Formation of beta-hydroxy histidine in the biosynthesis of nikkomycin antibiotics.
Nikkomycins, a group of peptidyl nucleoside antibiotics produced Streptomyces tendae Tü901, are potent competitive inhibitors of chitin synthase. In this study, three nikkomycin biosynthetic enzymes, NikP1, NikQ, and NikP2, were overexpressed, purified, and characterized. The NikP1 activated L-His and transferred it to the carrier protein domain to form L-His-S-NikP1, which served as the beta-hydroxylation substrate of NikQ. The beta-OH-His was then hydrolytically released from NikP1 by NikP2. The results reported here substantiate our earlier proposal that the covalent tethering of an amino acid onto a carrier protein domain prior to downstream modification is a general strategy for diverting a fraction of the amino acid into secondary metabolism.
Chen
Huawei
H
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
Hubbard
Brian K
BK
O'Connor
Sarah E
SE
Walsh
Christopher T
CT
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000494:pharmacology; D002687:Chitin Synthase / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006639:Histidine / Q000378:metabolism*; D006900:Hydroxylation; D013302:Streptomyces / Q000378:metabolism*; D013379:Substrate Specificity
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D006639:Histidine; C011952:nikkomycin; D002687:Chitin Synthase