Document Detail


Role of divalent metals in the kinetic mechanism of insulin receptor tyrosine kinase.
MedLine Citation:
PMID:  2833165     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The kinetic and thermodynamic interrelationships of peptide substrate (Val5-angiotensin 11), metal-ATP, and divalent metal cations with rat liver insulin receptor tyrosine kinase (IRTK) were investigated. Results of the initial rate studies with varying peptide and MnATP substrates indicates that the kinetic mechanism for IRTK is of the sequential type and therefore rules out a ping pong Bi Bi pathway. Hence, peptide substrate and metal-ATP bind to the kinase prior to the release of products. MnADP was a linear competitive inhibitor of MnATP and a noncompetitive inhibitor of peptide substrate. A synthetic tyrosine-containing pentapeptide, Glu-Glu-Phe-Tyr-Phe (EEFYF), was a linear competitive inhibitor of peptide substrate and a noncompetitive inhibitor of MnATP. Accordingly, the data show that phosphorylation of peptide substrate occurs via a rapid random equilibrium Bi Bi mechanism in which the kinase has the potential to react initially with either of the two substrates. In contrast, divalent metal cations and metal-ATP were found to interact with the kinase in a mutually inclusive manner, with metal binding to the kinase prior to MnATP. It was also found that divalent metals increase the affinity of the kinase for metal-ATP but do not affect the affinity of IRTK for metal-ADP product. Hence, divalent metals, during the reaction of association of enzyme with one of its substrates to form the binary complex, increase the relative concentration of E-ATP complex versus E-peptide complex, thus introducing a thermodynamic-dependent ordering for the interaction of substrates with the enzyme. To investigate the thermodynamics of this system, we assumed that under initial conditions the kinetic data we obtained reflected the association constants of reactants with the enzyme.
Authors:
P P Vicario; R Saperstein; A Bennun
Related Documents :
19696785 - Hsp90 is regulated by a switch point in the c-terminal domain.
23959225 - Discovery of a potent benzoxaborole-based anti-pneumococcal agent targeting leucyl-trna...
21592965 - Structural and biochemical studies on the regulation of biotin carboxylase by substrate...
7798215 - Investigation of the active site and the conformational stability of nucleoside diphosp...
8917315 - Genetic analysis of functional connectivity between substrate recognition domains of es...
19304935 - Characterization of solanum tuberosum multicystatin and its structural comparison with ...
Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Archives of biochemistry and biophysics     Volume:  261     ISSN:  0003-9861     ISO Abbreviation:  Arch. Biochem. Biophys.     Publication Date:  1988 Mar 
Date Detail:
Created Date:  1988-04-27     Completed Date:  1988-04-27     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0372430     Medline TA:  Arch Biochem Biophys     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  336-45     Citation Subset:  IM    
Affiliation:
Rutgers State University, Department of Biological Sciences, Newark, New Jersey 07102.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism
Angiotensin II / analogs & derivatives,  metabolism
Animals
Cations, Divalent
Enzyme Activation / drug effects
Insulin / pharmacology
Kinetics
Male
Metals / metabolism*
Peptides / metabolism
Phosphorylation
Protein-Tyrosine Kinases / metabolism*
Rats
Receptor, Insulin / metabolism
Thermodynamics
Grant Support
ID/Acronym/Agency:
RR070509-21/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Cations, Divalent; 0/Metals; 0/Peptides; 11061-68-0/Insulin; 11128-99-7/Angiotensin II; 53-75-8/angiotensin II, Asp(1)-Val(5)-; 56-65-5/Adenosine Triphosphate; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.1/Receptor, Insulin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  The effectiveness of inhibitors of soluble prolyl hydroxylase against the enzyme in the cisternae of...
Next Document:  Oxygen radical-mediated lipid peroxidation and inhibition of Ca2+-ATPase activity of cardiac sarcopl...