Tropic acid ester biosynthesis in Datura stramonium and related species

O’Hagan, David; Robins, Richard J.

doi:10.1039/a827207z

Cited by 32 publications

(19 citation statements)

References 24 publications

(38 reference statements)

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“…The last and most intriguing step in the biosynthesis of the tropane alkaloids hyoscyamine and scopolamine is the carbon skeleton rearrangement depicted in Scheme. 1 (for a review see [1]). Due to its similarity to the rearrangement of methylmalonyl CoA to succinyl‐CoA it was originally speculated that coenzyme B 12 is involved in the reaction [2–4].…”

Section: Introductionmentioning

confidence: 99%

“…More recently it has been surmised that cytochrome P450 is the agent abstracting the benzylic hydrogen atom and redonating a hydroxyl group after the rearrangement [10, 11]. Accordingly, clotrimazole, a known P‐450 inhibitor, has been said to inhibit the formation of hyoscyamine [1], and the 3‐H Re atom abstracted from the benzylic position was lost during the biosynthetic experiment [12]. When the OH group of littorine was labelled with the isotope 18 O, 25–29% of the label was lost in the product [11].…”

Section: Introductionmentioning

confidence: 99%

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The role and source of 5′‐deoxyadenosyl radical in a carbon skeleton rearrangement catalyzed by a plant enzyme

1998

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The last step in the biosynthesis of tropane alkaloids is the carbon skeleton rearrangement of littorine to hyoscyamine. The reaction is catalyzed by a cell-free extract prepared from cultured hairy roots of Datura stramonium. Adenosylmethionine stimulated the rearrangement 10^20-fold and showed saturation kinetics with an apparent K m of 25 W WM. It is proposed that S-adenosylmethionine is the source of a 5P-deoxyadenosyl radical which initiates the rearrangement in a similar manner as it does in analogous rearrangements catalyzed by coenzyme B IPdependent enzymes. Possible roles of S-adenosylmethionine as a radical source in higher plants are discussed.z 1998 Federation of European Biochemical Societies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The role and source of 5′‐deoxyadenosyl radical in a carbon skeleton rearrangement catalyzed by a plant enzyme

1998

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“…Much of the detail of this metabolism has been established in a series of experiments in root cultures, which have recently been reviewed. 106 Crucial to this pathway is the rearrangement of the C 6 -n-C 3 of phenylalanine into the C 6 -iso-C 3 of 76. Clear evidence for this process came from experiments 107 in Datura innoxia plants fed (R,S)-[1,3-13 C 2 ]-1, wherefrom label was incorporated intact into the tropate moiety of 59 by an intramolecular rearrangement, the two isotopes becoming contiguous in the derived tropate.…”

Section: Tropane and Related Alkaloidsmentioning

confidence: 99%

The application of root cultures to problems of biological chemistry

Robins¹

1998

Nat. Prod. Rep.

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Introduction 2 The role of root cultures 3 Production, cultivation and properties of root cultures 4 The range of natural products in root cultures 4.1 General aromatic compounds 4.2 Anthraquinones 4.3 Alkaloids 4.3.1 Pyrrolidine alkaloids 4.3.2 Indole alkaloids 4.3.3 Pyrrolizidine alkaloids 4.3.4 Tropane and related alkaloids 4.3.5 Indolizidine alkaloids 4.3.6 Benzylisoquinoline alkaloids 4.4 Terpenoids and steroids 4.4.1 Sesquiterpenes 4.4.2 Diterpenes 4.4.3 Triterpenes and steroids 4.5 Miscellaneous nitrogen compounds 4.6 Miscellaneous sulfur compounds 5 Future prospects 6 References

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“…[1,2] The biosynthetic origin of the tropate ester moiety in tropane alkaloids has been the subject of conjecture for many years, as it requires the unusual carbon skeletal rearrangement of a straight chain phenylpropionate moiety to a branched chain tropic acid residue. [3,4] Recently a cytochrome P450 enzyme (CYP80F1) from the Hyoscyamus niger plant (black henbane) has been identified as the catalyst responsible for the first step of this rearrangement.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Insights into the Cytochrome P450‐Mediated Oxidation and Rearrangement of Littorine in Tropane Alkaloid Biosynthesis

et al. 2009

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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.

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Tropic acid ester biosynthesis in Datura stramonium and related species

Cited by 32 publications

References 24 publications

The role and source of 5′‐deoxyadenosyl radical in a carbon skeleton rearrangement catalyzed by a plant enzyme

The role and source of 5′‐deoxyadenosyl radical in a carbon skeleton rearrangement catalyzed by a plant enzyme

The application of root cultures to problems of biological chemistry

Mechanistic Insights into the Cytochrome P450‐Mediated Oxidation and Rearrangement of Littorine in Tropane Alkaloid Biosynthesis

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