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Mechanistic insights into the cytochrome P450-mediated oxidation and rearrangement of littorine in tropane alkaloid biosynthesis

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Mechanistic insights into the cytochrome P450-mediated oxidation and rearrangement of littorine in tropane alkaloid biosynthesis. / Nasomjai, Pitak; Reed, Darwin W.; Tozer, David J.; Peach, Michael J. G.; Slawin, Alexandra M. Z.; Covello, Patrick S.; O'Hagan, David.

In: ChemBioChem, Vol. 10, No. 14, 21.09.2009, p. 2382-2393.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Nasomjai, P, Reed, DW, Tozer, DJ, Peach, MJG, Slawin, AMZ, Covello, PS & O'Hagan, D 2009, 'Mechanistic insights into the cytochrome P450-mediated oxidation and rearrangement of littorine in tropane alkaloid biosynthesis', ChemBioChem, vol. 10, no. 14, pp. 2382-2393. https://doi.org/10.1002/cbic.200900318

APA

Nasomjai, P., Reed, D. W., Tozer, D. J., Peach, M. J. G., Slawin, A. M. Z., Covello, P. S., & O'Hagan, D. (2009). Mechanistic insights into the cytochrome P450-mediated oxidation and rearrangement of littorine in tropane alkaloid biosynthesis. ChemBioChem, 10(14), 2382-2393. https://doi.org/10.1002/cbic.200900318

Vancouver

Author

Nasomjai, Pitak ; Reed, Darwin W. ; Tozer, David J. ; Peach, Michael J. G. ; Slawin, Alexandra M. Z. ; Covello, Patrick S. ; O'Hagan, David. / Mechanistic insights into the cytochrome P450-mediated oxidation and rearrangement of littorine in tropane alkaloid biosynthesis. In: ChemBioChem. 2009 ; Vol. 10, No. 14. pp. 2382-2393.

Bibtex

@article{da1f67ab288f4f45894e1fddd3830fac,
title = "Mechanistic insights into the cytochrome P450-mediated oxidation and rearrangement of littorine in tropane alkaloid biosynthesis",
abstract = "During the biosynthesis of certain tropane alkaloids, littorine (1) is rearranged to hyoscyamine (3). Recent evidence indicates that this isomerisation is a two-step process in which the first step is an oxidation/rearrangement to give hyoscyamine aldehyde (2). This step is catalysed by CYP80F1, a cytochrome P450 enzyme, which was recently identified from the plant Hyoscyamus niger; CYP80F1 also catalyses the hydroxylation of littorine at the 3'-position. The mechanisms of the reactions catalysed by CYP80F1 were probed with synthetic deutero and arylfluoro analogues of 1. Measurement of the primary kinetic isotope effects indicates that C3' hydrogen abstraction is the rate-limiting step for the oxidation/rearrangement of natural littorine, and for the 3'-hydroxylation reaction of the unnatural S enantiomer of littorine. The character of the intermediates in the oxidation/rearrangement and hydroxylation reaction was probed with the use of arylfluorinated analogues of (R)-littorine (natural stereoisomer) and (S)-littorine (unnatural stereoisomer) as substrates for CYP80F1. The relative conversions of ortho-, meta- and para-fluorolittorine analogues were used to obtain information on the likely intermediacy of either a benzylic radical or benzylic carbocation intermediate. The data suggest that hydroxylation takes place via a benzylic carbocation intermediate, whereas the product profile arising from rearrangement is more consistent with a benzylic radical intermediate.",
keywords = "DATURA-STRAMONIUM, STEREOCHEMICAL COURSE, isomerization, alkaloids, P450-CATALYZED HYDROXYLATION, SUBSTITUTION, CARBON-SKELETON REARRANGEMENT, TROPIC ACID, cytochromes, PROBES, enzyme catalysis, ENZYME, fluorine, HYOSCYAMINE, REACTIVITY",
author = "Pitak Nasomjai and Reed, {Darwin W.} and Tozer, {David J.} and Peach, {Michael J. G.} and Slawin, {Alexandra M. Z.} and Covello, {Patrick S.} and David O'Hagan",
year = "2009",
month = sep,
day = "21",
doi = "10.1002/cbic.200900318",
language = "English",
volume = "10",
pages = "2382--2393",
journal = "ChemBioChem",
issn = "1439-4227",
publisher = "Wiley-VCH Verlag",
number = "14",

}

RIS

TY - JOUR

T1 - Mechanistic insights into the cytochrome P450-mediated oxidation and rearrangement of littorine in tropane alkaloid biosynthesis

AU - Nasomjai, Pitak

AU - Reed, Darwin W.

