Dihydrofolate reductase analogous forms

The answer is E. Methotrexate is an analog of folic acid that binds with very high affinity to the substrate-binding site of dihydrofolate reductase, the enzyme that catalyzes conversion of DHF to THE, which is used in various forms by enzymes of both the purine and pyrimidine de novo synthetic pathways. Thus, synthesis of dTMP from dUMP catalyzed by thymidylate synthetase and several steps in purine synthesis catalyzed by formyltransferase are indirectly blocked by the action of methotrexate because both those enzymes require THE coenzymes. 

Methotrexate and aminopterin, a similar compound, are analogs of dihydro folate (DHF) and inhibitors of dihydrofolate reductase, an enzyme that converts DHF to tetrahydro-folate (THF). The thymidylate synthase reaction converts N, N °-methylenetetrahydro-folate to DHF in the process of methylating dUMP to form dTMP In the presence of one of the inhibitors, this reaction functions as a sink that reduces the THF level of the cell by converting THF to DHF. Since THF derivatives are substrates in two reactions of purine metabolism and one of pyrimidine metabolism, both pathways are affected by the inhibitor. 

The ability of various diaminopyrimidines to distinguish between analogous forms of the enzyme dihydrofolate reductase is the basis of some of the best contemporary anti-malarial and anti-bacterial therapy (see Section 4.0, p. 123, Tables 4.1 and 4.2, and Section 9.3.3 and 9.6). Let us first look at the differences that exist between various vertebrate types of the enzyme, none of which is much inhibited by trimethoprim (4.P), and then proceed to invertebrate types, which are highly susceptible to this drug. The enzyme from chicken liver has only 75% identity of amino acid sequence with that from ox liver. Moreover, methylmercuric hydroxide activates the avian type twelvefold whereas it inactivates the bovine type. The avian type is much richer in basic amino acids and has an isoelectric point of 8.4 compared to 6.8 for the bovine type. This result is achieved in the avian type by the presence of lysine at positions 32,106, and 154, whereas the bovine type has glycine, threonine, and glutamic acid, respectively, in these positions (Kumars/a/., 1980). 

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