Abstract |
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 para-ortho 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.
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Authors | Nadja Grobe, Baichen Zhang, Ursula Fisinger, Toni M Kutchan, Meinhart H Zenk, F Peter Guengerich |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 284
Issue 36
Pg. 24425-31
(Sep 04 2009)
ISSN: 0021-9258 [Print] United States |
PMID | 19561069
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Benzylisoquinolines
- Morphinans
- Phenols
- Morphine
- salutaridine
- Iron
- Cytochrome P-450 CYP2D6
- Cytochrome P-450 CYP3A
- CYP3A4 protein, human
- reticuline
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Topics |
- Animals
- Benzylisoquinolines
(chemistry, metabolism)
- Catalysis
- Cell Line, Tumor
- Cytochrome P-450 CYP2D6
(chemistry, metabolism)
- Cytochrome P-450 CYP3A
(chemistry, metabolism)
- Humans
- Iron
(chemistry, metabolism)
- Mice
- Morphinans
(chemistry, metabolism)
- Morphine
(biosynthesis)
- Oxidation-Reduction
- Phenols
(chemistry, metabolism)
- Rats
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