Dihydrofolate reductase properties

Methotrexate is an antimetabolite of folic acid and has immunosuppressant properties. It inhibits the enzyme dihydrofolate reductase that is required for the synthesis of purines and pyrimidines. It is used in malignant disease, Crohn s disease, rheumatic disease and psoriasis. Folic acid is given with methotrexate to reduce the occurrence of side-effects particularly the risk of mucositis. 

Some of the structural properties which have been ascribed to DA receptors appear to deserve attention for their heuristic value, but painfully few should engender much confidence in their reality. A sobering lesson is available from analysis of complexes of dihydrofolate reductase (], 8). Methotrexate is a very close analog of folic acid and is a potent inhibitor of the enzyme, but it is now almost certain that these ligands bind in the enzyme active site in aspects differing by a rota-... 

Several additional lines of evidence indicate that presequence function is governed by conformational properties of the precursor. The target peptide of yeast mitochondrial cytochrome oxidase subunit IV (COX), fused to murine dihydrofolate reductase (DHFR, a cytoplasmic enzyme). 

Structural, Conformational, and Electronic Properties of Antifolate Inhibitors of Dihydrofolate Reductase. ... 

Methotrexate is a foUc acid antagonist that acts by inhibiting dihydrofolate reductase. Owing to its immunosuppressive and anti-inflammatory properties, low-dosage methotrexate (7.5-15 mg/week) has been extensively investigated for other therapeutic purposes characterized by inflammation or cellular proliferation. Since the mid-... 

Because of its significance in cancer therapy and its small size, dihydrofolate reductase is one of the most studied of all enzymes. Numerous NMR studies " and investigations of catalytic mechanism and of other properties have been conducted. Many mutant forms have been created. For example, substitution of Asp 27 (Asp 26 in L. casei) of the E. coli... 

FIGURE 6-4 Complementary shapes of a substrate and its binding site on an enzyme. The enzyme dihydrofolate reductase with its substrate NADP" (red), unbound (top) and bound (bottom). Another bound substrate, tetrahydrofolate (yellow), is also visible (PDB ID 1 RA2).The NADP binds to a pocket that is complementary to it in shape and ionic properties. In reality, the complementarity between protein and ligand (in this case substrate) is rarely perfect, as we saw in Chapter 5. The interaction of a protein with a ligand often involves changes in the conformation of one or both molecules, a process called induced fit. This lack of perfect complementarity between enzyme and substrate (not evident in this figure) is important to enzymatic catalysis. 

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