''and'' '''UDP''' prevent the enzyme CAD from catalyzing the reaction in animals. Conversely, [[Chemistry:Phosphoribosyl pyrophosphate|PRPP]] and [[Chemistry:Adenosine triphosphate|ATP]] act as positive effectors that enhance the enzyme's activity.<ref>{{cite journal | vauthors = Jones ME | title = Pyrimidine nucleotide biosynthesis in animals: genes, enzymes, and regulation of UMP biosynthesis | journal = Annual Review of Biochemistry | volume = 49 | issue = 1 | pages = 253–79 | date = June 1980 | pmid = 6105839 | doi = 10.1146/annurev.bi.49.070180.001345 }}</ref>

==Pharmacotherapy==
Modulating the pyrimidine metabolism pharmacologically has therapeutical uses, and could implement in cancer treatment.<ref>{{cite journal |last1=Alqahtani |first1=Saad Saeed |last2=Koltai |first2=Tomas |last3=Ibrahim |first3=Muntaser E. |last4=Bashir |first4=Adil H. H. |last5=Alhoufie |first5=Sari T. S. |last6=Ahmed |first6=Samrein B. M. |last7=Molfetta |first7=Daria Di |last8=Carvalho |first8=Tiago M. A. |last9=Cardone |first9=Rosa Angela |last10=Reshkin |first10=Stephan Joel |last11=Hifny |first11=Abdelhameed |last12=Ahmed |first12=Mohamed E. |last13=Alfarouk |first13=Khalid Omer |title=Role of pH in Regulating Cancer Pyrimidine Synthesis |journal=Journal of Xenobiotics |date=6 July 2022 |volume=12 |issue=3 |pages=158–180 |doi=10.3390/jox12030014|doi-access=free |pmc=9326563 }}</ref>

''Pyrimidine synthesis inhibitors'' are used in active moderate to severe [[Medicine:Rheumatoid arthritis|rheumatoid arthritis]] and [[Medicine:Psoriatic arthritis|psoriatic arthritis]], as well as in multiple sclerosis. Examples include [[Chemistry:Leflunomide|Leflunomide]] and [[Chemistry:Teriflunomide|Teriflunomide]] (the active metabolite of leflunomide).

==Prebiotic synthesis of pyrimidine nucleotides==

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 [[Biology:Abiogenesis|prebiotic conditions]].  The [[Biology:RNA world|RNA world]] hypothesis holds that in the [[Biology:Primordial soup|primordial soup]] there existed free-floating pyrimidine and purine [[Biology:Ribonucleotide|ribonucleotide]]s, the fundamental molecules that combine in series to form [[Biology:RNA|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 [[Chemistry:Pyrimidine|pyrimidine]] and [[Chemistry:Purine|purine]]  nucleotides, both of which are necessary for reliable information transfer, and thus natural selection and Darwinian [[Biology:Evolution|evolution]].  Becker et al. showed how pyrimidine [[Biology:Nucleoside|nucleoside]]s can be synthesized from small molecules and [[Chemistry:Ribose|ribose]], driven solely by wet-dry cycles.<ref>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</ref>

== References ==
{{reflist}}

== External links ==
* [https://web.archive.org/web/20090814181536/http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/misc/pyrimid.html Overview] at Queen Mary, University of London

{{MetabolismMap}}
{{Protein metabolism}}
{{Nucleotide metabolism}}
{{Purinergics}}

[[Category:Pyrimidines]]
[[Category:Metabolism]]

{{Sourceattribution|Pyrimidine metabolism}}