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Biosynthesis of the (2S,3R)-3-methyl glutamate residue of nonribosomal lipopeptides

Milne, C, Powell, A, Al Nakeeb, M, Micklefield, J, Jim, J and Smith, CP (2006) Biosynthesis of the (2S,3R)-3-methyl glutamate residue of nonribosomal lipopeptides Journal of the American Chemical Society, 128 (34). pp. 11250-11259.

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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. © 2006 American Chemical Society.

Item Type: Article
Authors :
Milne, C
Powell, A
Al Nakeeb, M
Micklefield, J
Jim, J
Smith, CP
Date : 30 August 2006
DOI : 10.1021/ja062960c
Depositing User : Symplectic Elements
Date Deposited : 28 Mar 2017 14:39
Last Modified : 31 Oct 2017 14:26

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