Methotrexate Chemical Biology

Thymidylate synthase (TS) is a highly conserved, 70 IcDa dimeric protein that catalyzes the reductive methylation of 2 -deoxyuridine 5 -monophosphate (dUMP) by 5,10-methylene-5,6,7,8-tetrahydrofolate to give 2 -deoxythymidine 5 -monophosphate (dTMP) and 7,8-dihydrofolate. Because TS plays a crucial role in DNA biosynthesis, it has been the focus of intense chemical, biological, and clinical research aimed at generating novel antitumor drugs with properties different from those of other antifolates such as methotrexate, which acts by inhibiting dihydrofolate reductase. 

Shepard, A.R., Conrow, R.E., Pang, I.-H. et al. (2013) Identification of PDE6D as a molecular target of anecortave acetate via a methotrexate-anchored yeast three-hybrid screen. ACS Chemical Biology, 8, 549-558. 

Many other examples of this concept exist. A recent example is methotrexate, a derivative of folic acid that has been used successfully in treating certain carcinomas as well as rheumatoid arthritis. Just as in the case above, methotrexate, because of its resemblance to folic acid, can enter into some of the same chemical reactions as folic acid, but it cannot ultimately serve the same inherent biological function. Here that role is involvement in reactions critical to cellular division. Although methotrexate is toxic to all dividing cells, those cells that divide most rapidly—cancer cells—are most vulnerable to its effect. 

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