Cytochrome P450 3A Enzymes Catalyze the O6-Demethylation of Thebaine, a Key Step in Endogenous Mammalian Morphine Biosynthesis

Kramlinger, Valerie M.; Rojas, Mónica Alvarado; Kanamori, Tatsuyuki; Guengerich, F. Peter

doi:10.1074/jbc.m115.665331

Cited by 30 publications

(20 citation statements)

References 67 publications

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“…Cytochrome P450 and germin-like protein (GLPs) were the most downregulated gene families representing with 5 and 7 members, respectively. Cytochrome P450s are the class of heme binding oxidase involved in a wide range of metabolic reactions of cell leading to synthesis of fatty acid, hormone, secondary metabolites and defense compounds 32 33 34 . Numerous reports exposed the important role of GLPs in maintaining the basal immunity by affecting the defense process in plants 35 36 .…”

Section: Resultsmentioning

confidence: 99%

Comparative transcriptome and proteome analysis to reveal the biosynthesis of gold nanoparticles in Arabidopsis

Tiwari

Krishnamurthy

Shukla

et al. 2016

Sci Rep

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A large number of plants have been tested and exploited in search of a green chemistry approach for the fabrication of gold or other precious metal nanomaterials. Despite the potential of plant based methods, very little is known about the underlying biochemical reactions and genes involved in the biotransformation mechanism of AuCl4 into gold nanoparticles (AuNPs). In this research, we thus focused on studying the effect of Au on growth and nanoparticles formation by analyses of transcriptome, proteome and ionome shift in Arabidopsis. Au exposure favored the growth of Arabidopsis seedling and induced formation of nanoparticles in root and shoot, as indicated by optical and hyperspectral imaging. Root transcriptome analysis demonstrated the differential expression of the members of WRKY, MYB and BHLH gene families, which are involved in the Fe and other essential metals homeostasis. The proteome analysis revealed that Glutathione S-transferases were induced in the shoot and suggested its potential role in the biosynthesis AuNPs. This study also demonstrated the role of plant hormone auxin in determining the Au induced root system architecture. This is the first study using an integrated approach to understand the in planta biotransformation of KAuCl4 into AuNPs.

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Section: Resultsmentioning

confidence: 99%

Comparative transcriptome and proteome analysis to reveal the biosynthesis of gold nanoparticles in Arabidopsis

Tiwari

Krishnamurthy

Shukla

et al. 2016

Sci Rep

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“…64 Subsequent studies showed that human P450s 3A4 and 3A5 can catalyze the O 6 -demethylation of thebaine (derived from salutaridine) and that P450 2D6 catalyzes the O 3 -demethylation of codeine, and thus all of the steps in morphine biosynthesis are now established in humans. 67 However, the extent of contribution of this pathway to endogenous control of pain remains to be determined.…”

Section: C-c Bond Forming Reactionsmentioning

confidence: 99%

“…In some cases, the same reaction can be catalyzed by an Fe/ α -KG dioxygenase in one species and by a P450 in another (e.g. thebaine O 6 -demethylation by an Fe/ α -KG dioxygenase in plants 465 and by P450s in mammals 67 ).…”

Section: C-c Bond Breaking Reactionsmentioning

confidence: 99%

Formation and Cleavage of C–C Bonds by Enzymatic Oxidation–Reduction Reactions

2018

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Many oxidation-reduction (redox) enzymes, particularly oxygenases, have roles in reactions that make and break C-C bonds. The list includes cytochrome P450 and other heme-based monooxygenases, heme-based dioxygenases, nonheme iron mono- and dioxygenases, flavoproteins, radical S-adenosylmethionine enzymes, copper enzymes, and peroxidases. Reactions involve steroids, intermediary metabolism, secondary natural products, drugs, and industrial and agricultural chemicals. Many C-C bonds are formed via either (i) coupling of diradicals or (ii) generation of unstable products that rearrange. C-C cleavage reactions involve several themes: (i) rearrangement of unstable oxidized products produced by the enzymes, (ii) oxidation and collapse of radicals or cations via rearrangement, (iii) oxygenation to yield products that are readily hydrolyzed by other enzymes, and (iv) activation of O in systems in which the binding of a substrate facilitates O activation. Many of the enzymes involve metals, but of these, iron is clearly predominant.

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“…The choice of a human oxidase and reductase was derived from the increasing knowledge that mammalian cells are able to synthesize morphine. The biosynthetic pathway delineated so far ( [24 ] and literature cited therein) includes similar metabolites and enzymes as in P. somniferum. After production of salutaridine in yeast the next challenge was the formation of morphine.…”

Section: Biosynthetic Steps: Enzymes and Genesmentioning

confidence: 99%