{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T05:03:19Z","timestamp":1768453399900,"version":"3.49.0"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"2-3","license":[{"start":{"date-parts":[[2016,3,1]],"date-time":"2016-03-01T00:00:00Z","timestamp":1456790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"},{"start":{"date-parts":[[2016,3,1]],"date-time":"2016-03-01T00:00:00Z","timestamp":1456790400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Genome mining of cyslabdan-producing Streptomyces cyslabdanicus K04-0144 revealed that a set of four genes, cldA, cldB, cldC, and cldD (the cld cluster), which formed a single transcriptional unit, were involved in the biosynthesis of cyslabdan that potentiates imipenem activity against methicillin-resistant Staphylococcus aureus. Experimental studies supported the heterologous expression of the cld cluster of S. cyslabdanicus K04-0144 in S. avermitilis SUKA22, and transformants carrying the cld cluster produced not only cyslabdan A (1), but also its new derivatives, 17-hydroxyl-1 (2) and 2-hydroxyl-1 (3), in the culture broth. An analysis of diterpene metabolites in the mycelia showed that a large amount of a novel intermediate had accumulated and its structure was elucidated as (7S, 8S, 12E)-8,17-epoxy-7-hydroxylabda-12,14-diene (4). The cld-like cluster (rmn cluster) was also detected in the genome of S. anulatus GM95 by searching our in-house genome databases, and the heterologous expression of the rmn cluster in S. avermitilis SUAK22 demonstrated that the rmn cluster was involved in the biosynthesis of the labdane-type bicyclic diterpene, raimonol (7). CldA\/RmnA catalyzed the generation of geranylgeranyl diphosphate (GGPP) from dimethylallyl diphosphate and isopentenyl diphosphate. CldB\/RmnB converted GGPP to (+)-copalyl diphosphate, and CldD\/RmnD generated labda-8(17),12(E),14-triene (5). CldC introduced two oxygen atoms at C-7 and C-8,17 to generate 4, while RmnC hydroxylated 5 at C-7 to generate 7. The heterologous expression of the cld cluster suggested that four gene products catalyzed to generate 4, but not 1. The deletion mutant of the gene encoding the mycothiol (MSH)-S-conjugate amidase (mca) of S. avermitilis SUKA22 carrying the cld cluster failed to produce 1, but accumulated 4 in the mycelia, whereas S. avermitilis SUKA22 and its mca-deletion mutant carrying the cld cluster both produced the MSH-S-conjugate of 4. The intermediate 4 was converted into the MSH-S-conjugate with MSH, which was achieved through a non-enzymatic nucleophilic reaction. The MSH-S-conjugate of 4 generated was further hydrolyzed to generate the mercapturic acid derivative, 1, by MSH-S-conjugate amidase and 1 was excreted from the mycelia.<\/jats:p>","DOI":"10.1007\/s10295-015-1694-6","type":"journal-article","created":{"date-parts":[[2015,10,27]],"date-time":"2015-10-27T05:03:35Z","timestamp":1445922215000},"page":"325-342","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Biosynthesis of mercapturic acid derivative of the labdane-type diterpene, cyslabdan that potentiates imipenem activity against methicillin-resistant <i>Staphylococcus aureus<\/i>: cyslabdan is generated by mycothiol-mediated xenobiotic detoxification"],"prefix":"10.1093","volume":"43","author":[{"given":"Haruo","family":"Ikeda","sequence":"first","affiliation":[{"name":"grid.410786.c 0000000092062938 Kitasato Institute for Life Sciences Kitasato University 1-15-1 Kitasato 252-0373 Sagamihara Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuo","family":"Shin-ya","sequence":"additional","affiliation":[{"name":"grid.208504.b 0000000122307538 National Institute of Advanced Industrial Science and Technology 2-4-7 Aomi 135-0064 Koto-ku Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tohru","family":"Nagamitsu","sequence":"additional","affiliation":[{"name":"grid.410786.c 0000000092062938 School of Pharmacy Kitasato University 5-9-1 Shirokane 108-8641 Minato-ku Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Tomoda","sequence":"additional","affiliation":[{"name":"grid.410786.c 0000000092062938 School of Pharmacy Kitasato University 5-9-1 Shirokane 108-8641 Minato-ku Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2016,3,1]]},"reference":[{"key":"2021032716191044100_CR1","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1046\/j.1365-313X.1995.7040649.x","article-title":"Site-specific integration of DNA into wild-type and mutant lox sites placed in the plant genome","volume":"7","author":"Albert","year":"1995","journal-title":"Plant