Large-scale, protection-free synthesis of Se-adenosyl-L-selenomethionine analogues and their application as cofactor surrogates of methyltransferases - PubMed (original) (raw)

. 2014 Jun 6;16(11):3056-9.

doi: 10.1021/ol501169y. Epub 2014 May 22.

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Large-scale, protection-free synthesis of Se-adenosyl-L-selenomethionine analogues and their application as cofactor surrogates of methyltransferases

Ian R Bothwell et al. Org Lett. 2014.

Abstract

S-adenosyl-L-methionine (SAM) analogues have previously demonstrated their utility as chemical reporters of methyltransferases. Here we describe the facile, large-scale synthesis of Se-alkyl Se-adenosyl-L-selenomethionine (SeAM) analogues and their precursor, Se-adenosyl-L-selenohomocysteine (SeAH). Comparison of SeAM analogues with their equivalent SAM analogues suggests that sulfonium-to-selenonium substitution can enhance their compatibility with certain protein methyltransferases, favoring otherwise less reactive SAM analogues. Ready access to SeAH therefore enables further application of SeAM analogues as chemical reporters of diverse methyltransferases.

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Figures

Figure 1

Figure 1

Biosynthesis of SAM and retrosynthesis of SAM, SeAM, and their chalcogen–alkyl analogues.

Scheme 1

Scheme 1. Protection-Free Synthesis of SeAH, SeAM, and SeAM Analogues with Yields and Purification Methods Highlighted for Key Intermediates

Figure 2

Figure 2

(a) SAM and SeAM analogues examined as cofactor surrogates for native and engineered PMTs. (b) Relative transalkylation efficiency (S vs Se) on known peptide substrates for selected engineered PMTs and SAM/SeAM analogues. Degrees of alkylation (equivalent to units of the consumed cofactor) per unit peptide were quantified via MALDI-MS (see the Supporting Information for more details). The difference between SeAM and their equivalent SAM analogues were then compared and categorized. NR, no reaction; =, no observable difference; +, an increase of 0.1–0.5 equiv alkylation/substrate; ++, an increase of >0.5 equiv alkylation/substrate; −, a decrease of 0.1–0.5 equiv alkylation/substrate from _S_- to _S_e-alkyl SAM analogues. Relative values for units of the consumed cofactors per unit peptide substrate are shown in parentheses as (_S_-analogue, _Se_-analogue) (c, d) Representative MALDI-MS analysis: PRMT3M233G-catalyzed reactions using hexyne–SAM and −SeAM cofactors (13a vs 13b); G9a Y1154A-catalyzed reactions using enyne–SAM and −SeAM cofactors (12a vs 12b).

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