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Production of Hygromycin a Analogs in Streptomyces Hygroscopicus NRRL 2388 Through Identification and Manipulation of the Biosyn

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Production of Hygromycin a Analogs in Streptomyces Hygroscopicus NRRL 2388 Through Identification and Manipulation of the Biosyn View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Chemistry & Biology 13, 753–764, July 2006 ª2006 Elsevier Ltd All rights reserved DOI 10.1016/j.chembiol.2006.05.013 Production of Hygromycin A Analogs in Streptomyces hygroscopicus NRRL 2388 through Identification and Manipulation of the Biosynthetic Gene Cluster Nadaraj Palaniappan,1 Sloan Ayers,2 Shuchi Gupta,1 recent footprinting experiments have shown that macro- El-Sayed Habib,2 and Kevin A. Reynolds1,* lides only block binding of hygromycin A to the ribosome 1 Department of Chemistry if they contain a mycarose unit [5]. Crystallographic ev- Portland State University idence indicates that in such macrolides, the C5-disac- P.O. Box 751 charide group extends from the polypeptide exit chan- Portland, Oregon 97207 nel into peptidyl transferase center [6]. Hygromycin A 2 Departments of Medicinal Chemistry is not a macrolide and thus offers a distinct carbon skel- Virginia Commonwealth University eton and binding mode to other antibiotics that target Richmond, Virginia 23219 the bacterial ribosome. As such, it represents a promis- ing starting point for generating new antibiotics to treat infections with drug-resistant pathogens. Summary Hygromycin A has also been reported to have addi- tional activities and potential applications. It exhibits Hygromycin A, an antibiotic produced by Streptomy- hemagglutination inactivation activity and high antitre- ces hygroscopicus NRRL 2388, offers a distinct car- ponemal activity [7, 8], leading to the possible applica- bon skeleton structure for development of antibacte- tion of hygromycin A-related compounds for the treat- rial agents targeting the bacterial ribosomal peptidyl ment of swine dysentery, a severe mucohemorrhagic transferase. A 31.5 kb genomic DNA region covering disease thought to be caused by Serpulina (Treponema) the hygromycin A biosynthetic gene cluster has been hyodysenteriae [8, 9]. Hygromycin A has also been re- identified, cloned, and sequenced. The hygromycin ported to possess an immunosuppressant activity in gene cluster has 29 ORFs which can be assigned to the mixed poor lymphocyte reaction but does not work hygromycin A resistance as well as regulation and via suppression of interleukin 2 production [10]. Most re- biosynthesis of the three key moieties of hygromycin cently, methoxyhygromycin A (compound 2)(Figure 1), A (5-dehydro-a-L-fucofuranose, (E)-3-(3,4-dihydroxy- an analog of hygromycin A produced in the same fer- phenyl)-2-methylacrylic acid, and 2L-2-amino-2-deoxy- mentation broth, has been shown to have herbicidal ac- 4,5-O-methylene-neo-inositol. The predicted Hyg26 tivity and has led to the suggestion that it could be de- protein has sequence homology to short-chain alco- veloped as a biological agent for weed control [11]. hol dehydrogenases and is assigned to the final step Semisynthetic programs based on hygromycin A and in production of the 5-dehydro-a-L-fucofuranose, cat- its attractive biological properties have been reported alyzing the reduction of a-L-fucofuranose. A hyg26 [12–14]. This work has led to the synthesis of over 100 mutant strain was generated and shown to produce analogs and determination of their activity, both in terms no hygromycin A but 500-dihydrohygromycin A, 500-di- of MICs for Serpulina hyodysenteriae and their ability to hydromethoxyhygromycin A, and a 500-dihydrohygro- inhibit protein synthesis in an E. coli cell extract. The re- mycin A product lacking the aminocyclitol moiety. To sulting structure activity relationship (SAR) has revealed the best of our knowledge, these shunt metabolites that the unusual aminocyclitol moiety is an important of biosynthetic pathway intermediates have not previ- component for the antibacterial activity, while the 5-de- ously been identified. They provide insight into the hydro-a-L-fucofuranose moiety is not essential and can ordering of the multiple unusual steps which com- be replaced with hydrophobic allyl group. Reduction in promise the convergent hygromycin A biosynthetic the antibacterial activity is also observed with replace- pathway. ment in methyl group of central (E)-3-(3,4-dihydroxy- phenyl)-2-methylacrylic acid moiety with propyl, allyl, Introduction or hygrogen [14, 15]. For the most part, these structural analogs were prepared by a semisynthetic method with Hygromycin A (compound 1)(Figure 1) is an antibiotic hygromycin A as a starting point. A total synthesis of hy- 00 first isolated from the fermentation broth of several gromycin A and C2 epi-hygromycin A has also been re- strains of Streptomyces hygroscopicus in 1953 [1].A