5-[(4-Methyl-1,2,3,4-tetrahydroquinoxalyl)methyl]-2'-deoxyuridine 5'-phosphate: an analogue of a proposed intermediate in thymidylate synthetase catalysis.
In a study of the sequence steps involved in the mechanism of thymidylate synthetase catalysis, 5-[(N-methyl-piperazinyl)methyl]- (5) and 5-[(4-methyl-1,2,3,4-tetrahydroquinoxalyl)methyl]-2'-deoxyuridine 5'-phosphate (6) were synthesized. Compound 6 has high affinity for the Lactobacillus casei enzyme (Ki = 0.75 microM, KI/Km - 0.23), which is 50 times stronger than that of the piperazinyl derivative 5. Compound 6, a possible multisubstrate inhibitor, is an analogue of a proposed intermediate in the reaction mechanism wherein the enzyme is eliminated from the covalent complex (enzyme--substrate--cofactor) prior to the redox reaction leading to the products 2'-deoxythymidine 5'-phosphate and 7,8-dihydrofolic acid.
D003856:Deoxyuracil Nucleotides / Q000138:chemical synthesis* / Q000378:metabolism; D007780:Lacticaseibacillus casei / Q000201:enzymology; D008780:Methyltransferases / Q000378:metabolism*; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism*
D003856:Deoxyuracil Nucleotides; D011810:Quinoxalines; D008780:Methyltransferases; D013940:Thymidylate Synthase