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For the Heptoses of Septacidin and Hygromycin B D-Sedoheptulose-7-phosphate is a common precursor for the heptoses of septacidin and hygromycin B Wei Tanga,b,1, Zhengyan Guoa,1, Zhenju Caoa,b, Min Wanga, Pengwei Lia, Xiangxi Menga,b, Xuejin Zhaoa, Zhoujie Xiea, Wenzhao Wangc, Aihua Zhoud, Chunbo Loua, and Yihua Chena,b,2 aState 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; bCollege of Life Sciences, University of Chinese Academy of Sciences, 100049 Beijing, China; cState Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China; and dPharmacy School, Jiangsu University, 212013 Jiangsu, China Edited by Jerrold Meinwald, Cornell University, Ithaca, NY, and approved February 8, 2018 (received for review June 29, 2017) Seven-carbon-chain–containing sugars exist in several groups of im- β-substitution reaction (6). Not surprisingly, a LipK homolog protein- portant bacterial natural products. Septacidin represents a group of encoding gene, abmH, is present in the albomycin biosynthetic gene L-heptopyranoses containing nucleoside antibiotics with antitumor, an- cluster, indicating that the heptothiofuranose is formed through a tifungal, and pain-relief activities. Hygromycin B, an aminoglycoside similar carbon-chain extension process (5). anthelmintic agent used in swine and poultry farming, represents a Group II contains four highly reduced heptopyranoses from group of D-heptopyranoses–containing antibiotics. To date, very little several clinically important aminoglycoside antibiotics, including is known about the biosynthesis of these compounds. Here we se- gentamicin, verdamicin, and fortimicin (Fig. 1B) (7). Both in vivo quenced the genome of the septacidin producer and identified the and in vitro data support that a cobalamin-dependent radical septacidin gene cluster by heterologous expression. After determining SAM enzyme, GenK, catalyzes the C-6ʹ methylation of genta- the boundaries of the septacidin gene cluster, we studied septacidin micin X2, forming the 2ʹ-amino-2ʹ,7ʹ-dideoxy-α-D-gluco-heptose biosynthesis by in vivo and in vitro experiments and discovered that moiety of G418 (8–10), which is then converted to the highly SepB, SepL, and SepC can convert D-sedoheptulose-7-phosphate (S-7-P) reduced heptopyranoses in gentamicin or verdamicin by different β to ADP-L-glycero- -D-manno-heptose, exemplifying the involvement of tailoring processes. Similarly, a yet to be identified cobalamin- ADP-sugar in microbial natural product biosynthesis. Interestingly, sep- dependent methyltransferase was proposed to be responsible for tacidin, a secondary metabolite from a gram-positive bacterium, shares the heptopyranose biosynthesis of fortimicin (11). MICROBIOLOGY the same ADP-heptose biosynthesis pathway with the gram-negative Group III contains at least two L-heptopyranoses: a 4ʹ-amino-4ʹ- bacterium LPS. In addition, two acyltransferase-encoding genes sepD deoxy-L-glycero-β-L-gluco-heptose (GGH) from septacidin (12) and its and sepH, were proposed to be involved in septacidin side-chain for- 2ʹ-epimer, 4ʹ-amino-4ʹ-deoxy-L-glycero-β-L-manno-heptose (LGMH), mation according to the intermediates accumulated in their mutants. from spicamycin (13) (Fig. 1C). The structure of the L-heptopyranose In hygromycin B biosynthesis, an isomerase HygP can recognize S-7-P ʹ ʹ ʹ β from anicemycin is either LGMH or its 6 -epimer, 4 -amino-4 -deoxy- and convert it to ADP-D-glycero- -D-altro-heptose together with GmhA β and HldE, two enzymes from the Escherichia coli LPS heptose biosyn- D-glycero- -L-manno-heptose (DGMH), which needs to be determined by further studies (14) (Fig. 1C). Septacidin, anicemycin, and thetic pathway, suggesting that the D-heptopyranose moiety of hygromycin B is also derived from S-7-P. Unlike the other S-7-P spicamycin are all nucleoside antibiotics consisting of a unique isomerases, HygP catalyzes consecutive isomerizations and controls the stereochemistry of both C2 and C3 positions. Significance natural product | heptose | biosynthesis | lipopolysaccharide | Septacidin and its analogs are potential anticancer and pain-relief Streptomyces drugs. Hygromycin B is an anthelmintic agent practically used in swine and poultry farming. A common feature of these com- accharides are common components found in bacterial natural pounds is that they all have heptose moieties. Here we show that Sproducts, which usually have a profound impact on the bi- the heptoses of septacidin and hygromycin B are both derived ological properties of the compounds (1, 2). A significant number from D-sedoheptulose-7-phosphate but are biosynthesized of glycosylated bacterial natural products, such as erythromycin, through different pathways. Septacidin