Thymidylate synthase

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TS <scene name='49/493689/Cv/4'>active site contains the substrate dUMP</scene><ref>PMID:9053905</ref>. Water molecules are shown as red spheres.
TS <scene name='49/493689/Cv/4'>active site contains the substrate dUMP</scene><ref>PMID:9053905</ref>. Water molecules are shown as red spheres.
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The active site Cysteine has two <scene name='49/493689/Ts_7jxf_percentb/2'>conformations</scene>. Conformation 1 shows the active site cysteine bound to the intermediate 3.84 Angstroms away from the C6 carbon of the dNMP ring. Conformation 2 shows the active site cysteine unbound to the intermediate 4.21 Angstroms away from the C6 carbon of the dNMP ring.
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The active site Cysteine has two <scene name='49/493689/Ts_7jxf_percentb/3'>conformations</scene>. Conformation 1 shows the active site cysteine bound to the intermediate 3.84 Angstroms away from the C6 carbon of the dNMP ring. Conformation 2 shows the active site cysteine unbound to the intermediate 4.21 Angstroms away from the C6 carbon of the dNMP ring.
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Revision as of 15:11, 15 April 2022

Thymidylate Synthase (TS) is an important enzyme in one-carbon metabolism. 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)

Thymidylate synthase complex with dUMP (PDB entry 1tsv)

Drag the structure with the mouse to rotate

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. ↑ Costi MP, Ferrari S, Venturelli A, Calo S, Tondi D, Barlocco D. Thymidylate synthase structure, function and implication in drug discovery. Curr Med Chem. 2005;12(19):2241-58. doi: 10.2174/0929867054864868. PMID:16178783 doi:http://dx.doi.org/10.2174/0929867054864868
  5. ↑ 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
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