Cellular proteins continuously undergo non-enzymatic covalent modifications (NECMs) that accumulate under normal physiological conditions and are stimulated by changes in the cellular microenvironment. Glycation, the hallmark of diabetes, is a prevalent NECM associated with an array of pathologies. Histone proteins are particularly susceptible to NECMs due to their long half-lives and nucleophilic disordered tails that undergo extensive regulatory modifications; however, histone NECMs remain poorly understood. Here we perform a detailed analysis of histone glycation in vitro and in vivo and find it has global ramifications on histone enzymatic PTMs, the assembly and stability of nucleosomes, and chromatin architecture. Importantly, we identify a physiologic regulation mechanism, the enzyme DJ-1, which functions as a potent histone deglycase. Finally, we detect intense histone glycation and DJ-1 overexpression in breast cancer tumors. Collectively, our results suggest an additional mechanism for cellular metabolic damage through epigenetic perturbation, with implications in pathogenesis.

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Anopheles mosquito microbiomes are intriguing ecological niches. Within the gut, microbes adapt to oxidative stress due to heme and iron after blood meals. Although metagenomic sequencing has illuminated spatial and temporal fluxes of microbiome populations, limited data exist on microbial growth dynamics. Here, we analyze growth interactions between a dominant microbiome species, Elizabethkingia anophelis, and other Anopheles‐associated bacteria. We find E. anophelis inhibits a Pseudomonas sp. via an antimicrobial‐independent mechanism and observe biliverdins, heme degradation products, upregulated in cocultures. Purification and characterization of E. anophelis HemS demonstrates heme degradation, and we observe hemS expression is upregulated when cocultured with Pseudomonas sp. This study reveals a competitive microbial interaction between mosquito‐associated bacteria and characterizes the stimulation of heme degradation in E. anophelis when grown with Pseudomonas sp.

Adenylate-forming enzymes represent one of the most important enzyme classes in biology, responsible for the activation of carboxylate substrates for biosynthetic modifications. The byproduct of the adenylate-forming enzyme acetyl-CoA synthetase, acetyl-CoA, is incorporated into virtually every primary and secondary metabolic pathway. Modification of acetyl-CoA by an array of other adenylate-forming enzymes produces complex classes of natural products including nonribosomal peptides, polyketides, phenylpropanoids, lipopeptides, and terpenes. Adenylation domains possess a variety of unique structural and functional features that provide for such diversification in their resulting metabolites. As the number of organisms with sequenced genomes increases, more adenylate-forming enzymes are being identified, each with roles in metabolite production that have yet to be characterized. In this Review, we explore the broad role of class I adenylate-forming enzymes in the context of natural product biosynthesis and how they contribute to primary and secondary metabolism by focusing on important work conducted in the field. We highlight features of subclasses from this family that facilitate the production of structurally diverse metabolites, including those from noncanonical adenylation domains, and additionally discuss when biological roles for these compounds are known.

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