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Polyketide Synthase Gene Coupled to the Peptide Synthetase Module Involved in the Biosynthesis of the Cyclic Heptapeptide Microcystinl

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Polyketide Synthase Gene Coupled to the Peptide Synthetase Module Involved in the Biosynthesis of the Cyclic Heptapeptide Microcystinl J. Biochem. 127, 779-789(2000) Polyketide Synthase Gene Coupled to the Peptide Synthetase Module Involved in the Biosynthesis of the Cyclic Heptapeptide Microcystinl Tomoyasu Nishizawa, Akiko Ueda, Munehiko Asayama,* Kiyonaga Fujii,•õ Ken-ichi Harada,i Kozo Ochi,•ö and Makoto Shirai*,•˜,2 * Division of Biotechnology, School ofAgriculture, Ibaraki University Ami , Ibaraki 300-0393; •õFaculty of Pharmacy, M eija University, Tempaku , Nagoya 468-8503, •öNational Food Research Institute, Tsukuba, Ibaraki 305-8642; and •˜ Gene Research Center, Ibaraki University, Ann, Ibaraki 300-0393 Received January 17, 2000; accepted February 11, 2000 The peptide synthetase gene operon, which consists of encyA, mcyB, and mcyC, for the activation and incorporation of the five amino acid constituents of microcystin has been identified [T. Nishizawa et al. (1999) J. Biochem. 126, 520-529] . By sequencing an addi tional 34 kb of DNA from microcystin-producing Microcystis aeruginosa K-139 , we identifi ed the residual microcystin synthetase gene operon, which consists of mcyD, mcyE, meyF, and mcyG, in the opposite orientation to the mcyABC operon. McyD consisted of two polyketide synthase modules, and McyE contained a polyketide synthase module at the N-terminus and a peptide synthetase module at the C-terminus. McyF was found to exhibit similarity to amino acid racemase. McyG consisted of a peptide synthetase mod ule at the N-terminus and a polyketide synthase at the C-terminus. The microcystin syn thetase gene cluster was conserved in another microcystin-producing strain, Microcystis sp. S-70, which produces Microcystin-LR, -RR, and -YR. Insertional mutagenesis of mcyA, mcyD, or meyE in Microcystis sp. S-70 abolished microcystin production. In conclusion, the mcyDEFG operon is presumed to be responsible for 3-amino-9-methoxy-2,6,8-trime thyl-10-phenyldeca-4,6-dienoic acid (Adda) biosynthesis, and the incorporation of Adda and glutamic acid into the microcystin molecule. Key words: cyanobacteria, microcystin biosynthesis, multifunctional enzyme complex, peptide synthetase gene, polyketide synthase gene. The mass production of cyanobacteria (blue-green algae), The general structure of microcystins is cyclo (-D-Ala-X oxygenic phototrophs, occurs world wide in eutrophic water - D-MeAsp-Z-Adda-D-Glu-Mdha-), in which X and Z are bodies. A serious problem is the production of potent cyclic various L-amino acids, Adda is 3-amino-9-methoxy-2,6,8-tri hepatotoxins, termed microcystins, in waterblooms (1, 2). methyl-10-phenyldeca-4,6-dienoic acid, D-MeAsp is D-ery Microcystins are produced by several cyanobacterial gen thro-ƒÀ-iso-asparic acid, and Mdha is N-methyl-dehydro era, Microcystis, Anabaena, Oscillatoria, and Nostoc, with alanine (2) (Fig. 1). Over 50 structural variations of micro Microcystis spp. are probably the most deleterious freshwa cystins have been isolated from cyanobacteria. Peptides ter bloom-forming cyanobacteria. In 1996, liver failure and containing non-protein amino acids are synthesized non death after exposure to microcystin were reported (3). Mi ribosomally by a large multifunctional enzyme complex, crocystins, which are potent inhibitors of protein phos utilizing a thio-template mechanism, called non-ribosomal phatases 1 and 2A, cause cytokeratin hyperphosphoryla peptide synthetase (NRPS) (6-8). In 1997, Dittmann et al. tion, which leads to the disruption of cytoskeletal com cloned and identified a part of the microcystin synthetase ponents and to cell deformation, followed by disruption of genes from Microcystis aeruginosa PCC7806 (9). Recently, the liver architecture (1, 4). Moreover, microcystins have we identified the microcystin synthetase gene operon been reported to hasten tumor development (2, 5). (mcyA, B, and C) including five amino acid activation mod ules from M. aeruginosa K-139, which produced 7-desme thyl-microcystin (MCYST)-LR and 3,7-didesmethyl-MCY 1 This work was supported by Grants for Scientific Research from ST-LR (10). A gene disruption experiment revealed that the the Ministry of Education, Science, Sports and Culture of Japan. mcy gene is responsible for the microcystin production by 2 To whom correspondence should be addressed. Tel +81-298-88 K-139 cells. The arrangement of amino acid activation mod - 8652, Fax: +81-298-88-8653, E-mail: [email protected] Abbreviations: MCYST, microcystin; D-MeAsp, D-erythro-ƒÀ-methyl ules suggests that the cloned genes are responsible for acti aspartic acid; Adda, 3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl vation of Mdha, D-Ala, 1,-Leu, D-MeAsp, and L-Arg. How deca-4,6-dienoic acid; Melba, N-methyldehydroalanine; NRPS, non ever, the complete gene structure for microcystin biosynthe ribosomal peptide synthetase; PKS, polyketide synthase; KS, ƒÀ- sis has yet to he identified. ketoacyl-ACP-synthase; AT, acyltransferase; ACP, acyl carrier pro Adda in the microcystin molecule is an amino acid with tein; KR, ƒÀ-ketoacyl-ACP-reductase; DH, dehydratase; ER, enoyl an unusual and modified structure. Moore et al. reported reductase; SAM, S-adenosylmethionine; GSA, glutamate-1-semial that Adda is biosynthesized from the carbon skeleton of - dehyde aminotransferase; Rae, racemase; Cm, chloramphenicol. phenylalanine and four molecules of acetate (11). These ? 