Three-dimensional structures dihydrofolate reductase

The dihydrofolate reductase enzyme (DHFR) is involved in one-carbon metabolism and is required for the survival of prokaryotic and eukaryotic cells. The enzyme catalyzes the reduction of dihydrofolate to tetrahydrofolate, which is required for the biosynthesis of serine, methionine, purines, and thymidylate. The mouse dihydrofolate reductase (mDHFR) is a small (21 kD), monomeric enzyme that is highly homologous to the E. coli enzyme (29% identify) (Pelletier et al., 1998). The three-dimensional structure of DHFR indicates that it is comprised of three structural fragments F[l], F[2] andF[3] (Gegg etal., 1997). 

During thymine formation the coenzyme is oxidized to dihydrofolate, which must be reduced by dihydrofolate reductase to complete the catalytic cycle. A possible mechanistic sequence for thymidylate synthase, an enzyme of known three-dimensional structure,354/418-4213 is given in Fig. 15-21. In the first step (a) a thiolate anion, from the side chain of Cys 198 of the 316-residue Lactobacillus enzyme, adds to the 5 position of the substrate 2 -deoxyuridine monophosphate... 

Thiosulfate cyanide sulfurtransferase symmetry in 78 TTiiouridine 234 Three-dimensional structures of aconitase 689 adenylate kinase 655 aldehyde oxido-reductase 891 D-amino acid oxidase 791 a-amylase, pancreatic 607 aspartate aminotransferase 57,135 catalytic intermediates 752 aspartate carbamyltransferase 348 aspartate chemoreceptor 562 bacteriophage P22 66 cadherin 408 calmodulin 317 carbonic acid anhydrase I 679 carboxypeptidase A 64 catalase 853 cholera toxin 333, 546 chymotrypsin 611 citrate synthase 702, 703 cutinase 134 cyclosporin 488 cytochrome c 847 cytochrome c peroxidase 849 dihydrofolate reductase 807 DNA 214, 223,228,229, 241 DNA complex... 

R. Li, R. Sirawarapom, P. Chitnumsub, W. Sirawarapom, J. Wooden, F. Athappilly, S. Turley, and W.G. Hoi. 2000. Three-dimensional structure ofM tuberculosis dihydrofolate reductase reveals opportunities for the design of novel tuberculosis drugs J. Mol. Biol. 295 307-323. (PubMed)... 

FIGURE 1.23 Three-dimensional structures of two proteins, ch)miotrypsin (top) and di-hydrofolate reductase (bottom). Dihydrofolate reductase is shown not in its natural state, but with a drug molecule bound to its surface. [Reprinted by permission from Nature 214, 652-656 (cop)ndght 1967 Macnvillan Magazines Limited) and Science 197,452 (cop)night 1977 by the AAAS (London)).]... 

The three dimensional structure of dihydrofolate reductase colored by its surface potential. Positive values are depicted in red, negative values in blue. 

Some of the early attempts that were successful may be illustrative. Trimethoprin (TM) has been known as a useful inhibitor of dihydrofolate reductase (DHFR) since the mid-1960s. The enzyme s three-dimensional structure had also been fully characterized by X-ray crys-... 

A review is given of the application of Molecular Dynamics (MD) computer simulation to complex molecular systems. Three topics are treated in particular the computation of free energy from simulations, applied to the prediction of the binding constant of an inhibitor to the enzyme dihydrofolate reductase the use of MD simulations in structural refinements based on two-dimensional high-resolution nuclear magnetic resonance data, applied to the lac repressor headpiece the simulation of a hydrated lipid bilayer in atomic detail. The latter shows a rather diffuse structure of the hydrophilic head group layer with considerable local compensation of charge density. 

Sutherland, J., Weaver, D.F. Three-dimensional Quantitative Structure-Activity and Structure-Selectivity Relationships of Dihydrofolate Reductase Inhibitors./. Comput.-Aided Mol. Des. 2004, 18, 309-331. 

Ghose, A.K. and Crippen, G.M. (1985b). Use of Physicochemical Parameters in Distance Geometry and Related Three-Dimensional Quantitative Structure-Activity Relationships A Demonstration Using Escherichia coli Dihydrofolate Reductase Inhibitors. J.MecLChem., 28, 333-346. 

Sutherland, J.J. and Weaver, D.F. (2004) Three-dimensional quantitative structure-activity and structure-selectivity relationships of dihydrofolate reductase inhibitors. J. Comput. Aid. Mol. Des., 18, 309-331. 

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