S-Adenosylmethionine-dependent alkylation reactions: When are radical reactions used?

Abstract

S-adenosylmethionine (SAM) is a versatile small molecule used in many biological reactions. This review focuses on the mechanistic consideration of SAM-dependent methylation and 3-amino-3-carboxypropylation reactions. Special emphasis is given to methylation and 3-amino-3-carboxypropylation of carbon atoms, for which both nucleophilic mechanisms and radical mechanisms are used, depending on the specific enzymatic reactions. What is the logic behind Nature’s choice of different reaction mechanisms? Here I aim to rationalize the choice of different reaction mechanisms in SAM-dependent alkylation reaction by analyzing a few enzymatic reactions in depth. These reactions include SAM-dependent cyclopropane fatty acid synthesis, DNA cytosine methylation, RNA adenosine C2 and C8 methylation, and 3-amino-3-carboxypropylation involved in diphthamide biosynthesis and wybutosine biosynthesis.

The biosynthesis and biological function of diphthamide

“…Unlike most other radical SAM enzymes, PhDph2 does not generate a 5'-deoxyadenosyl radical (Figure 4). Instead, PhDph2 cleaves the C γ,Met –S bond of SAM to form 5'-deoxy-5'-methylthioadenosine (MTA) and an ACP radical (Zhu et al, 2011, Lin, 2011). The ACP radical then likely adds to the imidazole ring of the histidine residue to give the product (Figure 4).…”

Evolution of tRNAPhe:imG2 methyltransferases involved in the biosynthesis of wyosine derivatives in Archaea

“…One could imagine that, after emergence of the Taw1 enzyme that catalyzes the formation of the imG-14 intermediate of the mimG pathway, the N 1 -methylating enzyme may have evolved to methylate the C 7 -atom of imG-14 as well. Such intrinsically relaxed specificity may be created by the existence of the mesomeric forms of the imG-14 substrate, allowing the C 7 -atom to become sufficiently negatively charged to act as a nucleophile (Lin 2011;Urbonavicǐus et al 2014). After the subsequent gene duplication events, each gene may have evolved differently: It may encode either the bifunctional enzyme (e.g., aTrm5a/Taw22 enzymes PAB2272 and NEQ228), G37-specific N 1 -methyltransferase (aTrm5b, c, e.g., PAB0505), imG-14-C 7 -methyltransferase (Taw21, as in the case of SSO2439), or imG-14-C 7 -3-amino-3-carboxypropyltransferase (Taw2, e.g., MJ1557, PH0793 [Umitsu et al 2009]).…”

SAMbinder: A web server for predicting SAM binding residues of a protein from its amino acid sequence

“…SAM is a conjugate molecule of two ubiquitous biological compounds; (i) adenosine moiety of ATP and (ii) amino acid methionine (CATONI, 1953;Waddell et al, 2000). One of the most important functions of the SAM is the transfer or donation of different chemical groups such as methyl (Thomas et al, 2004;Wuosmaa and Hager, 1990), aminopropyl (Lin, 2011), ribosyl (Kozbial and Mushegian, 2005), 5'deocxyadenosyl and methylene group (Gana et al, 2013;Kozbial and Mushegian, 2005) for carrying out covalent modification of a variety of substrates. SAM is also used as a precursor molecule in the biosynthesis of nicotinamide phytosiderophores, plant hormone ethylene, spermine, and spermidine; carry out chemical reactions such as hydroxylation, fluorination which takes place in bacteria (Cadicamo et al, 2004).…”