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Biosynthetic Origin of Anthracimycin: a Tricyclic Macrolide from Streptomyces Sp

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Biosynthetic Origin of Anthracimycin: a Tricyclic Macrolide from Streptomyces Sp The Journal of Antibiotics (2016) 69, 403–405 & 2016 Japan Antibiotics Research Association All rights reserved 0021-8820/16 www.nature.com/ja NOTE Biosynthetic origin of anthracimycin: a tricyclic macrolide from Streptomyces sp. Enjuro Harunari1, Hisayuki Komaki2 and Yasuhiro Igarashi1 The Journal of Antibiotics (2016) 69, 403–405; doi:10.1038/ja.2015.118; published online 2 December 2015 Anthracimycin (1) is a decalin-fused tricyclic macrolide isolated from signals arising from the 13C–13C coupling were clearly observed for all terrestrial and marine Streptomyces species (Figure 1).1–3 1 shows the carbons except for three methyl groups (C-23, C-24 and C-25) strong activity against Gram-stain-positive bacteria including Bacillus and C-11 and C-12 (Supplementary Figure S1). The outer split peaks anthracis and methicillin-resistant Staphylococcus aureus (MRSA).3,4 were invisible owing to the roof effect7 caused by the close chemical The most intriguing feature of this molecule is its enantiomerism to shifts between C-11 and C-12 (Δ 0.11 p.p.m.) although these carbons chlorotonil A (2), a secondary metabolite of a myxobacterium are likely derived from a single acetate unit. In the 2D-INADEQUATE 5 1 Sorangium cellulosum (Figure 1). Except for a methyl substitution at spectrum measured with a parameter set optimized for JCC 45 Hz, 13 C-8 in 2, the absolute configurations of the remaining chiral centers at cross peaks derived from the intact C2 acetate units were observed C-2, C-6, C-7, C-12, C-15 and C-16 are opposite between 1 and 2 for C-1/C-2, C-3/C-4, C-5/C-6, C-7/C-8, C-9/C-10, C-13/C-14, C-15/ although the dichrorination at C-4 in 2 is an additional difference C-16, C-17/C-18, C-19/C-20 and C-21/C-22 (Table 1, Supplementary between these compounds. In nature, such enantiomeric natural Figure S3). The INADEQUATE correlation for C-11/C-12 could not products can be seen in various organisms from bacteria to plants.6 be observed owing to the strong coupling also caused by their close Simple examples include monoterpenes such as (+)-limonene and chemical shift. The peak separation for C-11 and C-12 was then ( À)-limonene produced from a common linear precursor geranylger- compared in different solvents and the best separation (Δ 0.31 p.p.m.) À anyl pyrophosphate by the catalysis of (+)-limonene and ( ) was obtained in benzene-d6 (Supplementary Figure S2). The -limonene synthases, respectively (Figure 2). One of the more complex 2D-INADEQUATE spectrum in this solvent, however, still did not examples is a fungal alkaloid notoamide. ( À)-Notoamide B is give a cross peak for C-11/C-12. It is theoretically predicted that the produced by a marine Aspergillus species, whereas its enantiomer conventional parameter setting for 13C–13C coupling detection is not (+)-notoamide B is produced by a terrestrial Aspergillus strain.6 The appropriate for carbons with such a small chemical shift difference.8 1 enantiomeric biosynthesis of notoamides is proposed to include a According to this prediction, instead of a normal setting τ = 1/4 JCC 1 common achiral precursor, which is enantiomerically cyclized to a pair for delay, τ was set to be 3/4 JCC, which successfully allowed detection of enantiomers through intramolecular Diels–Alder reaction of a coupling between C-11 and C-12 (Supplementary Figure S4). (Figure 2). In these cases, a common single achiral precursor cyclizes The labeling experiment with the doubly labeled acetate indicated into respective enantiomeric products: no chiral centers exist in the methyl groups (C-23, C-24, and C-25) were not derived from precursors. Meanwhile, in the biosynthesis of 1 and 2 it is likely that methylmalonate. To clarify the origin of these methyl carbons, a 13 a pair of chiral precursors independently produced in actinobacterial feeding experiment of a plausible precursor L-[methyl- C]methionine and myxobacterial cells undergo the intramolecular Diels–Alder was carried out. High levels of enrichments of the methyl carbons reaction (Figure 3). To the best of our knowledge, there exist no were observed in the 13CNMRspectrum,confirming that the methyl such natural products that are generated from a pair of enantiomeric branching is created by C-methylation of the polyketide chain precursors into highly modified structures. In order to understand this (Table 1, Figure 4, Supplementary Figure S5). unusual enantiomeric biosynthesis, we investigated the biosynthetic There are three major features that make anthracimycin (1) unusual origins of 1 for further genetic and/or enzymatic analysis. Herein, we as an actinomycete metabolite. First, three methyl groups in the describe the results from the 13C-labeling experiment of 1. polyketide chain of 1 are derived from methionine. In