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Biosynthesis of the (2S,3R)-3-Methyl Glutamate Residue of Nonribosomal Lipopeptides

C. Milne, A. Powell, J. Jim, M. Al Nakeeb C. P. Smith and J. Micklefield

Journal of the American Chemical Society. 2006;128:11250-11259.

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Abstract

The calcium-dependent antibiotics (CDAs) and daptomycin are therapeutically relevant nonribosomal lipopeptide antibiotics that contain penultimate C-terminal 3-methyl glutamate (3-MeGlu) residues. Comparison with synthetic standards showed that (2S,3R)-configured 3-MeGlu is present in both CDA and daptomycin. Deletion of a putative methyltransferase gene glmT from the cda biosynthetic gene cluster abolished the incorporation of 3-MeGlu and resulted in the production of Glu-containing CDA exclusively. However, the 3-MeGlu chemotype could be re-established through feeding synthetic 3-methyl-2-oxoglutarate and (2S,3R)-3-MeGlu, but not (2S,3S)-3-MeGlu. This indicates that methylation occurs before peptide assembly, and that the module 10 A-domain of the CDA peptide synthetase is specific for the (2S,3R)-stereoisomer. Further mechanistic analyses suggest that GlmT catalyzes the SAM-dependent methylation of α-ketoglutarate to give (3R)-methyl-2-oxoglutarate, which is transaminated to (2S,3R)-3-MeGlu. These insights will facilitate future efforts to engineer lipopeptides with modified glutamate residues, which may have improved bioactivity and/or reduced toxicity.

Bibliographic metadata

Type of resource:
Content type:
Publication type:
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Published date:
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Volume:
128
Start page:
11250
End page:
11259
Total:
10
Pagination:
11250-11259
Digital Object Identifier:
10.1021/ja062960c
Access state:
Active

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University researcher(s):

Record metadata

Manchester eScholar ID:
uk-ac-man-scw:1a9548
Created:
6th August, 2009, 15:27:58
Last modified by:
Micklefield, Jason
Last modified:
25th September, 2009, 17:15:30

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