Document Detail


Evidence for a common intermediate in insulin deamidation and covalent dimer formation: effects of pH and aniline trapping in dilute acidic solutions.
MedLine Citation:
PMID:  7616363     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The effects of pH and aniline trapping on the partitioning of the A-21 cyclic anhydride intermediate of human insulin into deamidated insulin and covalent dimer were investigated at low pH and 35 degrees C. Characterization of the covalent dimer was achieved by proteolytic cleavage and electrospray mass spectrometry and indicated that the deamidated A-21 asparagine of one insulin molecule and the B-1 phenylalanine residue of another are involved. Anhydride trapping with aniline at pH 4.0 provided evidence that the rate-limiting generation of a cyclic anhydride intermediate is involved in the formation of both deamidated and dimeric insulin. In the presence of aniline at pH 4.0 insulin formed two anilide products, A-21 N delta 2-phenylasparagine and N delta 2-phenylasparagine and N gamma 2-phenylaspartic acid human insulin at the expense of both desamido A-21 and covalent dimer formation, consistent with the formation of a common intermediate. At 35 degrees C and under conditions where the insulin monomer predominates, the fraction of insulin reacting to form [desamidoA-21] insulin decreased with a concurrent increase in formation of [desamidoA-21-PheB-1] dimer with an increase in pH from 2.0 to 5.0. The pH dependence of insulin product distribution could not be quantitatively rationalized solely in terms of the fraction of the PheB-1 amine group in un-ionized form. Rather, consideration of the charge states of ionizable residues near the reacting groups was necessary to fully account for the observed pH effects on product formation.
Authors:
R T Darrington; B D Anderson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of pharmaceutical sciences     Volume:  84     ISSN:  0022-3549     ISO Abbreviation:  J Pharm Sci     Publication Date:  1995 Mar 
Date Detail:
Created Date:  1995-08-23     Completed Date:  1995-08-23     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985195R     Medline TA:  J Pharm Sci     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  275-82     Citation Subset:  IM    
Affiliation:
Department of Pharmaceuticals and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Salt Lake City 84112, USA.
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MeSH Terms
Descriptor/Qualifier:
Aniline Compounds*
Chemistry, Pharmaceutical
Chromatography, High Pressure Liquid
Hydrogen-Ion Concentration*
Insulin / analogs & derivatives,  chemistry*
Kinetics
Mathematics
Solutions
Time Factors
Chemical
Reg. No./Substance:
0/Aniline Compounds; 0/Solutions; 11061-68-0/Insulin; 62-53-3/aniline

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


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