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Biosynthesis of the 4-Methyloxazoline-Containing Nonribosomal Peptides, JBIR-34 and -35, in Streptomyces Sp

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Biosynthesis of the 4-Methyloxazoline-Containing Nonribosomal Peptides, JBIR-34 and -35, in Streptomyces Sp View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Chemistry & Biology Article Biosynthesis of the 4-Methyloxazoline-Containing Nonribosomal Peptides, JBIR-34 and -35, in Streptomyces sp. Sp080513GE-23 Adeline Muliandi,1 Yohei Katsuyama,1 Kaoru Sone,1 Miho Izumikawa,2 Tomohiro Moriya,1 Junko Hashimoto,2 Ikuko Kozone,2 Motoki Takagi,2 Kazuo Shin-ya,3 and Yasuo Ohnishi1,* 1Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan 2Japan Biological Informatics Consortium (JBIC), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan 3National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan *Correspondence: [email protected] http://dx.doi.org/10.1016/j.chembiol.2014.06.004 SUMMARY eties are probably derived from the nonproteinogenic amino acid, a-methylserine, or produced by methylation of oxazoline JBIR-34 and -35 produced by Streptomyces sp. synthesized from serine. The similar five-membered ring, Sp080513GE-23 are nonribosomal peptides that 4-methylthiazoline, which is found in the structures of yersinia- possess an unusual 4-methyloxazoline moiety. bactin (Figure 1C), hoiamides, largazoles, and thiazohalostatin, Through draft genome sequencing, cosmid cloning, is synthesized via a-methylation of cysteine during peptide elon- and gene disruption, the JBIR-34 and -35 biosyn- gation (Patel et al., 2003; Choi et al., 2010; Ungermannova et al., thesis gene cluster (fmo cluster) was identified; it 2012; Shindo et al., 1993). To date, however, there is no biosyn- thetic study on the origin of 4-methyloxazoline. encodes 20 proteins including five nonribosomal NRPs, some of which have valuable bioactivities, are produced peptide synthetases (NRPSs). Disruption of one of by a wide variety of microorganisms. Pharmaceutically important fmoA3 these NRPS genes ( ) resulted in no JBIR-34 antibiotics including vancomycin, daptomycin, and beta-lactam and -35 production and accumulation of 6-chloro- antibiotics belong to this class, which emphasizes the 4-hydroxyindole-3-carboxylic acid. Stable isotope- importance of NRPs in the industry (Martin, 2000; Walsh, 2004). feeding experiments indicated that the methyl group They also attract interest because combinatorial biosynthesis of the methyloxazoline ring is derived from alanine can be applied for production of novel NRPs (Walsh, 2004). rather than methionine. A recombinant FmoH pro- Typical nonribosomal peptide synthetases (NRPSs) show tein, a glycine/serine hydroxymethyltransferase ho- modular structure, and each module is responsible for the condensation of one amino acid. One module is usually molog, catalyzed conversion of a-methyl-L-serine composed of three domains, condensation (C) domain, adenyla- into D-alanine (the reverse reaction of a-methyl-L- tion (A) domain, and thiolation (T) domain. The T domain is a serine synthesis catalyzed by FmoH in vivo). Taken a carrier protein containing a serine residue that is phosphopante- together, we concluded that -methyl-L-serine syn- theinylated; an amino acid or a growing peptide is covalently thesized from D-alanine is incorporated into JBIR- attached to the phosphopantetheine arm via a thioester bond. 34 and -35 to form the 4-methyloxazoline moiety. The A domain is responsible for amino acid selection and We also propose the biosynthesis pathway of JBIR- catalyzes formation of a thioester bond between the phospho- 34 and -35. pantetheine arm of the T domain and an amino acid substrate by consuming ATP. The C domain is responsible for the peptide bond formation between an amino acid attached to one T domain INTRODUCTION and the growing peptide (or an amino acid in the initial condensa- tion) attached to another T domain. Sometimes, a module con- JBIR-34 and -35 (1 and 2) produced by Streptomyces sp. tains an accessory enzyme domain such as methyltransferase Sp080513GE-23 are small chlorinated nonribosomal peptides (MT) domain and epimerization (E) domain to modify the growing (NRPs) having a weak radical scavenging activity (Figure 1A; Mo- peptide or amino acid before condensation. In some cases, the tohashi et al., 2010). These compounds possess a characteristic C domain is substituted by the heterocyclization (CYC) domain, 4-methyloxazoline moiety, which is rarely found in natural prod- catalyzing formation of the oxazoline or thiazoline ring. In the ucts. BE-32030 derivatives, which are inhibitors of cancer prolif- end, the synthesized peptide is cleaved off from the enzyme by eration, are the only compounds that possess this moiety other the thioesterase (TE) domain, which catalyzes