Enzyme inhibition polypeptide protease inhibitors

A straightforward approach is to hunt for short polypeptides that meet the specificity requirement of an enzyme but which, because of peculiarities of the sequence, are acted upon very slowly. Such a peptide may contain unusual or chemically modified amino acids. For example, the peptide Thr-Pro-nVal-NMeLeu-Tyr-Thr (nVal=norvaline NMeLeu = N-methylleucine) is a very slow elastase substrate whose binding can be studied by X-ray diffraction and NMR spectroscopy.6 Thiol proteases are inhibited by succinyl-Gln-Val-Val-Ala-Ala-p-nitroanilide, which includes a sequence common to a number of naturally occurring peptide inhibitors called cystatins.f They are found in various animal tissues where they inhibit cysteine proteases. 

In the life cycle of HIV, its RNA is translated into a polypeptide chain that is composed of several individual proteins including protease, integrase and reverse transcriptase, but in this form these enzymes are not functional. They must be cleaved by viral proteases from the assembled sequence in order for them to become functional. These posttranslational modifications allow the enzymes to facilitate the production of new viruses. The protease itself is made up of two 99-amino-acid monomers, and an aspartic acid residue in the monomer is required for the cleavage. The protease inhibitors inhibit the enzyme protease and consequently interfere with viral replication and maturation by preventing proteases from cleaving proteins into peptides. In humans, these drugs inhibit cleavage of HIV gag and pol polyproteins, which are part of the essential viral structural components, P7, P9, P17 and P24, and... 

Protease inhibitors, which are important from the nutritional point of view, are proteins or polypeptides capable of inhibiting the digestive enzymes proteases. 

Both the 26S proteasome and the RC hydrolyze all four nucleotide triphosphates, with ATP and CTP preferred over GTP and UTP [58]. Although ATP hydrolysis is required for conjugate degradation, the two processes are not strictly coupled. Complete inhibition of the peptidase activity of the 26S proteasome by calpain inhibitor I has little effect on the ATPase activity of the enzyme. The nucleotidase activities of the RC and the 26S proteasome closely resemble those of E. coli Lon protease, which is composed of identical subunits that possess both proteolytic and nucleotidase activities in the same polypeptide chain. Like the regulatory complex and 26S proteasome, Lon hydrolyzes all four ribonucleotide triphosphates, but not ADP or AMP [18]. 

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