Abstract
In humans de novo synthesis of 2′-deoxythymidine-5′-monophosphate (dTMP), an essential building block of DNA, utilizes an enzymatic pathway requiring thymidylate synthase (TSase) and dihydrofolate reductase (DHFR). The enzyme flavin-dependent thymidylate synthase (FDTS) represents an alternative enzymatic pathway to synthesize dTMP, which is not present in human cells. A number of pathogenic bacteria, however, depend on this enzyme in lieu of or in conjunction with the analogous human pathway. Thus, inhibitors of this enzyme may serve as antibiotics. Here, we review the similarities and differences of FDTS vs. TSase including aspects of their structure and chemical mechanism. In addition, we review current progress in the search for inhibitors of flavin dependent thymidylate synthase as potential novel therapeutics.
Highlights
Replication of all cells requires thymidine, a pyrimidine that makes up DNA
The last step of the synthesis is catalyzed by the enzyme thymidylate synthase (TSase) coded by the thyA gene
The recycling of DHF is catalyzed by the folA encoded enzyme dihydrofolate reductase (DHFR), which synthesizes tetrahydrofolate (THF or H4 folate) (Scheme 1), which is converted to MTHF by serine hydroxymethyltransferase [1]
Summary
Replication of all cells requires thymidine, a pyrimidine that makes up DNA. Thymidine is synthesized in human cell de novo. TSase catalyzes the conversion of 21 -deoxyuridine-51 -monophosphate (dUMP) to 21 -deoxythymidine-51 -monophosphate (dTMP or thymidylate) using N5 ,N10 -methylene-5,6,7,8-tetrahydrofolate (MTHF or CH2 H4 folate) in a reductive methylation reaction (Scheme 1). Through this process, dTMP is made, which can be used in DNA synthesis. The recycling of DHF is catalyzed by the folA encoded enzyme dihydrofolate reductase (DHFR), which synthesizes tetrahydrofolate (THF or H4 folate) (Scheme 1), which is converted to MTHF by serine hydroxymethyltransferase [1]. Because of the importance of dTMP to the synthesis of DNA, it was thought that TSase and the enzymes required to regenerate MTHF were essential.
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