Thymidylate synthase

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Revision as of 15:07, 13 April 2022

Thymidylate Synthase (TS) is an important enzyme in one-carbon metabolism[1]. TS catalyzes the transfer of a methyl group and a hydride from 5,10-methylenetetrahydrofolate to 2-deoxyuridine-5'-monophosphate, resulting in the formation of thymidine 5'-monophosphate and dihydrofolate. This is the only de novo source of dTMP (a precursor to Thymine) in humans. ^[1]

2-deoxyuridine-5'-monophosphate(dUMP) + 5, 10-methylenetetrahydrofolate(CH₂H₄F) ⇌ thymidine 5'-monophosphate(dTMP) + Dihydrofolate(H₂F)

spinqualitylabelsall models Thymidylate synthase complex with dUMP (PDB entry 1tsv) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Contents 1 Function 2 Relevance 3 Structural highlights 4 3D structures of thymidylate synthase Function Thymidylate synthase (TS) catalyzes the methylation of dUMP to dTMP using 5,10-methylenetetrahydrofolate as a cofactor. TS is essential for DNA replication and repair[2]. In protozoa, dihydrofolate reductase (DHFR) and TS are expressed as a bifunctional monomeric enzyme (DHFR-TS) with the DHFR entity at the N terminal. DHFR and TS catalyze consecutive reactions in the dTMP biosynthesis. There are two different types of TS – ThyA and ThyX. The types differ in their activity and structure. The TS ThyX are flavin-dependent enzymes. Relevance TS inhibition at its folate-binding site is used in anticancer therapeutic drugs. DHFR-TS inhibitors are potential drug targets against parasite-transferred diseases. TS exhibits oncogene-like activity.[3] Structural highlights TS [4]. Water molecules are shown as red spheres. The active site Cysteine has two . 3D structures of thymidylate synthase Thymidylate synthase 3D structures

References

1. ↑ Kholodar SA, Finer-Moore JS, Swiderek K, Arafet K, Moliner V, Stroud RM, Kohen A. Caught in Action: X-ray Structure of Thymidylate Synthase with Noncovalent Intermediate Analog. Biochemistry. 2021 Apr 8. doi: 10.1021/acs.biochem.1c00063. PMID:33829766 doi:http://dx.doi.org/10.1021/acs.biochem.1c00063
2. ↑ Kaneda S, Nalbantoglu J, Takeishi K, Shimizu K, Gotoh O, Seno T, Ayusawa D. Structural and functional analysis of the human thymidylate synthase gene. J Biol Chem. 1990 Nov 25;265(33):20277-84. PMID:2243092
3. ↑ Rahman L, Voeller D, Rahman M, Lipkowitz S, Allegra C, Barrett JC, Kaye FJ, Zajac-Kaye M. Thymidylate synthase as an oncogene: a novel role for an essential DNA synthesis enzyme. Cancer Cell. 2004 Apr;5(4):341-51. PMID:15093541
4. ↑ Finer-Moore JS, Fauman EB, Morse RJ, Santi DV, Stroud RM. Contribution of a salt bridge to binding affinity and dUMP orientation to catalytic rate: mutation of a substrate-binding arginine in thymidylate synthase. Protein Eng. 1996 Jan;9(1):69-75. PMID:9053905