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Evolutionary Trajectories for the Functional Diversification of Anthracycline Methyltransferases.

ABSTRACT: Microbial natural products are an important source of chemical entities for drug discovery. Recent advances in understanding the biosynthesis of secondary metabolites has revealed how this rich chemical diversity is generated through functional differentiation of biosynthetic enzymes. For instance, investigations into anthracycline anticancer agents have uncovered distinct S-adenosyl methionine (SAM)-dependent proteins: DnrK is a 4-O-methyltransferase involved in daunorubicin biosynthesis, whereas RdmB (52% sequence identity) from the rhodomycin pathway catalyzes 10-hydroxylation. Here, we have mined unknown anthracycline gene clusters and discovered a third protein subclass catalyzing 10-decarboxylation. Subsequent isolation of komodoquinone B from two Streptomyces strains verified the biological relevance of the decarboxylation activity. Phylogenetic analysis inferred two independent routes for the conversion of methyltransferases into hydroxylases, with a two-step process involving loss-of-methylation and gain-of-hydroxylation presented here. Finally, we show that simultaneously with the functional differentiation, the evolutionary process has led to alterations in substrate specificities.

SUBMITTER: Grocholski T

PROVIDER: S-EPMC6750894 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Evolutionary Trajectories for the Functional Diversification of Anthracycline Methyltransferases.

Grocholski Thadée T Yamada Keith K Sinkkonen Jari J Tirkkonen Heli H Niemi Jarmo J Metsä-Ketelä Mikko M

ACS chemical biology 20190423 5

Microbial natural products are an important source of chemical entities for drug discovery. Recent advances in understanding the biosynthesis of secondary metabolites has revealed how this rich chemical diversity is generated through functional differentiation of biosynthetic enzymes. For instance, investigations into anthracycline anticancer agents have uncovered distinct S-adenosyl methionine (SAM)-dependent proteins: DnrK is a 4-O-methyltransferase involved in daunorubicin biosynthesis, where ...[more]

PMID: 30995392

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Project description:Big defensins are antimicrobial polypeptides believed to be the ancestors of ?-defensins, the most evolutionary conserved family of host defense peptides (HDPs) in vertebrates. Nevertheless, big defensins underwent several independent gene loss events during animal evolution, being only retained in a limited number of phylogenetically distant invertebrates. Here, we explore the evolutionary history of this fascinating HDP family and investigate its patchy distribution in extant metazoans. We highlight the presence of big defensins in various classes of lophotrochozoans, as well as in a few arthropods and basal chordates (amphioxus), mostly adapted to life in marine environments. Bivalve mollusks often display an expanded repertoire of big defensin sequences, which appear to be the product of independent lineage-specific gene tandem duplications, followed by a rapid molecular diversification of newly acquired gene copies. This ongoing evolutionary process could underpin the simultaneous presence of canonical big defensins and non-canonical (?-defensin-like) sequences in some species. The big defensin genes of mussels and oysters, two species target of in-depth studies, are subjected to gene presence/absence variation (PAV), i.e., they can be present or absent in the genomes of different individuals. Moreover, big defensins follow different patterns of gene expression within a given species and respond differently to microbial challenges, suggesting functional divergence. Consistently, current structural data show that big defensin sequence diversity affects the 3D structure and biophysical properties of these polypeptides. We discuss here the role of the N-terminal hydrophobic domain, lost during evolution toward ?-defensins, in the big defensin stability to high salt concentrations and its mechanism of action. Finally, we discuss the potential of big defensins as markers for animal health and for the nature-based design of novel therapeutics active at high salt concentrations.

Dataset Information

Evolutionary Trajectories for the Functional Diversification of Anthracycline Methyltransferases.

Publications

Evolutionary Trajectories for the Functional Diversification of Anthracycline Methyltransferases.

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