J"},{"key":"2021032716191044100_CR2","doi-asserted-by":"publisher","first-page":"30391","DOI":"10.1074\/jbc.273.46.30391","article-title":"Mycothiol biosynthesis and metabolism: cellular levels of potential intermediates in the biosynthesis and degradation of mycothiol","volume":"273","author":"Anderberg","year":"1998","journal-title":"J Biol Chem"},{"key":"2021032716191044100_CR3","doi-asserted-by":"publisher","first-page":"4126","DOI":"10.1073\/pnas.95.8.4126","article-title":"Plant terpenoid synthases: molecular biology and phylogenetic analysis","volume":"95","author":"Bohlmann","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021032716191044100_CR4","doi-asserted-by":"publisher","first-page":"37317","DOI":"10.1074\/jbc.M007695200","article-title":"Kinetic characterization of glutathione reductase from the malarial parasite Plasmodium falciparum. Comparison with the human enzyme","volume":"275","author":"Bohme","year":"2000","journal-title":"J Biol Chem"},{"key":"2021032716191044100_CR5","doi-asserted-by":"publisher","first-page":"3139","DOI":"10.1016\/S0040-4039(97)00616-3","article-title":"Seongomycin: a new sulfur-containing benzo[b]fluorene derived from genes clustered with those for kanamycin biosynthesis","volume":"38","author":"Camery","year":"1997","journal-title":"Tetrahedron Lett"},{"key":"2021032716191044100_CR6","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1038\/ja.2006.66","article-title":"Geosmin biosynthesis in Streptomyces avermitilis. Molecular cloning, expression, and mechanistic study of the germacradienol\/geosmin synthase","volume":"59","author":"Cane","year":"2006","journal-title":"J Antibiot"},{"key":"2021032716191044100_CR7","doi-asserted-by":"publisher","first-page":"2187","DOI":"10.1039\/jr9610002187","article-title":"Biformene","volume":"1961","author":"Carman","year":"1961","journal-title":"J Chem Soc"},{"key":"2021032716191044100_CR8","doi-asserted-by":"publisher","first-page":"6085","DOI":"10.1128\/JB.183.20.6085-6094.2001","article-title":"Eubacterial diterpene cyclase genes essential for production of the isoprenoid antibiotic terpentecin","volume":"183","author":"Dairi","year":"2001","journal-title":"J Bacteriol"},{"key":"2021032716191044100_CR9","doi-asserted-by":"publisher","first-page":"6640","DOI":"10.1073\/pnas.120163297","article-title":"One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products","volume":"97","author":"Datsenko","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021032716191044100_CR10","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1080\/13813450701661198","article-title":"The central role of glutathione in the pathophysiology of human diseases","volume":"113","author":"Franco","year":"2007","journal-title":"Arch Physiol Biochem"},{"key":"2021032716191044100_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/ja.2008.101","article-title":"Cyslabdan, a new potentiator of imipenem activity against methicillin-resistant Staphylococcus aureus, produced by Streptomyces sp. K04-0144 I. Taxonomy, fermentation, isolation and structural elucidation","volume":"61","author":"Fukumoto","year":"2008","journal-title":"J Antibiot"},{"key":"2021032716191044100_CR12","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/ja.2008.102","article-title":"Cyslabdan, a new potentiator of imipenem activity against methicillin-resistant Staphylococcus aureus, produced by Streptomyces sp. K04-0144 II. Biological activities","volume":"61","author":"Fukumoto","year":"2008","journal-title":"J Antibiot"},{"key":"2021032716191044100_CR13","doi-asserted-by":"publisher","first-page":"845","DOI":"10.7164\/antibiotics.51.845","article-title":"3-Amino-5-hydroxybenzoic acid in antibiotic biosynthesis. XI. Biological origins and semisynthesis of thionaphthomycins, and the structures of naphthomycins I and J","volume":"51","author":"Hooper","year":"1998","journal-title":"J Antibiot"},{"key":"2021032716191044100_CR14","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1093\/jb\/mvm004","article-title":"Functional analysis of eubacterial ent-copalyl diphosphate synthase and pimara-9(11),15-diene synthase with unique primary sequences","volume":"141","author":"Ikeda","year":"2007","journal-title":"J Biochem"},{"key":"2021032716191044100_CR15","doi-asserted-by":"crossref","first-page":"5615","DOI":"10.1128\/JB.169.12.5615-5621.1987","article-title":"Genetic studies of avermectin biosynthesis in Streptomyces avermitilis","volume":"169","author":"Ikeda","year":"1987","journal-title":"J