eprintid: 10125446
rev_number: 14
eprint_status: archive
userid: 608
dir: disk0/10/12/54/46
datestamp: 2021-04-01 13:27:39
lastmod: 2021-09-25 23:35:00
status_changed: 2021-04-01 13:27:39
type: article
metadata_visibility: show
creators_name: Popadić, D
creators_name: Mhaindarkar, D
creators_name: Dang Thai, MHN
creators_name: Hailes, HC
creators_name: Mordhorst, S
creators_name: Andexer, JN
title: A bicyclic S-adenosylmethionine regeneration system applicable with different nucleosides or nucleotides as cofactor building blocks
ispublished: inpress
divisions: UCL
divisions: B04
divisions: C06
divisions: F56
note: This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence (http://creativecommons.org/licenses/by-nc/3.0/).
abstract: The ubiquitous cofactor S-adenosyl-L-methionine (SAM) is part of numerous biochemical reactions in metabolism, epigenetics, and cancer development. As methylation usually improves physiochemical properties of compounds relevant for pharmaceutical use, the sustainable use of SAM as a methyl donor in biotechnological applications is an important goal. SAM-dependent methyltransferases are consequently an emerging biocatalytic tool for environmentally friendly and selective alkylations. However, SAM shows undesirable characteristics such as degradation under mild conditions and its stoichiometric use is economically not reasonable. Here, we report an optimised biomimetic system for the regeneration of SAM and SAM analogues consisting of effective nucleoside triphosphate formation and an additional L-methionine regeneration cycle without by-product accumulation. The bicyclic system uses seven enzymes, S-methylmethionine as methyl donor and a surplus of inorganic polyphosphate, along with catalytic amounts of L-methionine and cofactor building block reaching conversions of up to 99% (up to 200 turnovers). We also show that the cycle can be run with cofactor building blocks containing different purine and pyrimidine nucleobases, which can be fed in at the nucleoside or nucleotide stage. These alternative cofactors are in turn converted to the corresponding SAM analogues, which are considered to be a key for the development of bioorthogonal systems. In addition to purified enzymes, the bicyclic system can also be used with crude lysates highlighting its broad biocatalytic applicability.
date: 2021-03-22
date_type: published
publisher: Royal Society of Chemistry (RSC)
official_url: https://doi.org/10.1039/d1cb00033k
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1855787
doi: 10.1039/d1cb00033k
lyricists_name: Hailes, Helen
lyricists_id: HCHAI24
actors_name: Kalinowski, Damian
actors_id: DKALI47
actors_role: owner
full_text_status: public
publication: RSC Chemical Biology
citation:        Popadić, D;    Mhaindarkar, D;    Dang Thai, MHN;    Hailes, HC;    Mordhorst, S;    Andexer, JN;      (2021)    A bicyclic S-adenosylmethionine regeneration system applicable with different nucleosides or nucleotides as cofactor building blocks.                   RSC Chemical Biology        10.1039/d1cb00033k <https://doi.org/10.1039/d1cb00033k>.    (In press).    Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10125446/1/Hailes_A%20bicyclic%20S-adenosylmethionine%20regeneration%20system%20applicable%20with%20different%20nucleosides%20or%20nucleotides%20as%20cofactor%20building%20block_AOP.pdf