Deoxythymidine Monophosphate Synthesis

dUMP is converted to deoxythymidine monophosphate (dTMP) by thymidylate synthase, which uses N5,N10-methylene-THF as the source of the methyl group (see p. 267). This is an unusual reaction in that THF contributes not only a one-carbon unit but also two hydrogen atoms from the pteridine ring, resulting in the oxidation of THF to dihydrofolate ([DHF], Fig. 1). Inhibitors of thymidylate synthase include thymine analogs such as 5-fluorouracil, which serve as antitumor agents. 5-Fluorouracil is metabolically converted to 5-fluorodeoxyuridine monophosphate (5-FdUMP), which becomes permanently bound to the inactivated thymidylate synthase, making the drug a suicide inhibitor . DHF can be reduced to THF by dihydrofolate reductase , an enzyme that is inhibited by folate analogs such as methotrexate. By decreasing the supply of THF, these drugs not only inhibit purine synthesis , but, by preventing methylation of dUMP to dTMP, they also decrease the availability of this essential component of DNA. DNA synthesis is inhibited and cell growth slowed. Thus, these drugs are used to treat cancer. [Note: Acyclovir (a purine analog) and AZT (3′-azido-3′-deoxythymidine, a pyrimidine analog) are used to treat infections of herpes simplex virus and human immunodeficiency virus, respectively. Each inhibits the viral DNA polymerase.]

Figure 1:  Synthesis of dTMP from dUMP, illustrating sites of action of antineoplastic drugs.

مواضيع ذات صلة

آلية عمل المجموعة الأولى من الهرمونات

الهرمونات وآليات الاستتباب

تدرك (تقويض) الهرمونات وتعطيلها

نقل الهرمونات في البلازما

تغاير خزن الهرمونات وإفرازها

تخليق POMC ومعالجته

The Amino Acids

Absorption & Transport of Transition Metals

Physiologic Roles of The Essential Transition Metals

تخليق الأنجيوتنسين

تخلیق PTH

تخليق الأنسولين