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- Title
Semisynthetic production of unnatural L-a-amino acids by metabolic engineering of the cysteine-biosynthetic pathway.
- Authors
Maier, Thomas H. P.
- Abstract
There is an increasing demand for peptide-mimicking molecules to modulate the interactions between proteins of pharmaceutical and agrochemical interest and their target polypeptides. Unnatural L-a-amino acids differing from the 20 naturally proteinogenic amino acids only in their side chain are ideal for this purpose, but their chemical synthesis is complex. Here we describe a fermentation-based approach for biosynthesis of unnatural amino acids after re-engineering the cysteine-biosynthetic pathway in Escherichia coli. O-acetylation of serine, the committed step of the pathway, was released from feedback inhibition by mutating the serine acetyltransferase gene. Next, the naturally broad substrate specificity of O-acetylserine sulfhydrylase was exploited for the direct in vivo incorporation of an unnatural side chain in a semisynthetic fermentation process comparable to the production of B-lactams. O-acetyl-L-serine extruded from the cells by way of the O-acetylserine efflux protein was amenable to further biotransformations.
- Subjects
AMINO acid synthesis; ESCHERICHIA coli; ACYLTRANSFERASES
- Publication
Nature Biotechnology, 2003, Vol 21, Issue 4, p422
- ISSN
1087-0156
- Publication type
Article
- DOI
10.1038/nbt807