Trimethoprim, complex with DHFR

Fleischman SH, Brooks CL. Protein-drug interactions Characterization of inhibitor binding in complexes of DHFR with trimethoprim and related derivatives. Proteins 1990 7 52-61. 

S. H. Fleishman and C. L. Brooks III, Proteins, 7, 52 (1990). Protein-Drug Interactions Characterization of Inhibitor Binding in Complexes of DHFR with Trimethoprim and Related Derivatives. 

Multiple conformations have been detected in several other complexes of L. easel DHFR (for example, with NADP and trimethoprim, and with substituted pyrimethamines) and also in complexes with 5. faeelum DHFR and E. eoU DHFR it seems likely that many other protein ligand complexes will exist as mixtures of conformations. Of course, such conformations are more difficult to detect directly if they are in fast exchange. 

E. coli enzyme. But, studies on the chicken liver enzyme may not be relevant to the human enzyme. Indeed, crystal studies of Oefner et al. (1988) on complexes of human DHFR with folate, methotrexate and trimethoprim itself do not support the explanation given by Matthews, and so we are still not sure of the basis for the species selectivity exhibited by trimethoprim. 

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. 

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