2000 by The Japanese Biochemical Society. results suggest that the synthesis of Adda is catalyzed by a Vol. 127,No. 5, 2000 779 780 T Nishizawa et al. Fig. 1. General structure of mi crocystin. The general structure of microcystin (MCYST-XZ) is cyclo (-D-Ala-X-D-MeAsp-Z-Adda-D - Glu-Mdha-), in which X and Z are various L amino acids, D-McAsp is D-erythro-ƒÀ-methylaspartic acid, Adda is 3-amino-9-methoxy-l0 - phenyl-2,6,8-trimethyl-deca-4,6-di enoic acid, and Mdha is N-methyl - dehydroalanine. This figure shows microcystin-LR (MCYST-LR). modular polyketide synthase mufti-enzyme complex. Fur 3.5 kb ClaI fragment was isolated (Fig. 2). Next, a cosmid thermore, we detected the open reading frame, which pCOTnƒÀ13 containing a 14.4 kb fragment was isolated showed high degrees of similarity to modular polyketide from a Lorist6 DNA genomic library (10) using a 1.6 kb synthases, upstream of mcyA (10). These findings encour ClaI EcoRI fragment from the 3•Œ-end of the insert of aged us to investigate the polyketide synthase (PKS) gene pKCA2 as a probe. The following recombinant plasmids in microcystin-producing cells. were isolated from the plasmid libraries using appropriate Polyketide formation is analogous to fatty acid synthesis DNA fragments as probes (the probes are indicated in (FAS) (12-14). PKS systems are classified into two types parentheses); pKCB1 containing a 5.0 kb ClaI fragment (a (15, 16): type I PKSs (modular PKSs) are large multifunc 0.5 kb CtaI-XbaI fragment from pCOTnƒÀl3), pMCQ3 con tional enzymes with a unique modular structure in which taining a 6.0 kb XbaI fragment and pMCP1 containing a each module is responsible for the activation, initiation, 9.1 kb Hind‡V fragment (a 0.3 kb EcoRI fragment from elongation and termination steps. Type ‡U PKSs are sys pKCB1), pMCN5 containing a 2.3 kb XbaI fragment (a 1.8 tems made up of individual enzymes. kb Hind‡V-XbaI fragment from pMCP1), pMCM1 contain In this study, we found a unique PKS module coupled to ing a 1.9 kb Hinc‡U fragment (a 1.0 kb Hinc‡U-XbaI frag a peptide synthetase module and revealed that the PKS ment from pMCN5), pMCL9 containing a 2.4 kb Hind‡V genes were responsible for microcystin production. fragment (a 1.0 kb Hinc‡U-XbaI fragment from pMCM1), and pMCK3 containing a 4.3 kb XbaI fragment (a 1.3 kb EXPERIMENTAL PROCEDURES XbaI-Hind‡V fragment from pMCL9). Construction of Gene Disruption Plasmids and Integra Bacterial Strains, Culture Conditions, and Plasmids-All tive Conjugation of Microcystis-Plasmids for gene disrup strains and plasmids used in this work are described in tion of mcyB, mcyD, and )ncyE by homologous recombina Table I. Microcystis strains were grown under 2,000-lx con tion were constructed as follows. The 4,325 by XbaI Hin tinuous illumination from fluorescent (cool white) lighting d‡V fragment containing an amino acid activation domain at 30•Ž in CB medium (17). Escherichia coli DH5ƒ¿MCR of mcyB from pCOTnƒÀ5 was cloned into the XbaI-Hind‡V (Cosmo Bio., Tokyo) was used as a host for recombinant sites of pUC119, generating pMCWX. The 1.2 kb SmaI plasmids and grown at 37•Ž for 16 h in LB broth. When fragment containing the Cm•Œ gene cassette from pR107XH necessary, antibiotics were added at the following final con and the 1.8 kb BamHI fragment containing the mob gene centrations: 75ƒÊg/ml ampicillin and 30ƒÊg/ml neomycin. from pSUP5011 were inserted into the EcoRV site (in Lorist6 DNA (Nippon Gene, Toyama), for the cosmid mcyB) and Hind‡V site (at the multicloning site) of pMC library, and pBluescript ‡U KS+ and pUC118/119 (TOYO WX, respectively, generating pFXS3. The 1,699 bp XbaI BO), for cloning, were used. - Hind‡V fragment containing the DH-KR domain of module DNA Manipulation-Total DNA of Microcystis strains 6/mcyD from pKCA2 was inserted into the XbaI-Hind‡V was isolated from cells grown to a late logarithmic phase by sites of pUC118, generating pNOR-f A Hinc‡U fragment of means of the previously described procedure (18). DNA the Cm•Œ gene cassette and the mob fragment were inserted manipulations were performed as described (19). into the Hinc‡U site (in mcyD) and BamHI site of pNOR-f, Cloning of the mcy Genes-Total DNA of M. aeruginosa respectively, generating pEXS5. The 3,636 by Bgl‡U frag K-139 was digested with ClaI, XbaI, Hind‡U, or Hind‡V and ment containing an amino acid activation domain of mod then inserted into the pBluescnpt ‡U KS+ phagemid vector ule 10/mcyE from pKCB1 was cloned into the BamHI site or the pUC vector, generating plasmid-libraries.
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