CTP synthetase: Difference between revisions
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== Enzyme Mechanism == |
== Enzyme Mechanism == |
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CTP synthase catalyzes the last committed step in de novo pyrimidine nucleotide biosynthesis:<ref>{{cite book |last1=Koshland |first1=D. E. |title=The Enzymes |year=1974 |publisher=Academic Press |location=New York |pages=539–59 |edition=3rd |last2=Levitzki |first2=A. |editor1-last=Boyer |editor1-first=Paul D |isbn=978-0-12-122710-4 |chapter=CTP Synthetase and Related Enzymes |chapterurl=http://books.google.com/books?id=9Jz_CZs5lFgC&pg=PA539}}</ref> |
CTP synthase catalyzes the last committed step in de novo pyrimidine nucleotide biosynthesis:<ref>{{cite book |last1=Koshland |first1=D. E. |title=The Enzymes |year=1974 |publisher=Academic Press |location=New York |pages=539–59 |edition=3rd |last2=Levitzki |first2=A. |editor1-last=Boyer |editor1-first=Paul D |isbn=978-0-12-122710-4 |chapter=CTP Synthetase and Related Enzymes |chapterurl=http://books.google.com/books?id=9Jz_CZs5lFgC&pg=PA539}}</ref> It is the rate-limiting enzyme for the synthesis of cytosine nucleotides from both the ''de novo'' and uridine salvage pathways <ref name=pmid11783495>{{cite journal |pages=257-61|doi= |title= Isoforms of human CTP synthetase |year=2000 |last1= van Kuilenburg |first1=AB |last2= Meinsma |first2= R |last3= Vreken |first3=P |last4= Waterham |first4= HR |last5= van Gennip |first5=AH |journal= Adv Exp Med Biol |volume=486 |issue= |pmid=11783495}}</ref> |
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ATP + UTP + glutamine --> ADP + Pi + CTP + glutamate |
ATP + UTP + glutamine --> ADP + Pi + CTP + glutamate |
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Revision as of 00:08, 17 May 2011
| CTP synthase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 Cytidine triphosphate | |||||||||
| Identifiers | |||||||||
| EC no. | 6.3.4.2 | ||||||||
| CAS no. | 9023-56-7 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
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CTP synthase (or CTP synthetase) is an enzyme involved in pyrimidine biosynthesis.[1][2] It intraconverts UTP and CTP.
The source of the amine/amino group in CTP is glutamine. CTP synthase is activated by GTP, a purine. This acts to balance the relative amounts of purine and pyrimidine nucleotides.
Enzyme Structure
Active CTP synthase exists as a homeotetrameric enzyme. At low enzyme concentrations and in the absence of ATP and UTP, CTP synthase exists as inactive monomer. As enzyme concentration increases, it polymerizes first to a dimer (such as the form shown to the right) and, in the presence of ATP and UTP, forms a tetramer.[3][4]
The enzyme contains two major domains, responsible for the aminotransferase and synthase activity, respectively. The amidotransferase domains are located away from the tetramer interfaces and are not affected by the oligomeric state. The ATP-binding site and CTP-binding site in the synthase domain are located at the tetramer interface. It is for this reason that AT and UTP are required for tertamerization.[5]
Two isozymes with CTP synthase activity exist in humans, encoded by the following genes:
Enzyme Mechanism
CTP synthase catalyzes the last committed step in de novo pyrimidine nucleotide biosynthesis:[6] It is the rate-limiting enzyme for the synthesis of cytosine nucleotides from both the de novo and uridine salvage pathways [7]
ATP + UTP + glutamine --> ADP + Pi + CTP + glutamate
The reaction proceeds by the ATP-dependent phosphorylation of UTP on the 4-oxygen atom, making the 4-carbon electrophilic and vulnerable to attack by ammonia. [3] Glutamine is hydrolysed in a glutamine amidotransferase domain, while ammonia is channeled through the interior of the enzyme to the synthase domain.[8] Here, ammonia reacts with the intermediate 4-phosphoryl UTP.[9]
Regulation
CTP synthase is inhibited reversibly by CTP and irreversibly by, for example, the glutamine analogon DON.[10]
Cytoophidium
The cytoophidium (Greek: cyto-, meaning cell, and ophidium, meaning serpent) is a snake-like filamentary structure containing CTP synthase. It was first reported in the fruit flies (D. melanogaster, D. virilis and D. peudoobscura).[11] The CTP synthase-contained filaments (i.e., cytoophidium) have also been found in bacteria including C. crescentus and E. coli,[12] indicating that the cytoophidium is well conserved from prokaryotes to eukaryotes.[citation needed]
Disease Relevance
Upregulated CTP synthase activity has been widely seen in human and rodent tumors.[13]
Mutations in the CTP synthase have been seen to confer resistance to cytotoxic drugs such as cytosine arabinoside (ara-C) in a Chinese hamster ovary (CHO) cell model of leukemia though such mutations were not found in human patients with ara-C resistance.[14]
See also
References
- ^ Lieberman, Irving (1956). "Enzymatic amination of uridine triphosphate to cytidine triphosphate". The Journal of Biological Chemistry. 222 (2): 765–75. PMID 13367044.
