Engineering pathways for transformations of morphine alkaloids

Bruce, Neil C.; French, Christopher E.; Hailes, A M; Long, Marianne T.; Rathbone, Deborah A.

doi:10.1016/s0167-7799(00)88946-5

Cited by 26 publications

(9 citation statements)

References 12 publications

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“…reductase system has been applied to the biocatalytic production of the medically useful semisynthetic opiates hydromorphone and hydrocodone [9][10][11].…”

Section: Figure 1 Reaction Catalysed By Morphine Dehydrogenasementioning

confidence: 99%

Mechanistic studies of morphine dehydrogenase and stabilization against covalent inactivation

Walker¹,

French²,

Rathbone

et al. 2000

Biochemical Journal

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Morphine dehydrogenase (MDH) of Pseudomonas putida M10 catalyses the NADP(+)-dependent oxidation of morphine and codeine to morphinone and codeinone. This enzyme forms the basis of a sensitive detection and assay method for heroin metabolites and a biotransformation process for production of hydromorphone and hydrocodone. To improve these processes we have undertaken a thorough examination of the kinetic mechanism of MDH. Sequence comparisons indicated that MDH belongs within the aldose reductase enzyme family. MDH was shown to be specific for the pro-R hydrogen of NADPH. In steady-state kinetic studies, product inhibition patterns suggested that MDH follows a Theorell-Chance mechanism for codeinone reduction at pH 7, and a non-Theorell-Chance sequential ordered mechanism for codeine oxidation at pH 9.5. Residues corresponding to the catalytically important Tyr-48, Lys-77 and Asp-43 of aldose reductase were modified by site-directed mutagenesis, resulting in substantial loss of activity consistent with a catalytic role for these residues. Loss of activity of MDH in the presence of the reaction product morphinone was found to be due to the formation of a covalent adduct with Cys-80; alteration of Cys-80 to serine resulted in an enzyme with greatly enhanced stability.

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“…reductase system has been applied to the biocatalytic production of the medically useful semisynthetic opiates hydromorphone and hydrocodone [9][10][11].…”

Section: Figure 1 Reaction Catalysed By Morphine Dehydrogenasementioning

confidence: 99%

Mechanistic studies of morphine dehydrogenase and stabilization against covalent inactivation

Walker¹,

French²,

Rathbone

et al. 2000

Biochemical Journal

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“…Considerable research has been centred on the production of still more e¡ective analgesics by using microorganisms to transform the naturallyoccurring compounds into known or novel derivatives [1]. Bruce et al [2] have reported the metabolism of morphine alkaloids by Pseudomonas putida M10 and the use of speci¢c enzymes isolated from this organism for the production of semi-synthetic opiate drugs. This organism was isolated from opiate waste liquors by its ability to utilise morphine and codeine as carbon sources for growth, albeit very slowly [3].…”

Section: Introductionmentioning

confidence: 99%

Transformations of codeine to important semisynthetic opiate derivatives by Pseudomonas putida m10

Lister¹

1999

FEMS Microbiology Letters

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A biotransformation mixture which contained codeine and washed cells of Pseudomonas putida M10 gave rise to a number of transformation products that are of clinical importance which included hydrocodone, dihydrocodeine and 14L-hydroxycodeine. Incubations with the same organism and codeinone gave rise to 14L-hydroxycodeinone and 14L-hydroxycodeine. Cell-free extracts and membrane fractions of P. putida M10 were shown to catalyse the 14L-hydroxylation of codeinone. In addition, the potent analgesic oxycodone was shown to be produced from 14L-hydroxycodeinone. ß

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“…Considerable research has been centred on the production of still more effective analgesics by using microorganisms to transform the naturally‐occurring compounds into known or novel derivatives [1]. Bruce et al [2] have reported the metabolism of morphine alkaloids by Pseudomonas putida M10 and the use of specific enzymes isolated from this organism for the production of semi‐synthetic opiate drugs. This organism was isolated from opiate waste liquors by its ability to utilise morphine and codeine as carbon sources for growth, albeit very slowly [3].…”

Section: Introductionmentioning

confidence: 99%

Transformations of codeine to important semisynthetic opiate derivatives byPseudomonas putidam10

Lister

Kanungo

Rathbone

et al. 1999

FEMS Microbiology Letters

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A biotransformation mixture which contained codeine and washed cells of Pseudomonas putida M10 gave rise to a number of transformation products that are of clinical importance which included hydrocodone, dihydrocodeine and 14beta-hydroxycodeine. Incubations with the same organism and codeinone gave rise to 14beta-hydroxycodeinone and 14beta-hydroxycodeine. Cell-free extracts and membrane fractions of P. putida M10 were shown to catalyse the 14beta-hydroxylation of codeinone. In addition, the potent analgesic oxycodone was shown to be produced from 14beta-hydroxycodeinone.

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Engineering pathways for transformations of morphine alkaloids

Cited by 26 publications

References 12 publications

Mechanistic studies of morphine dehydrogenase and stabilization against covalent inactivation

Mechanistic studies of morphine dehydrogenase and stabilization against covalent inactivation

Transformations of codeine to important semisynthetic opiate derivatives by Pseudomonas putida m10

Transformations of codeine to important semisynthetic opiate derivatives byPseudomonas putidam10

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