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Producing proficient methyl donors from alternative substrates of S-adenosylmethionine synthetase.

ABSTRACT: Bacteria use quorum sensing to probe and respond to population densities in their external environment. The detection of quorum signaling molecules causes a virulence response in many pathogenic bacteria. Blocking this signaling pathway, without interfering with critical metabolic functions, would produce compounds that can disarm pathogens without killing them. By not blocking growth per se, this therapeutic approach would have a lower associated risk for the development of bacterial resistance. Modified forms of l-methionine can yield analogues of the essential methyl donor, S-adenosyl-l-methionine (AdoMet), by serving as substrates for AdoMet synthetase [Zano, S., et al. (2013) Arch. Biochem. Biophys. 536, 64]. The AdoMet analogues examined here were chosen for their putative inability to serve as precursors for the synthesis of the acylhomoserine lactone class of quorum sensing molecules. We now show that these AdoMet analogues can still function as methyl donors, for methylation of both DNA and catechol-based neurotransmitters. The rates of methyl transfer for several of these altered AdoMet analogues are comparable to those observed with unmodified AdoMet. Additional refinement of these structures is expected to produce lead compounds to be tested as selective therapeutic agents against infections by a broad range of pathogenic Gram-negative bacteria.

SUBMITTER: Wijayasinghe YS

PROVIDER: S-EPMC3985469 | biostudies-other | 2014 Mar

REPOSITORIES: biostudies-other

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Alternative substrates selective for S-adenosylmethionine synthetases from pathogenic bacteria.

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The catalytic flexibility of tRNAIle-lysidine synthetase can generate alternative tRNA substrates for isoleucyl-tRNA synthetase.

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Structure of a critical metabolic enzyme: S-adenosylmethionine synthetase from Cryptosporidium parvum.

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Importance of methyl donors during reproduction.

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<i>S</i>-Adenosylmethionine: more than just a methyl donor.

Project description:Covering: from 2000 up to the very early part of 2023S-Adenosyl-L-methionine (SAM) is a naturally occurring trialkyl sulfonium molecule that is typically associated with biological methyltransfer reactions. However, SAM is also known to donate methylene, aminocarboxypropyl, adenosyl and amino moieties during natural product biosynthetic reactions. The reaction scope is further expanded as SAM itself can be modified prior to the group transfer such that a SAM-derived carboxymethyl or aminopropyl moiety can also be transferred. Moreover, the sulfonium cation in SAM has itself been found to be critical for several other enzymatic transformations. Thus, while many SAM-dependent enzymes are characterized by a methyltransferase fold, not all of them are necessarily methyltransferases. Furthermore, other SAM-dependent enzymes do not possess such a structural feature suggesting diversification along different evolutionary lineages. Despite the biological versatility of SAM, it nevertheless parallels the chemistry of sulfonium compounds used in organic synthesis. The question thus becomes how enzymes catalyze distinct transformations via subtle differences in their active sites. This review summarizes recent advances in the discovery of novel SAM utilizing enzymes that rely on Lewis acid/base chemistry as opposed to radical mechanisms of catalysis. The examples are categorized based on the presence of a methyltransferase fold and the role played by SAM within the context of known sulfonium chemistry.

| S-EPMC10491745 | biostudies-literature

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