S-Adenosyl methionine cofactor modifications enhance the biocatalytic repertoire of small molecule C-Alkylation

Iain J. W. Mckean; Joanna C. Sadler; Anibal Cuetos; Amina Frese; Luke D. Humphreys; Gideon Grogan; Paul A. Hoskisson; Glenn A. Burley

doi:10.1002/anie.v58.49

S-Adenosyl methionine cofactor modifications enhance the biocatalytic repertoire of small molecule C-Alkylation

Iain J. W. Mckean, Joanna C. Sadler, Anibal Cuetos, Amina Frese, Luke D. Humphreys, Gideon Grogan, Paul A. Hoskisson, Glenn A. Burley

Research output: Contribution to journal › Article › peer-review

Abstract

A tandem enzymatic strategy to enhance the scope of C‐alkylation of small molecules via the in situ formation of S‐adenosyl methionine (SAM) cofactor analogues is described. A solvent‐exposed channel present in the SAM‐forming enzyme SalL tolerates 5′‐chloro‐5′‐deoxyadenosine (ClDA) analogues modified at the 2‐position of the adenine nucleobase. Coupling SalL‐catalyzed cofactor production with C‐(m)ethyl transfer to coumarin substrates catalyzed by the methyltransferase (MTase) NovO forms C‐(m)ethylated coumarins in superior yield and greater substrate scope relative to that obtained using cofactors lacking nucleobase modifications. Establishing the molecular determinants that influence C‐alkylation provides the basis to develop a late‐stage enzymatic platform for the preparation of high value small molecules.

Original language	English
Pages (from-to)	17583-17588
Journal	Angewandte Chemie International Edition
Volume	58
Issue number	49
Early online date	1 Oct 2019
DOIs	https://doi.org/10.1002/anie.v58.49
Publication status	E-pub ahead of print - 1 Oct 2019

Keywords / Materials (for Non-textual outputs)

alkylation
biocatalysis
coumarin
methyltransferase
S-adenosylmethionine

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10.1002/anie.v58.49

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title = "S-Adenosyl methionine cofactor modifications enhance the biocatalytic repertoire of small molecule C-Alkylation",

abstract = "A tandem enzymatic strategy to enhance the scope of C‐alkylation of small molecules via the in situ formation of S‐adenosyl methionine (SAM) cofactor analogues is described. A solvent‐exposed channel present in the SAM‐forming enzyme SalL tolerates 5′‐chloro‐5′‐deoxyadenosine (ClDA) analogues modified at the 2‐position of the adenine nucleobase. Coupling SalL‐catalyzed cofactor production with C‐(m)ethyl transfer to coumarin substrates catalyzed by the methyltransferase (MTase) NovO forms C‐(m)ethylated coumarins in superior yield and greater substrate scope relative to that obtained using cofactors lacking nucleobase modifications. Establishing the molecular determinants that influence C‐alkylation provides the basis to develop a late‐stage enzymatic platform for the preparation of high value small molecules.",

keywords = "alkylation, biocatalysis, coumarin, methyltransferase, S-adenosylmethionine",

author = "Mckean, {Iain J. W.} and Sadler, {Joanna C.} and Anibal Cuetos and Amina Frese and Humphreys, {Luke D.} and Gideon Grogan and Hoskisson, {Paul A.} and Burley, {Glenn A.}",

year = "2019",

month = oct,

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doi = "10.1002/anie.v58.49",

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volume = "58",

pages = "17583--17588",

journal = "Angewandte Chemie International Edition",

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T1 - S-Adenosyl methionine cofactor modifications enhance the biocatalytic repertoire of small molecule C-Alkylation

AU - Mckean, Iain J. W.

AU - Sadler, Joanna C.

AU - Cuetos, Anibal

AU - Frese, Amina

AU - Humphreys, Luke D.

AU - Grogan, Gideon

AU - Hoskisson, Paul A.

AU - Burley, Glenn A.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - A tandem enzymatic strategy to enhance the scope of C‐alkylation of small molecules via the in situ formation of S‐adenosyl methionine (SAM) cofactor analogues is described. A solvent‐exposed channel present in the SAM‐forming enzyme SalL tolerates 5′‐chloro‐5′‐deoxyadenosine (ClDA) analogues modified at the 2‐position of the adenine nucleobase. Coupling SalL‐catalyzed cofactor production with C‐(m)ethyl transfer to coumarin substrates catalyzed by the methyltransferase (MTase) NovO forms C‐(m)ethylated coumarins in superior yield and greater substrate scope relative to that obtained using cofactors lacking nucleobase modifications. Establishing the molecular determinants that influence C‐alkylation provides the basis to develop a late‐stage enzymatic platform for the preparation of high value small molecules.

AB - A tandem enzymatic strategy to enhance the scope of C‐alkylation of small molecules via the in situ formation of S‐adenosyl methionine (SAM) cofactor analogues is described. A solvent‐exposed channel present in the SAM‐forming enzyme SalL tolerates 5′‐chloro‐5′‐deoxyadenosine (ClDA) analogues modified at the 2‐position of the adenine nucleobase. Coupling SalL‐catalyzed cofactor production with C‐(m)ethyl transfer to coumarin substrates catalyzed by the methyltransferase (MTase) NovO forms C‐(m)ethylated coumarins in superior yield and greater substrate scope relative to that obtained using cofactors lacking nucleobase modifications. Establishing the molecular determinants that influence C‐alkylation provides the basis to develop a late‐stage enzymatic platform for the preparation of high value small molecules.

KW - alkylation

KW - biocatalysis

KW - coumarin

KW - methyltransferase

KW - S-adenosylmethionine

U2 - 10.1002/anie.v58.49

DO - 10.1002/anie.v58.49

M3 - Article

SN - 1433-7851

VL - 58

SP - 17583

EP - 17588

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

IS - 49

ER -

S-Adenosyl methionine cofactor modifications enhance the biocatalytic repertoire of small molecule C-Alkylation

Abstract

Keywords / Materials (for Non-textual outputs)

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