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Thymidylate synthetase — substrate complex formation

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Summary

The complexes that thymidylate synthetase (TSase) forms with various potent inhibitors have been intensively studied and thoroughly reviewed. Of particular significance is the covalent ternary complex of TSase-FdUMP-5,10-CH2H4PteGlu. HUMP is the active metabolite of the widely used anti-cancer drug 5-fluorouracil. This complex is thought to be analogous to a steady-state intermediate of the normal enzyme reaction with the substrate dUMP. In this review, we examine the properties of TSase-dUMP complexes in order to determine if there is an experimental basis for drawing a close analogy between dUMP and HUMP in their interaction with TSase, and also to evaluate data indicating a potential chemotherapeutic value for TSase-dUMP complexes formed in the presence of folate analogs.

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Abbreviations

TSase:

thymidylate synthetase

5,10-CH2H4Pte-Glu:

5,10-methylenetetrahydrofolic acid

dUMP:

2′-deoxyuridine-5′phosphate

FdUMP:

5-fluoro-2′deoxyuridine-5′-phosphate

dTMP:

thymidylic acid

H2PteGlu:

dihydrofolic acid

BrdUMP:

5-bromo-2′-deoxyuridylic acid

4-N-hydroxy dCMP:

4-N-hydroxy-2′-deoxycytidylic acid

MTX:

methotrexate

PteGlu3 :

pteroic acid triglutamate

5-FUra:

5-fluorouracil

DTNB:

2,2′-dithiobisnitrobenzoic acid

NEM:

N-ethylmaleimide

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Authors and Affiliations

  1. Dept. of Biochemistry and Comprehensive Cancer Center, University of Southern California, School of Medicine, 90033, Los Angeles, CA, USA

    P. V. Danenberg & A. Lockshin

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  1. P. V. Danenberg
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  2. A. Lockshin
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Danenberg, P.V., Lockshin, A. Thymidylate synthetase — substrate complex formation. Mol Cell Biochem 43, 49–57 (1982). https://doi.org/10.1007/BF00229539

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