Thymidylate synthetase, properties

In 1968, my graduate student Charles Walsh and I addressed the following question What are the pyrimidine sources for nucleic acid synthesis by Plasmodium lophurae We found the parasite synthesized pyrimidines de novo (Walsh and Sherman, 1968b). The evidence for a de novo synthesis was the presence of the key enzymes, thymidylate synthetase and oroti-dine-5-monophosphate pyrophosphorylase, as well as the demonstration of the incorporation of 14C-bicarbonate into cytosine, uracil and thymine. Finding a de novo pathway for the synthesis of pyrimidines by the malaria parasite would, in the next three decades, provide a biochemical basis for the mechanism of action of anti-folate anti-malarials as well as contributing to an understanding of the unique properties of the malaria parasite mitochondrion. 

Garvey, E. P., Coderre, J. A. and Santi, D. V. (1985) Selection and properties of Leishmania tropica resistant to 10-propargyl-5,8-dideazafolate, an inhibitor of thymidylate synthetase. Mol. Biochem. Parasitol. 17 79-91. 

Thymidylate synthetase is an SH enzyme, and free SH groups are required for activity. The reaction involves the formation of a complex between the methylene derivative of folic acid and the enzyme, which in the presence of dUMP yields dTMP and a dihydro-folic acid enzyme complex. The properties of this enzyme will be discussed in more detail in other sections of this book. 

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