Ribosomally synthesized and post-translationally modified peptide natural product discovery in the genomic era

Hetrick, Kenton J.; Donk, Wilfred A. van der

doi:10.1016/j.cbpa.2017.02.005

Cited by 133 publications

(118 citation statements)

References 55 publications

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“…1 Recent genome sequencing efforts have revealed that RiPPs form a large natural product class produced by all domains of life. 2,3 In general, RiPP biosynthesis commences with the post-translational modification (PTM) of a precursor peptide, typically consisting of N -terminal leader and C -terminal core regions. 1–4 The RiPP precursor peptide gene is often encoded adjacent to other genes responsible for regulation, biosynthesis, and export.…”

Section: Introductionmentioning

confidence: 99%

Radical S-Adenosylmethionine Enzymes Involved in RiPP Biosynthesis

2017

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Ribosomally synthesized and post-translationally modified peptides (RiPPs) display a diverse range of structures and continue to expand as a natural product class. Accordingly, RiPPs exhibit a wide array of bioactivities, such as broad and narrow spectrum growth suppressors, antidiabetics, as well as antinociception and anticancer agents. Owing to these properties, and the complex repertoire of post-translational modifications (PTMs) that give rise to these molecules, RiPP biosynthesis has been intensely studied. RiPP biosynthesis often involves enzymes that perform unique chemistry with intriguing reaction mechanisms, which attract chemists and biochemists alike to study and re-engineer these pathways. One particular type of RiPP biosynthetic enzyme is the so-called radical S-adenosylmethionine (rSAM) enzyme, which utilize radical-based chemistry to install several distinct PTMs. Here, we describe the rSAM enzymes characterized over the past decade that catalyze six reactions types from several RiPP biosynthetic pathways. We present the current state of mechanistic understanding and conclude with possible directions for future characterization of this enzyme family.

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Section: Introductionmentioning

confidence: 99%

Radical S-Adenosylmethionine Enzymes Involved in RiPP Biosynthesis

2017

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“…In some rare cases, a leader peptide is not attached at the N terminus of the core peptide, but rather at the C terminus, which is hence termed a follower peptide . RiPPs are found in all three domains of life and have highly diverse biological activities, representing a promising source for the development of novel drug leads .…”

mentioning

confidence: 99%

Convergent evolution of the Cys decarboxylases involved in aminovinyl‐cysteine (AviCys) biosynthesis

Yuan

Wang

et al. 2019

FEBS Letters

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S‐[(Z)‐2‐aminovinyl]‐d‐cysteine (AviCys) is a unique motif found in several classes of ribosomally synthesized and post‐translationally modified peptides (RiPPs). Biosynthesis of AviCys requires flavin‐dependent Cys decarboxylases, which are highly divergent among different RiPP classes. In this study, we solved the crystal structure of the cypemycin decarboxylase CypD. We show that CypD is structurally highly similar to lanthipeptide decarboxylases despite the absence of sequence similarities between them. We further show that Cys decarboxylases from four RiPP classes have evolved independently and form two major clusters. These results reveal the convergent evolution of AviCys biosynthesis and suggest that all the flavin‐dependent Cys decarboxylases likely have a similar Rossmann fold despite their sequence divergences.

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“…The growing numbers of natural bioactive peptide structures, resulting from the genomic era discoveries, continue to inspire development of new molecular tools and peptide design. If the past ∼35 years' growth trends continue, we anticipate seeing many more and interesting naturally occurring and designed peptide/protein structures in the PDB and CSD.…”

Section: Discussionmentioning

confidence: 99%

“…If the past ∼35 years' growth trends continue, we anticipate seeing many more and interesting naturally occurring and designed peptide/protein structures in the PDB and CSD. Although ribosomal biosynthetic machinery does not naturally support incorporation of amino acids with modified backbones, a recent study suggests that by using an editing‐deficient valine‐tRNA synthetase, the ribosomal translation machinery incorporated eleven non‐coded amino acids in proteins—including α,α‐disubstituted, and cyclic β‐amino acids . This and similar systems may be harnessed to design conformationally constrained peptides with applications in basic science, biotechnology, bio‐engineering, and for biomedical applications …”

Section: Discussionmentioning

confidence: 99%

Amino acid modifications for conformationally constraining naturally occurring and engineered peptide backbones: Insights from the Protein Data Bank

2018

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Extensive efforts invested in understanding the rules of protein folding are now being applied, with good effect, in de novo design of proteins/peptides. For proteins containing standard α‐amino acids alone, knowledge derived from experimentally determined three‐dimensional (3D) structures of proteins and biologically active peptides are available from the Protein Data Bank (PDB), and the Cambridge Structural Database (CSD). These help predict and design protein structures, with reasonable confidence. However, our knowledge of 3D structures of biomolecules containing backbone modified amino acids is still evolving. A major challenge in de novo protein/peptide design concerns the engineering of conformationally constrained molecules with specific structural elements and chemical groups appropriately positioned for biological activity. This review explores four classes of amino acid modifications that constrain protein/peptide backbone structure. Systematic analysis of peptidic molecule structures (eg, bioactive peptides, inhibitors, antibiotics, and designed molecules), containing these backbone‐modified amino acids, found in the PDB and CSD are discussed. The review aims to provide structure–function insights that will guide future design of proteins/peptides.

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Ribosomally synthesized and post-translationally modified peptide natural product discovery in the genomic era

Cited by 133 publications

References 55 publications

Radical S-Adenosylmethionine Enzymes Involved in RiPP Biosynthesis

Radical S-Adenosylmethionine Enzymes Involved in RiPP Biosynthesis

Convergent evolution of the Cys decarboxylases involved in aminovinyl‐cysteine (AviCys) biosynthesis

Amino acid modifications for conformationally constraining naturally occurring and engineered peptide backbones: Insights from the Protein Data Bank

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