Linked Life Data

10024026

Source:http://linkedlifedata.com/resource/pubmed/id/10024026

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
1999-4-23
pubmed:abstractText
Although both bacterial CYP102 (P450BM3) and mammalian CYP4A isozymes share a common function as fatty acid hydroxylases, distinctly different preferred sites of oxidation are observed with the CYP102 performing the usual non-terminal hydroxylation or epoxidation and the CYP4A enzymes performing the unusual and enigmatic terminal hydroxylation. The origin of this unique product specificity in human CYP4A11 has been explored in this work, focusing on possible differences in the binding site architecture of the two isozymes as the cause. To this end, 3D model structures of the human CYP4A11 enzyme were built and compared to the X-ray structure of CYP102. The substrate-binding channel identified in CYP4A11 was found to have a much more sterically restricted active site than that in CYP102 that could cause limited access of long-chain fatty acid to the ferryl oxygen leading to the preferred omega-hydroxylation. Results of docking of a common substrate, lauric acid, into the binding site of both CYP4A11 and CYP102 and molecular dynamics simulations provided additional support for this hypothesis. Specifically, in the CYP4A11-lauric acid simulations, the omega hydrogens were closest to the ferryl oxygen most of the time. By contrast, in the CYP102-lauric acid complex, the substrate could penetrate further into the active site providing access of the non-terminal (omega-1, omega-2) positions to the ferryl oxygen. These results, taken together, have elucidated the origin of the unusual product specificity of CYP4A11 and illustrated the central role of binding site architecture in subtle modulation of function.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0887-3585
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
34
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
403-15
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:10024026-Alkane 1-Monooxygenase, pubmed-meshheading:10024026-Amino Acid Sequence, pubmed-meshheading:10024026-Binding Sites, pubmed-meshheading:10024026-Computer Simulation, pubmed-meshheading:10024026-Conserved Sequence, pubmed-meshheading:10024026-Crystallography, X-Ray, pubmed-meshheading:10024026-Cytochrome P-450 Enzyme System, pubmed-meshheading:10024026-Humans, pubmed-meshheading:10024026-Lauric Acids, pubmed-meshheading:10024026-Ligands, pubmed-meshheading:10024026-Mixed Function Oxygenases, pubmed-meshheading:10024026-Models, Molecular, pubmed-meshheading:10024026-Molecular Sequence Data, pubmed-meshheading:10024026-Protein Binding, pubmed-meshheading:10024026-Sequence Alignment, pubmed-meshheading:10024026-Software, pubmed-meshheading:10024026-Substrate Specificity
pubmed:year
1999
pubmed:articleTitle
Homology modeling and substrate binding study of human CYP4A11 enzyme.
pubmed:affiliation
Molecular Research Institute, Palo Alto, California 94304, USA. chang@purisima.molres.org
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S.