Rate-determining steps in HIV-1 protease catalysis. The hydrolysis of the most specific substrate.

The Journal of Biological Chemistry
Z Szeltner, L Polgár

Abstract

The human immunodeficiency virus type-1 (HIV-1) encodes a protease which is essential for the production of infectious virus. The protease prefers substrates that contain glutamic acid or glutamine at the P2' position. The catalytic role of these residues has been studied by using a highly specific fluorogen substrate, 2-aminobenzoyl-Thr-Ile-Nle-Phe(NO2)-Gln-Arg (substrate QR), and its counterpart (substrate ER) containing Glu in place of Gln. The newly designed substrate ER that contains a pair of charged residues at P2' and P3' sites is the most specific substrate described so far for HIV-1 protease. The specificity rate constant (kcat/Km = 2.1 x 10(7) M-1 s-1) approaches, but does not reach, the diffusion limit. This follows from the appreciable solvent kinetic deuterium isotope effects on the rate constants, indicating that, independent of the salt concentration, the rate-limiting step of the catalysis is a chemical process rather than a physical one. The reaction also has positive entropy of activation. On the other hand, the rate-limiting step for substrate QR changes with increasing salt concentration from a physical to chemical step, while the negative activation entropy becomes positive. The rate increase with substrat...Continue Reading

References

Dec 1, 1990·International Journal of Peptide and Protein Research·M V Toth, G R Marshall
Jul 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·E Z BaumY Gluzman
Jan 1, 1995·Methods in Enzymology·R G Duggleby
Jan 1, 1994·Methods in Enzymology·B M DunnJ Kay
Jan 1, 1993·Annual Review of Biochemistry·A Wlodawer, J W Erickson
Sep 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·L TongP C Anderson
Jan 1, 1965·Annual Review of Biochemistry·M L BENDER, J KEZDY

❮ Previous
Next ❯

Citations

Apr 12, 2012·Proceedings of the National Academy of Sciences of the United States of America·D Randal KippVern L Schramm
Sep 19, 2002·Protein Science : a Publication of the Protein Society·Stefano PianaUrsula Rothlisberger
Mar 14, 2007·PLoS Computational Biology·Aleksejs KontijevskisJarl E S Wikberg
Jun 23, 2009·Bioorganic & Medicinal Chemistry·Aleksejs KontijevskisJarl E S Wikberg
Feb 23, 2007·Chemical Biology & Drug Design·Chia-En A ChangJ Andrew McCammon
Aug 21, 2015·Chemical Communications : Chem Comm·Yun-Kun QiJi-Shen Zheng
May 22, 2002·Bioorganic Chemistry·Julie J HaSuzanne Beckham Shuker
Jun 14, 2016·Journal of Structural Biology·Rosemberg O SoaresPedro G Pascutti
Dec 10, 2016·Journal of the American Chemical Society·Agnieszka KrzemińskaKatarzyna Świderek
Jul 4, 2018·Acta Crystallographica. Section D, Structural Biology·Ian W Windsor, Ronald T Raines
May 16, 2017·Biochemistry·Rajeswari Appadurai, Sanjib Senapati

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.