Document Detail


Multiple determinants for the high substrate specificity of an angiotensin II-forming chymase from the human heart.
MedLine Citation:
PMID:  1918036     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Human heart chymase, a chymotrypsin-like serine proteinase that hydrolyzes the Phe8-His9 bond in angiotensin I (Ang I) to yield the octapeptide hormone angiotensin II (Ang II) and His-Leu, is the most specific, efficient Ang II-forming enzyme described. Other mammalian chymases display a much broader substrate specificity. To better define its substrate specificity, we have mapped the extended substrate-binding site of human heart chymase using Ang I analogs. The enzyme has a preference for aromatic amino acids phenylalanine, tyrosine, and tryptophan at the P1 site. At the S2 subsite there is a significant preference for proline over hydrophobic or hydrophilic amino acids. There is no clear preference for hydrophobic or hydrophilic amino acids at the S'1 and S'2 subsites, but an Ang I analog containing a P'1 proline is not hydrolyzed and one with a P'2 proline is hydrolyzed poorly. An increasing reduction in reactivity occurs when the P position amino acids in Ang I are deleted sequentially from the N terminus. An increase or decrease in the length of the His-Leu leaving group also produces a marked decrease in reactivity. No single determinant in Ang I is preeminently required for efficient catalysis, but several factors acting synergistically appear to be important. Thus, we propose that ideal substrates for human heart chymase should contain the structure nXaa-Pro-[Phe, Tyr, or Trp]-Yaa-Yaa, where n greater than or equal to 6; Xaa = any amino acid; Yaa = any amino acid except proline. This structure exists in Ang I and neurotensin, both of which are good substrates for human heart chymase. These findings indicate that the selection of the scissile bond by the extended substrate-binding site of human heart chymase is more restricted than that in other chymases.
Authors:
A Kinoshita; H Urata; F M Bumpus; A Husain
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  266     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1991 Oct 
Date Detail:
Created Date:  1991-11-14     Completed Date:  1991-11-14     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  19192-7     Citation Subset:  IM    
Affiliation:
Department of Heart and Hypertension Research, Research Institute of the Cleveland Clinic Foundation, Ohio 44195-5069.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Angiotensin II / metabolism*
Chymases
Humans
Hydrolysis
Kinetics
Molecular Sequence Data
Myocardium / enzymology*
Neurotensin / metabolism
Sequence Homology, Nucleic Acid
Serine Endopeptidases / metabolism*
Substrate Specificity
Grant Support
ID/Acronym/Agency:
HL 33713/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
11128-99-7/Angiotensin II; 39379-15-2/Neurotensin; EC 3.4.21.-/Serine Endopeptidases; EC 3.4.21.39/Chymases

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


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