polyketide As the carbon skeleton of 1 suggested its generation through the biosynthesis, actinobacteria mostly utilize methylmalonyl CoA for 13 malonate pathway, [1,2- C2]acetate was fed to the culture to ensure generation of methyl branching in the carbon chain, whereas the the alignment of extender units. In the 13C NMR spectrum, split fungal polyketide synthase (PKS) exclusively use methionine as a 1Biotechnology Research Center and Department of Biotechnology, Toyama Prefectural University, Toyama, Japan and 2Biological Resource Center, National Institute of Technology and Evaluation (NBRC), Chiba, Japan Correspondence: Professor Y Igarashi, Biotechnology Research Center and Department of Biotechnology, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan. E-mail: [email protected] Received 31 August 2015; revised 8 October 2015; accepted 14 October 2015; published online 2 December 2015 Biosynthetic origin of anthracimycin EHarunariet al 404 substrate for C-methylation to create methyl branching.9 It is work will be directed toward biochemical analysis to elucidate the uncommon for actinobacteria to generate the methyl substitution in molecular basis of enantiomeric biosynthesis. the polyketide chain by C-methylation in type I polyketides. Examples are limited to several secondary metabolites: aplasmomycin,10 GENERAL PROCEDURE 11 12 13 13 boromycin, aurodox and lankacidin C. Second, anthracimycin Sodium [1,2- C2]acetate was purchased from Cambridge Isotope Laboratories 13 (1) has the same carbon framework as a myxobacterial metabolite (Tewksbury, MA, USA), Inc. L-[Methyl- C]methionine was purchased from chlorotonil A (2) except for an extra methyl substitution and ISOTEC Inc. (Miamisburg, OH, USA). NMR spectra were obtained on a halogenation modification. Actinobacteria and myxobacteria are Bruker AVANCE 500 spectrometer (Bruker BioSpin KK Kanagawa, Japan) in 13 phylogenetically distinct: the former are Gram-stain-positive and the CDCl3 and benzene-d6. C chemical shifts were referenced to the residual δ δ latter are Gram-stain-negative. It is known that distantly related solvent signals (CDCl3: C 77.0; benzene-d6: C 127.7). microbes can engage in horizontal transfer of secondary metabolite biosynthetic genes. However, it is very rare that actinomycetes and Microorganism myxobacteria are producing secondary metabolites that share a Streptomyces sp. strain TP-A0875 was isolated from compost material collected common carbon framework. One such example only includes in Ishikawa, Japan. The strain was identified as a member of the genus actinofuranones from Streptomyces and aurafurones from a Stigmas- Streptomyces on the basis of 99.4% 16S rRNA gene sequence identity tella strain although the structural similarity is lower than the case of 1 (1453 nucleotides; DDBJ accession number AB451554) with Streptomyces collinus NBRC 12759T (accession number AB184123). and 2.14 Third, anthracimycin (1) and chlorotonil A (2)havethe opposite absolute configuration. There is no other example of enantiomeric compounds with polycyclic, complex structures among FERMENTATION the type I PKS-derived secondary metabolites. Strain TP-A0875 growing on a plate culture was inoculated into a fl Recently, we reported the draft genome sequencing of the produ- 500-ml K-1 ask containing 100 ml of the V-22 seed medium cing strain Streptomyces sp. TP-A0875.15 Two type I PKS gene clusters consisting of soluble starch 1.0%, glucose 0.5%, NZ-case 0.3%, yeast exist in the genome and one of them is assigned to the biosynthetic extract, 0.2%, Tryptone (Difco Laboratories, Detroit, MI, USA) 0.5%, · gene cluster of 1 on the basis of PKS gene function prediction. Future K2HPO4 0.1%, MgSO4 7H2O 0.05% and CaCO3 0.3% (pH 7.0). The flask was placed on a rotary shaker (200 r.p.m.) at 30 °C for 4 days. Then, the seed culture (3 ml) was transferred into 500-ml K-1 flasks each containing 100 ml of the A-3M production medium consisting of soluble starch 2.0%, glycerol 2.0%, glucose 0.5%, Pharmamedia (Traders Protein, Memphis, TN, USA) 1.5%, yeast extract 0.3% and Diaion HP-20 resin (Mitsubishi Chemical Co., Kanagawa, Japan) 1%. The pH of the medium was adjusted to 7.0 before sterilization. The inoculated flasks were placed on a rotary shaker (200 r.p.m.) at 30 °C Figure 1 Structures of anthracimycin (1) and chlorotonil A (2). for 6 days. Figure 2 Enantiomeric natural products from achiral precursors. Figure 3 Plausible biogenesis of anthracimycin (1) and chlorotonil A (2) from chiral precursors. The Journal of Antibiotics Biosynthetic origin of anthracimycin EHarunariet al 405 Table 1 Incorporation of 13C-labeled precursors into 1 purification was achieved by preparative HPLC (Cosmosil 5C18-AR- II, 10 × 250 mm, 4 ml min − 1) using a gradient of MeCN/0.1% 13 L-[methyl- C]methionine HCO2H (MeCN concentration: 80–100–100% for 0–10–20 min) at 13 − [1,2- C2]acetate (benzene-d6) (CDCl3) 4mlmin 1, yielding 1 (5.6 mg) with a retention time of 13.3 min.
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