Mammalian Cytochrome P450 Enzymes Catalyze the Phenol-coupling Step in Endogenous Morphine Biosynthesis

被引:44
作者
Grobe, Nadja [1 ]
Zhang, Baichen [1 ]
Fisinger, Ursula [2 ]
Kutchan, Toni M. [1 ]
Zenk, Meinhart H. [1 ]
Guengerich, F. Peter [3 ,4 ]
机构
[1] Donald Danforth Plant Sci Ctr, St Louis, MO 63132 USA
[2] Univ Munich, Lehrstuhl Pharmazeut Biol, D-80333 Munich, Germany
[3] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA
[4] Vanderbilt Univ, Sch Med, Ctr Mol Toxicol, Nashville, TN 37232 USA
基金
美国国家卫生研究院;
关键词
CELLS SYNTHESIZE MORPHINE; RAT-LIVER; BENZYLISOQUINOLINE ALKALOIDS; BERBERIS-STOLONIFERA; CYP2D6; MODULATION; MOLECULAR-CLONING; O-DEMETHYLATION; HUMAN BRAIN; SALUTARIDINE; CODEINE;
D O I
10.1074/jbc.M109.011320
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
A cytochrome P450 (P450) enzyme in porcine liver that catalyzed the phenol-coupling reaction of the substrate (R)-reticuline to salutaridine was previously purified to homogeneity (Amann, T., Roos, P. H., Huh, H., and Zenk, M. H. (1995) Heterocycles 40, 425-440). This reaction was found to be catalyzed by human P450s 2D6 and 3A4 in the presence of (R)-reticuline and NADPH to yield not a single product, but rather (-)-isoboldine, (-)-corytuberine, (-)-pallidine, and salutaridine, the paraortho coupled established precursor of morphine in the poppy plant and most likely also in mammals. (S)-Reticuline, a substrate of both P450 enzymes, yielded the phenol-coupled alkaloids (-)-isoboldine, (-)-corytuberine, (-)-pallidine, and sinoacutine; none of these serve as a morphine precursor. Catalytic efficiencies were similar for P450 2D6 and P450 3A4 in the presence of cytochrome b(5) with (R)-reticuline as substrate. The mechanism of phenol coupling is not yet established; however, we favor a single cycle of iron oxidation to yield salutaridine and the three other alkaloids from (R)-reticuline. The total yield of salutaridine formed can supply the 10 nM concentration of morphine found in human neuroblastoma cell cultures and in brain tissues of mice.
引用
收藏
页码:24425 / 24431
页数:7
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