Document Detail


Molecular basis for the omega-regiospecificity of the CYP4A2 and CYP4A3 fatty acid hydroxylases.
MedLine Citation:
PMID:  10869363     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The CYP4A fatty acid omega-hydroxylases are involved in important physiological processes such as the regulation of vascular pressure. A previous study of chimeras of the rat CYP4A2 and CYP4A3 enzymes established that the regiochemistry of fatty acid hydroxylation is determined by the first 119 amino acid residues (Hoch, U., Zhang. Z. P., Kroetz, D. L., and Ortiz de Montellano, P. R. (2000) Arch. Biochem. Biophys. 373, 63-71). The role of the individual amino acid differences in this region has therefore been examined by site-specific mutagenesis to determine which residues actually control the omega- versus (omega-1)-regiospecificity. The results indicate that regiospecificity is controlled by the presence or absence of a three-residue insert (Ser-114, Gly-115, Ile-116) in CYP4A3 and by the residue at position 119 (CYP4A3 numbering). Furthermore, analysis of the absolute stereochemistry of the 11-hydroxylauric acid product indicates that this stereochemistry is not very sensitive to changes in the residues that line the substrate access channel. These results define a model of the specificity determinants of an important class of cytochrome P450 enzymes.
Authors:
U Hoch; J R Falck; P R de Montellano
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  275     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2000 Sep 
Date Detail:
Created Date:  2000-10-03     Completed Date:  2000-10-03     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:  26952-8     Citation Subset:  IM    
Affiliation:
Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143-0446, USA.
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MeSH Terms
Descriptor/Qualifier:
Alkane 1-Monooxygenase
Amino Acid Sequence
Animals
Base Sequence
Catalysis
Chromatography, High Pressure Liquid
Cytochrome P-450 Enzyme System / chemistry,  genetics,  metabolism*
DNA Primers
Lauric Acids / metabolism
Mixed Function Oxygenases / chemistry,  genetics,  metabolism*
Molecular Sequence Data
Mutagenesis, Site-Directed
Rats
Sequence Homology, Amino Acid
Stereoisomerism
Substrate Specificity
Grant Support
ID/Acronym/Agency:
GM25515/GM/NIGMS NIH HHS; GM31278/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/DNA Primers; 0/Lauric Acids; 143-07-7/lauric acid; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.-/Mixed Function Oxygenases; EC 1.14.15.3/Alkane 1-Monooxygenase

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


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