Thymidine phosphorylase mechanism

Fig. 14.3 5 -FU catabolism, anabolism and mechanism of action. 5-FUH2, 5-fluoro-5,6-dihydrouracil 5-FdUMP, 5-fluorodeoxyuridine monophosphate TP, thymidine phosphorylase TK, thymidine kinase TS, thymidylate synthase CH2THF, 5,10-methylenetetrahydrofolate.

Sheppard DW, Burton NA, Hillier IH. Ab initio hybrid quantum mechanical/molecular mechanical studies of the mechanisms of the enzymes protein kinase and thymidine phosphorylase. J Mol Struct Theochem 2000 506 35 44. 

Purine nucleoside phosphorylase and thymidine phosphorylase have been shown to catalyze transfer of the deoxyribosyl group from one base to another by reaction sequences that involve the intermediate formation of free deoxyribose 1-phosphate by the following mechanism ... 

In addition to participation in the deoxyribosyl transfer reactions described above, in which free deoxyribose 1-phosphate is formed as an intermediate, thymidine phosphorylase also catalyzes deoxyribosyl transfers involving thymine and uracil in which deoxyribosyl phosphate is an intermediate but is enzyme-bound (18-20). Such transfers require non-stoichiometric amounts of phosphate (19). The reaction mechanisms of uridine phosphorylase and purine nucleoside phosphorylase are not of this type and, accordingly, direct deoxyribosyl transfers occur only between substrates for thymidine phosphorylase, as exemplified by reaction (5) above and the following (15) (the asterisk indicates C-labeling) ... 

Many LactobaciUus species have an absolute growth requirement for a purine, a pyrimidine, and a single deoxyribonudeoside of any sort because the entire complement of cellular deoxyribonucleotides is derived from these materials, there is an evident requirement for the capability of transferring the deoxyribosyl function between bases in these cells. However, in lactobacilli deoxyribosyl transfer is not accomplished by the phosphorylase mechanisms outlined above in this connection it may be noted that lactobacilli are devoid of thymidine phosphorylase (4). A specific enzyme activity, deoxyribosyl transfer in these bacteria this is accomplished without the intermediate formation of deoxyribose 1-phosphate, is readily reversible, and takes place in the absence of inorganic phosphate ... 

Thymidine phosphorylase can also use deoxyuridine as substrate [161-163], and the purine nucleoside enzyme can use either the ribonu-cleoside or the deoxyribonucleoside forms of adenine or guanine [115,164], Uridine phosphorylase (EC 2.4.2.3) is a separate entity and will not be considered here, since its regulation is not clearly understood. The four enzymes under consideration are interrelated in function and operate in concert in the regulation of nucleoside catabolism. The mechanisms of their regulation evolved from a number of independent and seemingly devious observations and events, the essence of which may be summarized as follows. 

Studies on the mechanism of inhibition of thymidine phosphorylase by 6-substituted-5-fluorouracil derivatives... 

---