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Chemoenzymatic Synthesis of Cryptophycin Anticancer Agents by an Ester Bond-Forming Non-ribosomal Peptide Synthetase Module

Ding, Yousong and Rath, Christopher M. and Bolduc, Kyle L. and Håkansson, Kristina and Sherman, David H. (2011) Chemoenzymatic Synthesis of Cryptophycin Anticancer Agents by an Ester Bond-Forming Non-ribosomal Peptide Synthetase Module. Journal of the American Chemical Society, 133 (37). pp. 14492-14495. ISSN 0002-7863. https://resolver.caltech.edu/CaltechAUTHORS:20111101-073439037

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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 themultifunctional enzyme CrpD-M2 that incorporates a 2-hydroxy acid moiety (unit D) into Crp analogues. CrpD-M2 is a unique nonribosomal 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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/ja204716fDOIUNSPECIFIED
http://pubs.acs.org/doi/full/10.1021/ja204716fPublisherUNSPECIFIED
Additional Information:© 2011 American Chemical Society. Received: May 23, 2011. Publication Date (Web): August 8, 2011. Y.D. was supported by a Rackham Predoctoral Fellowship. This work was supported by NIH grant CA108874, GM076477 and the Hans W. Vahlteich Professorship (toD.H.S.).Work in K.H.’s laboratory is supported by an NSF Career Award (CHE-05-47699).
Funders:
Funding AgencyGrant Number
Rackham Predoctoral FellowshipUNSPECIFIED
NIHCA108874
NIHGM076477
Hans W. Vahlteich ProfessorshipUNSPECIFIED
NSF Career AwardCHE-05-47699
Issue or Number:37
Record Number:CaltechAUTHORS:20111101-073439037
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20111101-073439037
Official Citation:Chemoenzymatic Synthesis of Cryptophycin Anticancer Agents by an Ester Bond-Forming Non-ribosomal Peptide Synthetase Module Yousong Ding, Christopher M. Rath, Kyle L. Bolduc, Kristina Hakansson, and David H. Sherman Journal of the American Chemical Society 2011 133 (37), 14492-14495
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:27538
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:01 Nov 2011 14:56
Last Modified:03 Oct 2019 03:24

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