Producing Proficient Methyl Donors from Alternative Substrates of S-adenosylmethionine Synthetase.

Biochemistry

PubMedID: 24528526

Wijayasinghe YS, Blumenthal RM, Viola RE. Producing Proficient Methyl Donors from Alternative Substrates of S-adenosylmethionine Synthetase. Biochemistry. 2014;.
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 analogs of the essential methyl donor, S-adenosyl-L-methionine (AdoMet), by serving as substrates for AdoMet synthetase [Zano, et al. (2013) Arch. Biochem. Biophys. 536, 64]. The AdoMet analogs 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 analogs 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 analogs are comparable to those observed with unmodified AdoMet. Additional refinement of these structures is expected to produce lead compounds to test as selective therapeutic agents against infections by a broad range of pathogenic Gram-negative bacteria.