- ^ Long, Cedric W.; Levitzki, Alexander; Koshland, D. E. (1970). "The subunit structure and subunit interactions of cytidine triphosphate synthetase". The Journal of Biological Chemistry. 245 (1): 80–7. PMID 5411547.
- ^ a b von der Saal, Wolfgang; Anderson, Paul M.; Villafranca, Joseph J. (1985). "Mechanistic investigations of Escherichia coli cytidine-5'-triphosphate synthetase. Detection of an intermediate by positional isotope exchange experiments". The Journal of Biological Chemistry. 260 (28): 14993–7. PMID 2933396. Cite error: The named reference "pmid2933396" was defined multiple times with different content (see the help page).
- ^ Anderson, Paul M. (1983). "CTP synthetase from Escherichia coli: an improved purification procedure and characterization of hysteretic and enzyme concentration effects on kinetic properties". Biochemistry. 22 (13): 3285–92. doi:10.1021/bi00282a038. PMID 6349684.
- ^ Lauritsen, Iben; Willemoës, Martin; Jensen, Kaj Frank; Johansson, Eva; Harris, Pernille (2011). "Structure of the dimeric form of CTP synthase fromSulfolobus solfataricus". Acta Crystallographica Section F Structural Biology and Crystallization Communications. 67 (2): 201–8. doi:10.1107/S1744309110052334. PMC 3034608. PMID 21301086.
- ^ Koshland, D. E.; Levitzki, A. (1974). "CTP Synthetase and Related Enzymes". In Boyer, Paul D (ed.). The Enzymes (3rd ed.). New York: Academic Press. pp. 539–59. ISBN 978-0-12-122710-4.
{{cite book}}: External link in|chapterurl=|chapterurl=ignored (|chapter-url=suggested) (help) - ^ van Kuilenburg, AB; Meinsma, R; Vreken, P; Waterham, HR; van Gennip, AH (2000). "Isoforms of human CTP synthetase". Adv Exp Med Biol. 486: 257–61. PMID 11783495.
- ^ Endrizzi, James A.; Kim, Hanseong; Anderson, Paul M.; Baldwin, Enoch P. (2004). "Crystal Structure ofEscherichia coliCytidine Triphosphate Synthetase, a Nucleotide-Regulated Glutamine Amidotransferase/ATP-Dependent Amidoligase Fusion Protein and Homologue of Anticancer and Antiparasitic Drug Targets". Biochemistry. 43 (21): 6447–63. doi:10.1021/bi0496945. PMC 2891762. PMID 15157079.
- ^ Lewis, Deborah A.; Villafranca, Joseph J. (1989). "Investigation of the mechanism of CTP synthetase using rapid quench and isotope partitioning methods". Biochemistry. 28 (21): 8454–9. doi:10.1021/bi00447a027. PMID 2532543.
- ^ Ahluwalia, Gurpreet S.; Grem, Jean L.; Hao, Zhang; Cooney, David A. (1990). "Metabolism and action of amino acid analog anti-cancer agents". Pharmacology & Therapeutics. 46 (2): 243–71. doi:10.1016/0163-7258(90)90094-I. PMID 2108451.
- ^ Liu, Ji-Long (2010). "Intracellular compartmentation of CTP synthase in Drosophila". Journal of Genetics and Genomics. 37 (5): 281–96. doi:10.1016/S1673-8527(09)60046-1. PMID 20513629.
- ^ Ingerson-Mahar, Michael; Briegel, Ariane; Werner, John N.; Jensen, Grant J.; Gitai, Zemer (2010). "The metabolic enzyme CTP synthase forms cytoskeletal filaments". Nature Cell Biology. 12 (8): 739–46. doi:10.1038/ncb2087. PMID 20639870.
- ^ Kizaki, Harutoshi; Williams, Jim C.; Morris, Harold P.; Weber, George (1980). "Increased cytidine 5'-triphosphate synthetase activity in rat and human tumors". Cancer research. 40 (11): 3921–7. PMID 7471043.
- ^ Whelan, J; Smith, T; Phear, G; Rohatiner, A; Lister, A; Meuth, M (1994). "Resistance to cytosine arabinoside in acute leukemia: the significance of mutations in CTP synthetase". Leukemia. 8 (2): 264–5. PMID 8309250.
External links
- CTP+synthetase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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