The AcbC protein from Actinoplanes species is a C7-cyclitol synthase related to 3-dehydroquinate synthases and is involved in the biosynthesis of the alpha-glucosidase inhibitor acarbose.
The putative biosynthetic gene cluster for the alpha-glucosidase inhibitor acarbose was identified in the producer Actinoplanes sp. 50/110 by cloning a DNA segment containing the conserved gene for dTDP-D-glucose 4,6-dehydratase, acbB. The two flanking genes were acbA (dTDP-D-glucose synthase) and acbC, encoding a protein with significant similarity to 3-dehydroquinate synthases (AroB proteins). The acbC gene was overexpressed heterologously in Streptomyces lividans 66, and the product was shown to be a C7-cyclitol synthase using sedo-heptulose 7-phosphate, but not ido-heptulose 7-phosphate, as its substrate. The cyclization product, 2-epi-5-epi-valiolone ((2S,3S,4S,5R)-5-(hydroxymethyl)cyclohexanon-2,3,4,5-tetrol), is a precursor of the valienamine moiety of acarbose. A possible five-step reaction mechanism is proposed for the cyclization reaction catalyzed by AcbC based on the recent analysis of the three-dimensional structure of a eukaryotic 3-dehydroquinate synthase domain (Carpenter, E. P., Hawkins, A. R., Frost, J. W., and Brown, K. A. (1998) Nature 394, 299-302).
Stratmann
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A
Chemische Mikrobiologie, FB9-Chemie, Bergische Universität GH Wuppertal, Gauss-Strasse 20, D-42097 Wuppertal, Germany.
Mahmud
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T
Lee
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S
Distler
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J
Floss
H G
HG
Piepersberg
W
W
D020909:Acarbose; D000192:Actinomycetales / Q000201:enzymology*; D000595:Amino Acid Sequence; D001426:Bacterial Proteins; D001483:Base Sequence; D002240:Carbohydrate Sequence; D003001:Cloning, Molecular; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000378:metabolism*; D065089:Glycoside Hydrolase Inhibitors; D019746:Intramolecular Oxidoreductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D005810:Multigene Family; D019761:Phosphorus-Oxygen Lyases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D014312:Trisaccharides / Q000096:biosynthesis*
D001426:Bacterial Proteins; D017931:DNA Primers; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D014312:Trisaccharides; C020001:3-dehydroquinate synthetase; D019761:Phosphorus-Oxygen Lyases; D019746:Intramolecular Oxidoreductases; C118743:ACBC protein, Actinoplanes; D020909:Acarbose