Reference : Active-site-directed inactivators of the Zn2+-containing D-alanyl-D-alanine-cleaving ...
Scientific journals : Article
Physical, chemical, mathematical & earth Sciences : Chemistry
Human health sciences : Pharmacy, pharmacology & toxicology
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/2268/78089
Active-site-directed inactivators of the Zn2+-containing D-alanyl-D-alanine-cleaving carboxypeptidase of Streptomyces albus G.
English
Charlier, Paulette mailto [Université de Liège - ULg > Faculté de Médecine, Institut de Chimie > Service de Microbiologie > >]
Dideberg, Otto [Université de Liège - ULg > Faculté des Sciences, Institut de Physique > Service de Cristallographie > > >]
Jamoulle, Jean-Claude [Université de Liège - ULg > Faculté des Médecine, Institut de Pharmacie > Service de Chimie Analytique > >]
Frère, Jean-Marie mailto [Université de Liège - ULg > Faculté de Médecine, Institut de Chimie > Service de Microbiologie > >]
Ghuysen, Jean-Marie [Université de Liège - ULg > Faculté de Médecine, Institut de Chimie > Service de Microbiologie > > >]
Dive, Georges mailto [Université de Liège - ULg > Faculté des Médecine, Institut de Pharmacie > Service de Chimie Analytique > >]
Lamotte, Josette mailto [Université de Liège - ULg > Faculté des Sciences, Institut de Physique > Service de Cristallographie > >]
1984
Biochemical Journal
Portland Press
219
3
763-772
Yes (verified by ORBi)
International
0264-6021
1470-8728
London
United Kingdom
[en] Binding Sites/drug effects ; Carboxypeptidases/antagonists & inhibitors ; Gold/pharmacology ; Iridium/pharmacology ; Metals/pharmacology ; Models, Molecular ; Platinum/pharmacology ; Streptomyces/enzymology ; Uranium/pharmacology ; X-Ray Diffraction
[en] Several types of active-site-directed inactivators (inhibitors) of the Zn2+-containing D-alanyl-D-alanine-cleaving carboxypeptidase were tested. (i) Among the heavy-atom-containing compounds examined, K2Pt(C2O4)2 inactivates the enzyme with a second-order rate constant of about 6 X 10(-2)M-1 X S-1 and has only one binding site located close to the Zn2+ cofactor within the enzyme active site. (ii) Several compounds possessing both a C-terminal carboxylate function and, at the other end of the molecule, a thiol, hydroxamate or carboxylate function were also examined. 3-Mercaptopropionate (racemic) and 3-mercaptoisobutyrate (L-isomer) inhibit the enzyme competitively with a Ki value of 5 X 10 X 10(-9)M. (iii) Classical beta-lactam compounds have a very weak inhibitory potency. Depending on the structure of the compounds, enzyme inhibition may be competitive (and binding occurs to the active site) or non-competitive (and binding causes disruption of the protein crystal lattice). (iv) 6-beta-Iodopenicillanate inactivates the enzyme in a complex way. At high beta-lactam concentrations, the pseudo-first-order rate constant of enzyme inactivation has a limit value of 7 X 10(-4)S-1 X 6-beta-Iodopenicillanate binds to the active site just in front of the Zn2+ cofactor and superimposes histidine-190, suggesting that permanent enzyme inactivation is by reaction with this latter residue.
Researchers ; Professionals
http://hdl.handle.net/2268/78089
also: http://hdl.handle.net/2268/97423

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