1. Academic Validation
  2. d-Sedoheptulose-7-phosphate is a common precursor for the heptoses of septacidin and hygromycin B

d-Sedoheptulose-7-phosphate is a common precursor for the heptoses of septacidin and hygromycin B

  • Proc Natl Acad Sci U S A. 2018 Mar 13;115(11):2818-2823. doi: 10.1073/pnas.1711665115.
Wei Tang 1 2 Zhengyan Guo 1 Zhenju Cao 1 2 Min Wang 1 Pengwei Li 1 Xiangxi Meng 1 2 Xuejin Zhao 1 Zhoujie Xie 1 Wenzhao Wang 3 Aihua Zhou 4 Chunbo Lou 1 Yihua Chen 5 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Microbial Resources, and CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China.
  • 2 College of Life Sciences, University of Chinese Academy of Sciences, 100049 Beijing, China.
  • 3 State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China.
  • 4 Pharmacy School, Jiangsu University, 212013 Jiangsu, China.
  • 5 State Key Laboratory of Microbial Resources, and CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China; [email protected].
Abstract

Seven-carbon-chain-containing sugars exist in several groups of important bacterial Natural Products. Septacidin represents a group of l-heptopyranoses containing nucleoside Antibiotics with antitumor, Antifungal, and pain-relief activities. Hygromycin B, an Aminoglycoside anthelmintic agent used in swine and poultry farming, represents a group of d-heptopyranoses-containing Antibiotics. To date, very little is known about the biosynthesis of these compounds. Here we sequenced the genome of the septacidin producer and identified the septacidin gene cluster by heterologous expression. After determining the boundaries of the septacidin gene cluster, we studied septacidin biosynthesis by in vivo and in vitro experiments and discovered that SepB, SepL, and SepC can convert d-sedoheptulose-7-phosphate (S-7-P) to ADP-l-glycero-β-d-manno-heptose, exemplifying the involvement of ADP-sugar in microbial natural product biosynthesis. Interestingly, septacidin, a secondary metabolite from a gram-positive bacterium, shares the same ADP-heptose biosynthesis pathway with the gram-negative bacterium LPS. In addition, two acyltransferase-encoding genes sepD and sepH, were proposed to be involved in septacidin side-chain formation according to the intermediates accumulated in their mutants. In hygromycin B biosynthesis, an isomerase HygP can recognize S-7-P and convert it to ADP-d-glycero-β-d-altro-heptose together with GmhA and HldE, two enzymes from the Escherichia coli LPS heptose biosynthetic pathway, suggesting that the d-heptopyranose moiety of hygromycin B is also derived from S-7-P. Unlike the other S-7-P isomerases, HygP catalyzes consecutive isomerizations and controls the stereochemistry of both C2 and C3 positions.

Keywords

Streptomyces; biosynthesis; heptose; lipopolysaccharide; natural product.

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