MECHANISTIC STUDIES ON AROMATASE AND RELATED C-C BOND CLEAVING P-450 ENZYMES

被引:126
|
作者
AKHTAR, M
NJAR, VCO
WRIGHT, JN
机构
[1] Department of Biochemistry, University of Southampton, Highfield, Southampton
来源
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY | 1993年 / 44卷 / 4-6期
基金
英国惠康基金;
关键词
D O I
10.1016/0960-0760(93)90241-N
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Some P-450 systems, notably aromatase and 14alpha-demethylase catalyse not only the hydroxylate reaction but also the oxidation of an alcohol into a carbonyl compound as well as a C-C bond cleavage process. All these reactions occur at the same active site. A somewhat analogous situation is noted with 17alpha-hydroxylase-17,20-lyase that participates in hydroxylation as well as C-C bond cleavage process. The C-C bond cleavage reactions catalysed by the above enzymes conform to the general equation: [GRAPHICS] It is argued that all three types of reaction catalyzed by these enzymes may be viewed as variations on a common theme. In P-450 dependent hydroxylation the initially formed Fe(III)-O-O' species is converted into Fe(III)-O-OH and the heterolysis of the oxygen-oxygen bond of the latter then gives the oxo-derivative for which a number of canonical structures are possible; for example Fe(V) = O <-- --> (+.)Fe(IV) = O <-- --> Fe(IV)-O.. One of these, Fe(IV)-O. behaves like an alkoxyl radical and participates in hydrogen abstraction from C-H bond to produce Fe(IV)-OH and carbon radical. The latter is then quenched by the delivery of hydroxyl radical from Fe(IV)-OH. The latter species may thus be regarded as a carrier of hydroxyl radical. We have proposed that the C-C bond cleavage reaction occurs through the participation of the Fe(III)-O-OH species that is trapped by the electrophilic property of the carbonyl compound giving a peroxide adduct that fragments to produce an acyl-carbon cleavage. Scientific developments leading up to this conclusion are considered. In the first author's views, ''The study of mechanisms is not a scientific but a cultural activity. Mechanisms do not aim at an absolute truth but are intended to be a ''running'' commentary on the status of knowledge in a field. As the structural knowledge in a field advances Mechanisms evolve to take note of the new findings. Just as a constructive ''running'' commentary provides the stimulus for higher standards of performance, so Mechanisms call for better and firmer structural information from their practitioners''.
引用
收藏
页码:375 / 387
页数:13
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