Linked Life Data

8130207

Source:http://linkedlifedata.com/resource/pubmed/id/8130207

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
1994-4-18
pubmed:abstractText
Cytochrome P450 systems are unusual in that many of them can convert a substrate to a number of different metabolites by several possible kinetic mechanisms. Steady-state equations describing the deuterium isotope effects for mechanisms in which different orientations of the substrate relative to the perferryl oxygen in the active site of the enzyme are achieved before a hydrogen (or possibly an electron) is abstracted have been derived and solved (Gillette et al., 1994). These equations have been used to elucidate the kinetic mechanisms by which CYP2C11 converts testosterone to 2 alpha-hydroxytestosterone on the one hand and 16 alpha-hydroxytestosterone and androstenedione on the other. We have synthesized testosterone-2,2,4,6,6-2H5 and compared its metabolism by CYP2C11 with that of nondeuterated testosterone. In this system, deuterated 2 alpha-hydroxytestosterone would be formed by a deuterium abstraction pathway via the active oxygen intermediate (EOSw) and the D-ring metabolites would be formed by non-deuterium abstraction pathways from active oxygen intermediates represented by (EOSx). The results revealed that testosterone in the activated enzyme-substrate complexes, (EOSw) and (EOSx), does not change orientations while it is in the active site of CYP2C11. Instead, two of the noncompetitive experiments indicated that testosterone is able to dissociate from the (EOS) complexes and reassociate in either the same or different orientations. A third noncompetitive experiment suggested that testosterone in the (EOS) complexes does not change orientations while it is in the active site of CYP2C11, nor does it dissociate from the (EOS) complexes; instead, the pattern of metabolite formation is governed almost solely by the orientation of testosterone in the (ESw) and ESx) complexes.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
33
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2938-44
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1994
pubmed:articleTitle
Deuterium isotope effects on A-ring and D-ring metabolism of testosterone by CYP2C11: evidence for dissociation of activated enzyme-substrate complexes.
pubmed:affiliation
Laboratory of Chemical Pharmacology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
pubmed:publicationType
Journal Article, Comparative Study