In microbial natural products, heptoses can be classified into four groups structurally: heptofuranoses, highly reduced heptopyranoses, L-heptopyranoses and D-heptopyranoses. The biosynthetic mechanisms of heptoses belonging to the first two groups have been well elucidated, while, very little is known about the biosynthesis of L-heptopyranoses and D-heptopyranoses, represented by septacidin and hygromycin B respectively.
In a paper published in PNAS, CHEN Yihua’s lab at Institute of Microbiology of Chinese Academy of Sciences (CAS) made progress on the biosynthesis of those heptoses.
Heptoses exist in the core region of lipopolysaccharide (LPS) of Gram-negative bacteria cell wall. These heptoses are biosynthesized using sedoheptulose-7-phosphate as a precursor, by isomeration (GmhA), phosphorylation at C1 position (HldE), dephosphorylation at C7 position (GmhB), adenylylation (HldE) and C6 epimeration of the hydroxyl group (HldD) to form an intermediate ADP-L-glycero-β-D-manno-heptose and transferred to the aglycon further.
The researchers found that the heptose of septacidin, an antifungal and antitumor compound from Gram-positive bacteria, is also derived from D-sedoheptulose-7-phosphate and uses the same biosynthetic logic as that in the LPS biosynthesis, and septacidin producer, a Gram-positive bacterium, shares the same ADP-heptose biosynthesis pathway with Gram-negative bacterium lipopolysaccharide biosynthesis.
The findings showed that the primary metabolite of Gram-negative bacteria and secondary metabolite of Gram-positive bacteria share a conserved heptose biosynthetic pathway. Worthy of particular note is the involvement of ADP-sugar in microbial natural product biosynthesis, which indicates that, besides GDP-, CDP-, UDP-, and dTDP-sugar, ADP-sugar may also serve as a donor for natural product glycosylation.
Hygromycin B contains a unique D-heptopyranos, which is also derived from D-sedoheptulose-7-phosphate. It was showed that HygP, together with HldE and GmhB from E. coli, was able to efficiently convert D-sedoheptulose-7-phosphate into ADP-D-glycero-β-D-altro-heptose.
The study set the stage for the generation of novel septacidin derivatives by combinatorial biosynthesis and structural modification of the heptoses in the LPS inner core of gram-negative bacterium.
The study was supported by Ministry of Science and Technology of China, National Natural Science Foundation of China, “Hundred Talents Program” of CAS, and the Youth Innovation Promotion Association of CAS.
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