Proteomics-Based Discovery of Koranimine, a Cyclic Imine Natural Product

Abstract

Nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) are large enzymes responsible for the biosynthesis of medically and ecologically important secondary metabolites. In a previous report we described a proteomics approach to screen for expressed NRPSs or PKSs from bacteria with or without sequenced genomes. Here we use this proteome mining approach to discover a novel natural product arising from rare adenylation (A) and reductase (Red) domains in its biosynthetic machinery. We also clone the entire gene cluster and elucidate the biosynthesis of the new compound produced by an unsequenced Bacillus sp. isolated from soil collected in Koran, Louisiana.

New Aspercryptins, Lipopeptide Natural Products, Revealed by HDAC Inhibition in Aspergillus nidulans

“…Iterative epimerase domains are not without precedent. 25 Because we observed that the alanine residue of aspercryptin A2 exists as a mixture of L- and D-enantiomers, we predict that the epimerase domain acts iteratively. Chronologically, L-serine (for aspercryptin A1) or L-alanine (for aspercryptin A2) is activated by the first adenylation domain of AtnA, and while serine is fully epimerized to the D-enantiomer by the epimerase domain, alanine is only partially converted to the D-enantiomer.…”

“…Terminal reductase domains generally use the energy from NAD(P)H to install a reactive aldehyde that serves as a warhead 26 or as an intermediate that rearranges to yield a mature natural product. 25 For the aspercryptins, the removal of a charge-bearing site from dominantly hydrophobic portion of the compound is a potential reason for the installation of this alcohol at the C-termini of aspercryptins. In fact, the putatively membrane-associated nature of the aspercryptins may be relevant to their function and is consistent with our ability to isolate these compounds mainly from the cell mass and little from the extracellular medium.…”

Gobichelin A and B: mixed-ligandsiderophores discovered using proteomics

“…5 Using the PrISM approach, new natural products have been discovered from strains both with known genomic sequences and without any genomic information. 6, 7 …”

Iminoboronate-Based Peptide Cyclization That Responds to pH, Oxidation, and Small Molecule Modulators

“…We note that several papers exist in literature documenting peptide cyclization via formation of intramolecular imines. 29–31 This unusual mechanism of peptide cyclization originates from the conformational rigidity of the linear precursor and is extremely sensitive to the amino acid composition of the peptides. 30 This is perhaps not surprising given the unfavorable thermodynamic equilibrium of imine formation in aqueous media.…”