ported [12, 16]. Several multistep syntheses of the 2L- second structurally unrelated antibiotic, the aminogly- 2-amino-2-deoxy-4,5-O-methylene-neo-inositol moiety coside hygromycin B, was later isolated from S. hygro- have also been reported [17]. The most recent synthesis scopicus [2]. Early studies demonstrated that hygromy- of this was enantioselective and accomplished in 14 cin A had a relatively broad spectrum of activity against steps with an overall 12% yield [18]. gram-positive and -negative bacteria [1, 3]. Almost three We have sought a complementary approach of deci- decades later, Guerrero and Modolell demonstrated that phering the biosynthetic process with a long-term aim the mode of action was inhibition of the ribosomal pep- of using this as an economical means for generating hy- tidyl transferase activity. Initial studies also demon- gromycin analogs for further development. In our pre- strated that hygromycin A (1) blocked the binding of ei- liminary work, we determined the biosynthetic origins ther chloramphenicol or lincomycin to the ribosomes [4] of the three unusual and structurally distinct moieties and (2) bound more tightly than chloramphenical. More of hygromycin A. Mannose was shown to provide the 5-dehydro-a-L-fucofuranose moiety, 4-hydroxybenzoic acid and propionic acid the central (E)-3-(3,4-dihydroxy- *Correspondence: [email protected] phenyl)-2-methylacrylic acid moiety, and glucose and Chemistry & Biology 754 Figure 1. Structures of Hygromycin A, Hy- gromycin A Analogs, and Related Com- pounds methionine the 2L-2-amino-2-deoxy-4,5-O-methylene- are a promising step toward the long-term objective of neo-inositol moiety [19]. A convergent biosynthetic this work. pathway was proposed (Figure 2) from these observa- tions, and we now report how this formed the basis for Results and Discussion a PCR approach that has led to the identification of the hygromycin A biosynthetic gene cluster of S. hygroscipi- Cloning and Sequencing of the Hygromycin A cus NRRL 2388. The gene cluster has been cloned, se- Biosynthetic Gene Cluster quenced, and analyzed, and putative assignments for Previous studies on hygromycin A have suggested a the majority of corresponding gene products in the bio- convergent biosynthesis from 5-dehydro-a-L-fucofura- synthesis of the three structural moieties of hygromycin nose, (E)-3-(3,4-dihydroxyphenyl)-2-methylacrylic acid, A have been proposed. Furthermore, manipulation of and 2L-2-amino-2-deoxy-4,5-O-methylene-neo-inositol the gene cluster has been shown to give rise to hygrom- [19]. The 5-dehydro-a-L-fucofuranose moiety was ycin A analogs and shunt products that have not previ- shown to be derived from mannose, and a pathway pro- ously been identified. These findings provide important ceeding from a nucleoside diphosphate (NDP) activated insights into the order of the biosynthetic steps and mannose, through NDP-4-keto-6-deoxymannose and Figure 2. Proposed Role of hyg Gene Prod- ucts in Hygromycin A Biosynthesis in S. hygroscopicus NRRL 2388 Hygromycin A Biosynthetic Gene Cluster 755 Figure 3. Organization of the Hygromycin A Biosynthetic Gene Cluster in S. hygroscopicus NRRL 2388 Each arrow indicates the direction of transcription of each predicted open reading frame. The overlapping cosmid clones namely 2F1, 12G10, 17E3, and 15A10 covering the entire gene cluster is also depicted. The entire putative hygromycin A biosynthetic gene cluster was obtained by shotgun sequencing 17E3 cosmid and primer walking 7 kb of cosmid 15A10 cosmid clone. The sequence of the entire gene cluster and the proposed function for individual ORFs is summarized in Table 1, and nucleotide sequence submitted to GenBank with accession number DQ314862. NDP-L-fucose, was proposed. Genes encoding proteins sequences of GenBank by using BLAST programs [26]. with homology to GDP-D-mannose-4,6-dehydratase The predicted functions of these hyg gene products (MDH) have been identified in the nystatin, candicidin, and their corresponding homologs are listed in Table and other antibiotic biosynthetic gene clusters [20–22]. 1. Genes adjacent to hyg1 encoded a hypothetical pro- Moreover, the partially reported antibiotic A201A gene tein and a putative glucose dehydrogenase, respec- cluster by A. Jimenez and coworker (GenBank accession tively, while those adjacent to hyg29 encoded a putative number X84374), which bears significant structural sim- pyruvate dehydrogenase and transcriptional regulator. ilarities to hygromycin A (Figure 1), also contains a gene These genes flanking the 29 hyg ORFs were highly ho- encoding a putative MDH. A BLAST search for similar mologous to genes identified in the genome sequences genes in two reported genome sequences from S. coeli- of S. coelicolor [23] and S. avermitilis [24], could not color A3(2) [23] and S. avermitilis MA-4680 [24] failed to readily be assigned a dedicated function in the biosyn-
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