Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 29, Issue 33, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202301056
Keywords
biosynthesis; carbamoylation; pactamycin; post-glycosylation modification; protein-bound
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This study reports the synthesis process of the potent antitumor antibiotic pactamycin, and reveals the synthetic pathway by post-glycosylation modifications of its sugar moiety.
The potent antitumor antibiotic pactamycin is an aminocyclopentitol-containing natural product produced by the soil bacterium Streptomyces pactum. Recent studies showed that the aminocyclopentitol unit is derived from N-acetyl-D-glucosamine, which is attached to an acyl carrier protein (ACP)-bound polyketide by a glycosyltransferase enzyme, PtmJ. Here, we report a series of post-glycosylation modifications of the sugar moiety of the glycosylated polyketide while it is still attached to the carrier protein. In vitro reconstitution of PtmS (an AMP-ligase), PtmI (an ACP), PtmJ, PtmN (an oxidoreductase), PtmA (an aminotransferase), and PtmB (a putative carbamoyltransferase) showed that the N-acetyl-D-glucosamine moiety of the glycosylated polyketide is first oxidized by PtmN and then transaminated by PtmA to give ACP-bound 3-amino-3-deoxy-N-acetyl-D-glucosaminyl polyketide. The amino group is then coupled with carbamoyl phosphate by PtmB to give a urea functionality. We also show that PtmG is a deacetylase that hydrolyses the C-2 N-acetyl group to give a free amine.
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