AU - Tozer, David J.

AU - Peach, Michael J. G.

AU - Slawin, Alexandra M. Z.

AU - Covello, Patrick S.

AU - O'Hagan, David

PY - 2009/9/21

Y1 - 2009/9/21

N2 - During the biosynthesis of certain tropane alkaloids, littorine (1) is rearranged to hyoscyamine (3). Recent evidence indicates that this isomerisation is a two-step process in which the first step is an oxidation/rearrangement to give hyoscyamine aldehyde (2). This step is catalysed by CYP80F1, a cytochrome P450 enzyme, which was recently identified from the plant Hyoscyamus niger; CYP80F1 also catalyses the hydroxylation of littorine at the 3'-position. The mechanisms of the reactions catalysed by CYP80F1 were probed with synthetic deutero and arylfluoro analogues of 1. Measurement of the primary kinetic isotope effects indicates that C3' hydrogen abstraction is the rate-limiting step for the oxidation/rearrangement of natural littorine, and for the 3'-hydroxylation reaction of the unnatural S enantiomer of littorine. The character of the intermediates in the oxidation/rearrangement and hydroxylation reaction was probed with the use of arylfluorinated analogues of (R)-littorine (natural stereoisomer) and (S)-littorine (unnatural stereoisomer) as substrates for CYP80F1. The relative conversions of ortho-, meta- and para-fluorolittorine analogues were used to obtain information on the likely intermediacy of either a benzylic radical or benzylic carbocation intermediate. The data suggest that hydroxylation takes place via a benzylic carbocation intermediate, whereas the product profile arising from rearrangement is more consistent with a benzylic radical intermediate.

AB - During the biosynthesis of certain tropane alkaloids, littorine (1) is rearranged to hyoscyamine (3). Recent evidence indicates that this isomerisation is a two-step process in which the first step is an oxidation/rearrangement to give hyoscyamine aldehyde (2). This step is catalysed by CYP80F1, a cytochrome P450 enzyme, which was recently identified from the plant Hyoscyamus niger; CYP80F1 also catalyses the hydroxylation of littorine at the 3'-position. The mechanisms of the reactions catalysed by CYP80F1 were probed with synthetic deutero and arylfluoro analogues of 1. Measurement of the primary kinetic isotope effects indicates that C3' hydrogen abstraction is the rate-limiting step for the oxidation/rearrangement of natural littorine, and for the 3'-hydroxylation reaction of the unnatural S enantiomer of littorine. The character of the intermediates in the oxidation/rearrangement and hydroxylation reaction was probed with the use of arylfluorinated analogues of (R)-littorine (natural stereoisomer) and (S)-littorine (unnatural stereoisomer) as substrates for CYP80F1. The relative conversions of ortho-, meta- and para-fluorolittorine analogues were used to obtain information on the likely intermediacy of either a benzylic radical or benzylic carbocation intermediate. The data suggest that hydroxylation takes place via a benzylic carbocation intermediate, whereas the product profile arising from rearrangement is more consistent with a benzylic radical intermediate.

KW - DATURA-STRAMONIUM

KW - STEREOCHEMICAL COURSE

KW - isomerization

KW - alkaloids

KW - P450-CATALYZED HYDROXYLATION

KW - SUBSTITUTION

KW - CARBON-SKELETON REARRANGEMENT

KW - TROPIC ACID

KW - cytochromes

KW - PROBES

KW - enzyme catalysis

KW - ENZYME

KW - fluorine

KW - HYOSCYAMINE

KW - REACTIVITY

U2 - 10.1002/cbic.200900318

DO - 10.1002/cbic.200900318

M3 - Journal article

VL - 10

SP - 2382

EP - 2393

JO - ChemBioChem

JF - ChemBioChem

SN - 1439-4227

IS - 14

ER -