Linked Life Data

8049236

Source:http://linkedlifedata.com/resource/pubmed/id/8049236

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
31
pubmed:dateCreated
1994-9-8
pubmed:abstractText
The most preferred residue in the substrates of human immunodeficiency virus (HIV-1) protease is glutamic acid in the P2' position. The catalytic importance of this charged residue has been studied to obtain a detailed insight into the mechanism of action, which will promote drug design to combat the virus. To this end, we have synthesized Lys-Ala-Arg-Val-Leu*Phe(NO2)-Glu-Ala-Nle (substrate E) and its counterpart containing the neutral Gln (substrate Q) in place of Glu. Kinetic analyses have shown that the specificity rate constants (kcat/Km) display bell-shaped pH dependencies for both substrates, but the pH-independent limiting value is 35-40-fold higher with substrate E than with substrate Q. In contrast to the pH-rate profiles of kcat/Km, there is a striking difference between the pH dependencies of Km and kcat for the two substrates. This indicates different ground state and transition state stabilizations in the two reactions. Solvent kinetic deuterium isotope effects show that the rate-limiting step for the hydrolysis of substrate E is a chemical step coupled with proton transfer whereas with substrate Q it is a physical step, presumably a conformational change. Accordingly, the charged residue in P2' alters the rate-limiting step and the nature of the enzyme-substrate complex, resulting in different mechanisms for the two substrates.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
9
pubmed:volume
33
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
9351-7
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1994
pubmed:articleTitle
Substrate-dependent mechanisms in the catalysis of human immunodeficiency virus protease.
pubmed:affiliation
Institute of Enzymology, Hungarian Academy of Sciences, Budapest.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't