AdoMet analog synthesis and utilization: current state of the art

Abstract

S-Adenosyl-l-methionine (AdoMet) is an essential enzyme cosubstrate in fundamental biology with an expanding range of biocatalytic and therapeutic applications. In recent years, technologies enabling the synthesis and utilization of novel functional AdoMet surrogates have rapidly advanced. Developments highlighted within this brief review include improved syntheses of AdoMet analogs, unique S-adenosyl-l-methionine isosteres with enhanced stability, and corresponding applications in epigenetics, proteomics and natural product/small molecule diversification (‘alkylrandomization‘).

Catalytic Alkylation Using a Cyclic S‐Adenosylmethionine Regeneration System

“…Thes ystem offers many advantages typical for in vitro biocatalytic systems involving isolated enzymes,f or example,u tility for the production of fine chemicals where precise control of the reaction is necessary,and the possibility to introduce selective isotopic labels.Anadded bonus is that many SAM-dependent MTs can also use av ariety of methionine analogues. [8,9] Our results with ethionine show that it should be feasible to develop an in vitro platform for more general alkylation reactions,t his will be explored in further studies.…”

“…[7] Ab iocatalytic approach using natures methylating agent, SAM, could fulfill these needs.Inaddition to methylation, alkylation using SAM derivatives that are accessible from methionine derivatives would extend the potential of these enzymes as biocatalysts. [8][9][10][11][12][13] Theinstability of SAM, [14][15][16] the inhibitory nature of its inevitable byproduct S-adenosylhomocysteine (SAH, AdoHcy), [17] and the need for stoichiometric amounts of SAM have so-far prohibited the development of up-scaled processes.T his highlights the demand for ac ofactor regeneration system for SAM-dependent enzymes. [3,5] In contrast to other group-delivering cofactors such as nicotinamide adenine dinucleotide (NAD + /NADH), the SAM regeneration pathway is not ao ne-step process that basically reverses the forward reaction.…”

S‐Adenosyl Methionine Cofactor Modifications Enhance the Biocatalytic Repertoire of Small Molecule C‐Alkylation

“…[18][19][20] Ahallmark of NovO is its substrate promiscuity (e.g., 1)and the ability to utilize S-alkylated analogues of SAM to form products such as 2 ( Figure 1a). [27,28] Am ore step-and atom-efficient strategy is to couple cofactor formation with C-alkyl transfer. [22][23][24][25][26] Furthermore,S AM analogues are inherently unstable in buffered solution (t 1/2 942 min for SAM at pH 8).…”

“…[22][23][24][25][26] Furthermore,S AM analogues are inherently unstable in buffered solution (t 1/2 942 min for SAM at pH 8). [27,28] Am ore step-and atom-efficient strategy is to couple cofactor formation with C-alkyl transfer. [15,29,30] One example of this one-pot process is the generation of cofactor analogues in situ from either ClDAo rA TP and (m)ethionine, [15,[29][30][31][32][33] followed by C-(m)ethyl transfer catalyzed by aM Tase (Figure 1b).…”

An ortho C-methylation/O-glycosylation motif on a hydroxy-coumarin scaffold, selectively installed by biocatalysis

“…17 [19][20][21][22] Alternatively, it was possible to vary the chemical groups transferred by MTs on applying different SAM analogues in a synthetic "alkylrandomization" approach. 18,23,24 Similarly, a somewhat relaxed specificity of certain GTs for the sugar donor substrate was exploited in the synthesis of different glycosides using an approach referred to as "glycorandomization". 16,17,25 The aim of the current study was the synthetic instalment of the prominent C-methyl/O-glycosyl motif by using a one-pot biotransformation involving the reactions of MT and GT combined (Scheme 1).…”