simple hydrolysis than JBIR-34 and -35 (Figure 1B; Tsukamoto et al., 1997). Almost or macrocycle formation. This modular structure enabled engi- all of the methyloxazoline moieties observed in natural products neering of NRPSs to produce various peptides by substituting are 5-methyloxazoline, which is derived from the proteinogenic A domains, which are responsible for amino acid selection. amino acid, threonine. In contrast, the 4-methyloxazoline moi- Nguyen et al. (2006) successfully produced daptomycin analogs Chemistry & Biology 21, 923–934, August 14, 2014 ª2014 Elsevier Ltd All rights reserved 923 Chemistry & Biology Biosynthetic Origin of Unusual 4-Methyloxazoline O O O A H BC N HO H OH N OH N R S O H OH S OH N O O OH N N R R N 2 OH O S OH H Cl N O N R1 N N H R1, R2 = H, yersiniabactin O O O R = Me, JBIR-34 (1) O N R1 = C5H12, R2 = Me, micacocidin R = H, JBIR-35 (2) OH BE-32030 derivatives NH O D H 2 E F HO N OH OH R O H O O HO O N N O OH OH OH NH HO O O N O Cl N Cl N R = NMe2, amicetin H H R = NHMe, bamicetin 34 Figure 1. Structures of the Compounds (A and B) JBIR-34, -35 (A), and BE-32030 derivatives (B) possess a distinct 4-methyloxazoline moiety. (C) Yersiniabactin and micacocidin possess a 4-methylthiazoline moiety, which is derived from cysteine via methylation by a SAM-dependent methyltransferase. (D) Amicetin possesses an a-methyl-L-serine moiety attached to the aromatic amine group. (E and F) 6-Chloro-4-hydroxyindole-3-carboxylic acid (E) and N-(6-chloro-4-hydroxyindole-3-carboxyl)-a-methyl-L-serine (F) were isolated from Streptomyces sp. Sp080513GE-23 in this study and are intermediates of JBIR-34 and -35 biosynthesis. by engineering the daptomycin-biosynthesis NRPSs. A fasci- In this study, we analyzed the biosynthesis of JBIR-34 and -35 nating feature of NRPSs is their ability to use nonproteinogenic by identifying their biosynthesis gene cluster, disrupting an amino acids (Walsh et al., 2013). For instance, hydroxyphenylgly- NRPS gene, stable isotope-feeding experiments, and in vitro cine, ornithine, and alkylproline moieties are observed in vanco- enzyme assays. We mainly focused on the biosynthesis origin mycin, daptomycin, and sibiromycin, respectively (Recktenwald of an intriguing 4-methyloxazoline ring and revealed that it is et al., 2002; Miao et al., 2005; Li et al., 2009). Incorporation of non- synthesized from a-methyl-L-serine. This key intermediate is proteinogenic amino acids is important for their structural diver- synthesized from D-alanine by FmoH, which is a glycine/serine sity and bioactivity. Therefore, exploring the enzymatic chemistry hydroxymethyltransferase homolog. Taken together with several of the A domain for incorporation of novel nonproteinogenic other results, we predicted the entire biosynthesis pathway of amino acids could enhance the structural diversity of NRPs JBIR-34 and -35. because it would be available for combinatorial biosynthesis. Glycine/serine hydroxymethyltransferase is a pyridoxal-50- RESULTS phosphate (PLP)-dependent enzyme and catalyzes the forma- tion of serine from glycine using 5,10-methylenetetrahydrofolate Search for JBIR-34 and -35 Biosynthesis Intermediates (mTHF) as a hydroxymethyl group donor. It is also predicted to To obtain insight into the biosynthesis pathway of JBIR-34 and be responsible for biosynthesis of nonproteinogenic amino acids -35, we attempted to isolate JBIR-34 and -35 derivatives from in secondary metabolite biosynthesis; AmiS in amicetin biosyn- the culture broth of the producer strain. We assumed that the thesis by Streptomyces vinaceusdrappus NRRL 2363 has been chlorine group of these compounds is incorporated at an early hypothesized to catalyze a-methylserine synthesis using alanine stage of biosynthesis and searched for compounds containing instead of glycine as a substrate (Zhang et al., 2012). In addition a chlorine group using liquid chromatography-mass spectrom- to AmiS, there are two examples of enzymes that catalyze the etry (LC-MS) analysis. Compounds containing a chlorine group conversion between D-alanine and a-methyl-L-serine. These en- show a characteristic isotope pattern, which enables us to search zymes were purified from Paracoccus sp. AJ110402 (BAG31000) for chlorine-containing compounds only with LC-MS. As a result, and Aminobacter sp. (BAG31001) and characterized in vitro (No- we succeeded in the detection of two compounds (compounds 3 zaki et al., 2008, 2009). A neighbor of glycine/serine hydroxyme- and 4), which showed [M + H]+ monoisotopic ions at m/z 212 thyltransferase, threonine aldolase, has recently been attracting and 313, respectively. These compounds were purified and their attention as an enzyme for synthesizing nonproteinogenic amino structures were analyzed with 1H nuclear magnetic resonance acids. Barnard-Britson
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