Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protease of human immunodeficiency virus (HIV) has been extensively studied. The structure and function relationships of this protease and its role in HIV life cycle is well known. We have use recombinant HIV protease and mutagenesis technology to study HIV protease and compare it to the eukaryotic aspartic proteases. When putative active-site hydrogen bonds are placed in the HIV protease, the pKa values of two active-site groups are only slightly downshifted. Corresponding removal of these H-bonds from the active sites of pepsin and rhizopuspepsin do not appreciably alter the active-site pKa values. The Kcat values are strongly decreased by these mutations. These observations suggest that the active-site H-bonds in HIV protease and other aspartic proteases control the rigidity of the catalytic apparatus but not the ionization of the active-site groups. A mechanism of catalysis by the HIV protease has been suggested based on kinetic and mutagenesis studies. The strategies involved in the development of HIV protease inhibitors are discussed. In spite of the pitfalls in each approach, it appears probable that a battery of inhibitors can be developed for the treatment of AIDS.
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PMID:Understanding HIV protease: can it be translated into effective therapy against AIDS? 145 75

The pH dependence of the kinetic parameters of pepsin, rhizopuspepsin, and their active-site hydrogen bond mutants has been determined. These data have permitted the calculation of two active-site ionization constants in the free enzymes (pKe1 and pK32) and in the enzyme-substrate complexes (pKes1 and pKes2). The pKe1 of rhizopuspepsin (2.8) is near that of a normal carboxyl group and near the pKe1 of human immunodeficiency virus type 1 (HIV-1) protease (3.32) (Ido, E., Han, H. P., Kezdy, F. J., and Tang, J. (1991) J. Biol. Chem. 266, 24359-24366). The pKe1 of pepsin (1.57) is thus abnormally low. The pKe2 of rhizopuspepsin (4.44) is lower than that of pepsin (5.02) and HIV protease (6.80). The binding of substrate to rhizopuspepsin causes the lowering of pKes1 to 1.8 and the elevating of pKes2 to above 6. The pK alpha shifts due to substrate binding are much less pronounced in pepsin. Thus, the two enzyme-substrate complexes have similar pK alpha values. For both pepsin and rhizopuspepsin, the removal of hydrogen bonds to the active-site carboxyls by mutagenesis results in negligible changes in the four pK alpha values. The major alteration caused by these mutations is the decrease in kcat values, while there is little change in Km. These observations suggest that these hydrogen bonds to the active-site aspartyls contribute little to the pH-activity relationships of the aspartic proteases. The role of the active-site hydrogen bonds may well be to preserve the conformational rigidity of the catalytic apparatus.
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PMID:pH dependence of kinetic parameters of pepsin, rhizopuspepsin, and their active-site hydrogen bond mutants. 152 82

The human immunodeficiency virus (HIV-1) encodes a protease that is essential for viral replication and is a member of the aspartic protease family. The recently determined three-dimensional structure of the related protease from Rous sarcoma virus has been used to model the smaller HIV-1 dimer. The active site has been analyzed by comparison to the structure of the aspartic protease, rhizopuspepsin, complexed with a peptide inhibitor. The HIV-1 protease is predicted to interact with seven residues of the protein substrate. This information can be used to design protease inhibitors and possible antiviral drugs.
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PMID:Molecular modeling of the HIV-1 protease and its substrate binding site. 253 31