Subject tetrahydrofolate

Inhibition of nucleobase synthesis (2). Tetrahydrofolic acid (THF) is required for the synthesis of both purine bases and thymidine. Formation of THF from folic acid involves dihydrofolate reductase (p. 272). The folate analogues aminopterin and methotrexate (ame-thopterin) inhibit enzyme activity as false substrates. As cellular stores of THF are depleted, synthesis of DNA and RNA building blocks ceases. The effect of these antimetabolites can be reversed Ltillmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of iicense. 

Kaye JM, Stanton KG, McCann VJ, Vasikaran VB, Taylors RR, van Bockxmeer FM. 2002. Homocysteine, folate, methylene tetrahydrofolate reductase genotype and vascular morbidity in diabetic subjects. Clin Sci 102 631-637. 

The enzymatic activity of amido phosphoribosyltransferase (P-Rib-PP— PR A) is low and flux through the de novo pathway in vivo is regulated by the end-products, AMP, IMP and GMP. Inhibition of reaction 1 by dihydrofolate polyglutamates would signal the unavailability of /V1()-formyl tetrahydrofolate, required as a substrate at reactions 3 and 9 of the pathway. The purine pathway is subject to further regulation at the branch point from IMP XMP is a potent inhibitor of IMP cyclohydrolase (FAICAR—> IMP), AMP inhibits adenylosuccinate synthetase (IMP—> sAMP) and GMP inhibits IMP dehydrogenase (IMP— XMP). 

Kang and coworkers (1991) reported a variant of methylene-tetrahydrofolate reductase, in which cytosine is replaced by thymidine, resulting in a change of alanine to valine, in people who were hyperhomocysteinemic (Section 10.3.4.2). The variant enzyme is thermolabile (i.e., it is unstable to heating to about 40° to 45°C), and subjects who are homozygous for the thermolabile enzyme have about 50% of normal enzyme activity in tissues. Not only is the enzyme labile on moderate heating in vitro, but it is also unstable in... 

About30% ofvitamin Bi2-deficient subjects have elevated serum folate. This is mainly methyl-tetrahydrofolate, the result of the methyl folate trap (Section 10.3.4.1). About one-third of folate-deficient subjects have low serum vitamin B12 the reason for this is not clear, but it responds to the administration of folate supplements. 

About30% of vitaminBi2-deficient subjects have elevated serum folate. This is mednly methyl-tetrahydrofolate, the result of the methyl folate trap (Section... 

Dihydrofolate reductase (DHFR, EC 1.5.1.3) is an essential enzyme required for normal folate metabolism in prokaryotes and eukaryotes. Its role is to maintain necessary levels of tetrahydrofolate to support the biosynthesis of purines, pyrimidines and amino acids. Many compounds of pharmacological value, notably methotrexate and trimethoprim, vork by inhibition of DHFR. Their clinical importance justified the study of DHFR in the rapidly evolving field of enzymology. Today, there is a vast amount of published literature (ca. 1000 original research articles) on the broad subject of dihydrofolate reductase contributed by scientists from diverse disciplines. We have selected kinetic, structural, and computational studies that have advanced our understanding of the DHFR catalytic mechanism with special emphasis on the role of the enzyme-substrate complexes and protein motion in the catalytic efficiency achieved by this enzyme. 

Many short-term kinetic studies have been reported on the basis of plasma and senun folate levels in humans. Typical protocols involve the administration of a folate tracer dose to folate-saturated subjects or else a large folate dose given to subjects of more normal folate status (Reich and Gonczy, 1979 Bunni et aL, 1989 Wolfrom et al, 1990 Priest et al, 1991 von der Porten et al, 1992). Although these studies have clinical relevance with respect to the short-term kinetics of acute doses of the vitamin (e.g., postchemotherapy 5-formyl-tetrahydrofolate), they often provide little or no information about the major body folate pool that exhibits much slower kinetics. 

JF Gregory, SD Bhandari, LB Bailey, JP Toth, JJ Cerda. Bioavailability of deuterium-labeled monoglutamyl forms of folic acid and tetrahydrofolates in human subjects. Am J Clin Nutr 55 1147-1153, 1992. 

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