producer, a gram-positive doxorubicin, vancomycin, and avermectin, are practically used as bacterium, shares the same ADP-heptose biosynthesis pathway drugs for the treatment of human and animal diseases, and it is well with gram-negative bacterium lipopolysaccharide biosynthesis. established that changing the carbohydrate moieties in these drugs These findings not only elucidate the biosynthesis mechanisms of can influence their pharmacological properties significantly (1, 2). A septacidin and hygromycin B but enable opportunities for ma- nipulation of their heptose moieties by combinatorial biosynthesis recent systematic analysis revealed that >20% of bacterial natural and for changing the structure of heptoses in gram-negative products are glycosylated with 344 distinct carbohydrates, including bacterium lipopolysaccharides. diverse pentoses, hexoses, and high-carbon-chain–containing sugars, which are usually derived from carbohydrate precursors generated Author contributions: W.T., Z.G., and Y.C. designed research; W.T., Z.G., Z.C., M.W., P.L., by primary metabolism (2). X.M., X.Z., W.W., and A.Z. performed research; W.T., Z.G., C.L., and Y.C. analyzed data; Among the sugar moieties of bacterial natural products, there are and W.T., Z.G., Z.X., and Y.C. wrote the paper. at least 11 seven-carbon-chain–containing carbohydrates (2), which The authors declare no conflict of interest. can be classified into four groups structurally. Group I seven-carbon- This article is a PNAS Direct Submission. chain–containing sugar has two members: a heptofuranose from the Published under the PNAS license. lipopeptidyl nucleoside family of translocase I inhibitors, represented Data deposition: The sequence reported in this paper has been deposited in the GenBank by liposidomycin (3) and A-90289 (4), and a heptothiofuranose from database (accession no. MF372757). the “Trojan horse” antibiotic albomycin (5) (Fig. 1A). A biosynthesis 1W.T. and Z.G. contributed equally to this work. study of A-90289 revealed that the heptofuranose of its 5ʹ-C- 2To whom correspondence should be addressed. Email: [email protected]. glycyluridine moiety was formed by an L-threonine:uridine-5ʹ-alde- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. hyde transaldolase, LipK, which extended the pentofuranose of 1073/pnas.1711665115/-/DCSupplemental. uridine-5ʹ-aldehyde to heptofuranose via an L-threonine–dependent www.pnas.org/cgi/doi/10.1073/pnas.1711665115 PNAS Latest Articles | 1of6 Downloaded by guest on September 27, 2021 A B C Fig. 1. Representative bacterial natural products with seven-carbon-chain–containing carbohydrate D structures. (A) Group I compounds with heptofura- noses or heptothiofuranose; (B) group II compounds with highly reduced heptopyranoses; (C) group III compounds with L-heptopyranoses; (D) group IV compounds with D-heptopyranoses. The seven-car- bon-chain–containing carbohydrate moiety of each compound is shown in red. 6-N-glycosylated heptosamine-adenine moiety and a side chain cluster, and discovered D-sedoheptulose-7-phosphate (S-7-P) as containing a glycyl group and varied fatty acyl groups (12–14). a common precursor for the heptose moieties of septacidin and Septacidin, discovered as an antifungal and antitumor antibi- hygromycin B in this work. We also discovered that the heptose otic (15, 16), was found to be an immunogenic cell death in- is activated as an ADP-sugar in septacidin biosynthesis, exem- ducer recently (17); anicemycin is a newly identified inhibitor of plifying the involvement of ADP-sugar in microbial natural anchorage-independent growth of tumor cells (14); spicamycin product biosynthesis. displays an excellent antitumor activity by inhibiting protein synthesis (18, 19), and one of its derivatives, KRN5500, is now Results an anticancer drug under clinical trial (20). An unexpected Identification of the Septacidin Biosynthetic Gene Cluster. The ge- discovery during the cancer treatment process of KRN5500 is nome of the septacidin producer Streptomyces fimbriatus CGMCC that it can relieve neuropathic pain of patients (21). Therefore, this 4.1598 was draft sequenced and searched for the septacidin bio- compound is also under a phase II clinical trial as a drug for pain synthesis gene cluster using enzymes possibly involved in GGH relief (21). Due to its importance, diverse synthesis routes were biosynthesis as probes. After careful analysis, a DNA region, developed for spicamycin by different groups (22, 23). However, which contains genes encoding glycosyltransferase (SepE), ami- very little is known about the biosynthesis of the three nucleoside notransferase (SepG), sugar isomerase (SepJ), and a tridomain
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