S-adenosyl methionine cofactor modifications enhance the biocatalytic repertoire of small molecule C-alkylation

Iain McKean, Joanna Sadler, Anibal Cuetos, Amina Frese, Luke Humphreys, Gideon Grogan, Paul Hoskisson, Glenn Burley

Research output: Contribution to journalArticle

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.

LanguageEnglish
Pages17583-17588
Number of pages6
JournalAngewandte Chemie International Edition
Volume58
Issue number49
Early online date1 Oct 2019
DOIs
Publication statusPublished - 2 Dec 2019

Fingerprint

Alkylation
Methionine
Coumarins
Molecules
Methyltransferases
Adenine
Substrates
Enzymes
5'-chloro-5'-deoxyadenosine
coumarin

Keywords

  • alkylation
  • methyltransferase
  • coumarin
  • biocatalysis

Cite this

McKean, Iain ; Sadler, Joanna ; Cuetos, Anibal ; Frese, Amina ; Humphreys, Luke ; Grogan, Gideon ; Hoskisson, Paul ; Burley, Glenn. / S-adenosyl methionine cofactor modifications enhance the biocatalytic repertoire of small molecule C-alkylation. In: Angewandte Chemie International Edition. 2019 ; Vol. 58, No. 49. pp. 17583-17588.
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S-adenosyl methionine cofactor modifications enhance the biocatalytic repertoire of small molecule C-alkylation. / McKean, Iain; Sadler, Joanna; Cuetos, Anibal ; Frese, Amina; Humphreys, Luke; Grogan, Gideon; Hoskisson, Paul; Burley, Glenn.

In: Angewandte Chemie International Edition, Vol. 58, No. 49, 02.12.2019, p. 17583-17588.

Research output: Contribution to journalArticle

TY - JOUR

T1 - S-adenosyl methionine cofactor modifications enhance the biocatalytic repertoire of small molecule C-alkylation

AU - McKean, Iain

AU - Sadler, Joanna

AU - Cuetos, Anibal

AU - Frese, Amina

AU - Humphreys, Luke

AU - Grogan, Gideon

AU - Hoskisson, Paul

AU - Burley, Glenn

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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 - methyltransferase

KW - coumarin

KW - biocatalysis

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