ArticleJournal of the American Chemical Society2011
Chemoenzymatic synthesis of cryptophycin anticancer agents by an ester bond-forming non-ribosomal peptide synthetase module.
Article in Journal of the American Chemical Society, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 44 citations in OpenAlex.
- Biosynthetic origin of anticancer dolastatin 15 reveals a noncanonical NRPS architecture enabling 2-keto acid activation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
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- Biosynthesis of Lyngbyastatins 1 and 3, Cytotoxic Depsipeptides from anJournal of natural products · 2023Article
- Current Progress in the Chemoenzymatic Synthesis of Natural Products.Molecules (Basel, Switzerland) · 2022Review
- Recent Advances in the Synthesis of Marine-Derived Alkaloids via Enzymatic Reactions.Marine drugs · 2022Review
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- Recent Advances in Small Peptides of Marine Origin in Cancer Therapy.Marine drugs · 2021Review
- Biosynthesis of depsipeptides, or Depsi: The peptides with varied generations.Protein science : a publication of the Protein Society · 2020Review
- Novel Modifications of Nonribosomal Peptides from Brevibacillus laterosporus MG64 and Investigation of Their Mode of Action.Applied and environmental microbiology · 2020Article
- Structural basis of keto acid utilization in nonribosomal depsipeptide synthesis.Nature chemical biology · 2020Article
- A Versatile Chemoenzymatic Synthesis for the Discovery of Potent Cryptophycin Analogs.ACS chemical biology · 2020Article
- Cyanobacterial Sfp-type phosphopantetheinyl transferases functionalize carrier proteins of diverse biosynthetic pathways.Scientific reports · 2017Article
- Identification of a novel sesquiterpene biosynthetic machinery involved in astellolide biosynthesis.Scientific reports · 2016Article
- Depsipeptide Intermediates Interrogate Proposed Biosynthesis of Cereulide, the Emetic Toxin of Bacillus cereus.Scientific reports · 2015Article
- Food-bacteria interplay: pathometabolism of emetic Bacillus cereus.Frontiers in microbiology · 2015Review
- Structure and noncanonical chemistry of nonribosomal peptide biosynthetic machinery.Natural product reports · 2012Review
- Efficient, divergent synthesis of cryptophycin unit A analogues.Chemical communications (Cambridge, England) · 2012Article
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Authors and funding
5 authors at 4 institutions in 2 countries.
Funding
Abstract
Cryptophycins (Crp) are a group of cyanobacterial depsipeptides with activity against drug-resistant tumors. Although they have been shown to be promising, further efforts are required to return these highly potent compounds to the clinic through a new generation of analogues with improved medicinal properties. Herein, we report a chemosynthetic route relying on the multifunctional enzyme CrpD-M2 that incorporates a 2-hydroxy acid moiety (unit D) into Crp analogues. CrpD-M2 is a unique non-ribosomal peptide synthetase (NRPS) module comprised of condensation-adenylation-ketoreduction-thiolation (C-A-KR-T) domains. We interrogated A-domain 2-keto and 2-hydroxy acid activation and loading, and KR domain activity in the presence of NADPH and NADH. The resulting 2-hydroxy acid was elongated with three synthetic Crp chain elongation intermediate analogues through ester bond formation catalyzed by CrpD-M2 C domain. Finally, the enzyme-bound seco-Crp products were macrolactonized by the Crp thioesterase. Analysis of these sequential steps was enabled through LC-FTICR-MS of enzyme-bound intermediates and products. This novel chemoenzymatic synthesis of Crp involves four sequential catalytic steps leading to the incorporation of a 2-hydroxy acid moiety in the final chain elongation intermediate. The presented work constitutes the first example where a NRPS-embedded KR domain is employed for assembly of a fully elaborated natural product, and serves as a proof-of-principle for chemoenzymatic synthesis of new Crp analogues.
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