Linked Life Data

16159284

Source:http://linkedlifedata.com/resource/pubmed/id/16159284

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
37
pubmed:dateCreated
2005-9-14
pubmed:abstractText
Human cytochromes P450 play a vital role in drug metabolism. The key step in substrate oxidation involves hydrogen atom abstraction or C=C bond addition by the oxygen atom of the Compound I intermediate. The latter has three unpaired electrons, two on the Fe-O center and one shared between the porphyrin ring and the proximal cysteinyl sulfur atom. Changes in its electronic structure have been suggested to affect reactivity. The electronic and geometric structure of Compound I in three important human subfamilies of cytochrome P450 (P450, 2C, 2B, and 3A) that are major contributors to drug metabolism is characterized here using combined quantum mechanical/molecular mechanical (QM/MM) calculations at the B3LYP:CHARMM27 level. Compound I is remarkably similar in all isoforms, with the third unpaired electron located mainly on the porphyrin ring, and this prediction is not very sensitive to details of the QM/MM methodology, such as the DFT functional, the basis set, or the size of the QM region. The presence of substrate also has no effect. The main source of variability in spin density on the cysteinyl sulfur (from 26 to 50%) is the details of the system setup, such as the starting protein geometry used for QM/MM minimization. This conformational effect is larger than the differences between human isoforms, which are therefore not distinguishable on electronic grounds, so it is unlikely that observed large differences in substrate selectivity can be explained to a large extent in these terms.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0002-7863
pubmed:author
pubmed:issnType
Print
pubmed:day
21
pubmed:volume
127
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
12900-8
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Electronic structure of compound I in human isoforms of cytochrome P450 from QM/MM modeling.
pubmed:affiliation
Centre for Computational Chemistry, School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS United Kingdom.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't