Bacteriol"},{"key":"2021032716191044100_CR16","doi-asserted-by":"publisher","first-page":"9509","DOI":"10.1073\/pnas.96.17.9509","article-title":"Organization of the biosynthetic gene cluster for the polyketide anthelmintic macrolide avermectin in Streptomyces avermitilis","volume":"96","author":"Ikeda","year":"1999","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021032716191044100_CR17","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1038\/nbt820","article-title":"Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis","volume":"21","author":"Ikeda","year":"2003","journal-title":"Nat Biotechnol"},{"key":"2021032716191044100_CR18","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1039\/b616489g","article-title":"Mycothiol: synthesis. Biosynthesis and biological functions of the major low molecular weight thiol in actinomyccetes","volume":"25","author":"Jothivasan","year":"2008","journal-title":"Nat Prod Rep"},{"key":"2021032716191044100_CR19","doi-asserted-by":"publisher","first-page":"161","DOI":"10.3109\/03602538209002234","article-title":"The role of nonenzymatic reactions of glutathione in xenobiotic metabolism","volume":"13","author":"Ketterer","year":"1982","journal-title":"Drug Metab Rev"},{"key":"2021032716191044100_CR20","doi-asserted-by":"publisher","first-page":"1534","DOI":"10.1111\/j.1365-2958.2006.05461.x","article-title":"Proteins encoded by the conservon of Streptomyces coelicolor A3(2) comprise a membrane-associated heterocomplex that resembles eukaryotic G protein-coupled regulatory system","volume":"62","author":"Komatsu","year":"2006","journal-title":"Mol Microbiol"},{"key":"2021032716191044100_CR21","doi-asserted-by":"publisher","first-page":"7422","DOI":"10.1073\/pnas.0802312105","article-title":"Identification and functional analysis of genes controlling biosynthesis of 2-methylisoborneol","volume":"105","author":"Komatsu","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021032716191044100_CR22","doi-asserted-by":"publisher","first-page":"2646","DOI":"10.1073\/pnas.0914833107","article-title":"Genome-minimized Streptomyces host for the heterologous expression of secondary metabolism","volume":"107","author":"Komatsu","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021032716191044100_CR23","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1021\/sb3001003","article-title":"Engineered Streptomyces avermitilis host for heterologous expression of biosynthetic gene cluster for secondary metabolites","volume":"2","author":"Komatsu","year":"2013","journal-title":"ACS Synth Biol"},{"key":"2021032716191044100_CR24","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1016\/j.apsb.2011.10.008","article-title":"New cyslabdans B and C, potentiators of imipenem activity against methicillin-resistant Staphylococcus aureus produced by Streptomyces sp. K04-0144","volume":"1","author":"Koyama","year":"2011","journal-title":"Acta Pharm Sin B"},{"key":"2021032716191044100_CR25","doi-asserted-by":"publisher","first-page":"e48981","DOI":"10.1371\/journal.pone.0048981","article-title":"The nonantibiotic small molecule cyslabdan enhances the potency of beta-lactams against MRSA by inhibiting pentaglycine interpeptide bridge synthesis","volume":"7","author":"Koyama","year":"2012","journal-title":"PLoS ONE"},{"key":"2021032716191044100_CR26","doi-asserted-by":"publisher","first-page":"1671","DOI":"10.1271\/bbb.63.1671","article-title":"Molecular analysis of prenyl chain elongation enzymes","volume":"63","author":"Koyama","year":"1999","journal-title":"Biosci Biotechnol Biochem"},{"key":"2021032716191044100_CR27","first-page":"107","article-title":"Prospects for the bioengineering of isoprenoid biosynthesis","volume":"55","author":"McCaskill","year":"1997","journal-title":"Adv Biochem Eng Bio\/Technol"},{"key":"2021032716191044100_CR28","doi-asserted-by":"publisher","first-page":"6958","DOI":"10.1128\/JB.182.24.6958-6963.2000","article-title":"N-Acetyl-1-d-myo-inosityl-2-amino-2-deoxy-\u03b1-d-glucopyranoside deacetylase (MshB) is a key enzyme in mycothiol biosynthesis","volume":"182","author":"Newton","year":"2000","journal-title":"J Bacteriol"},{"key":"2021032716191044100_CR29","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1007\/s00203-002-0469-4","article-title":"Mycothiol biochemistry","volume":"178","author":"Newton","year":"2002","journal-title":"Arch Microbiol"},{"key":"2021032716191044100_CR30","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/S0031-9422(00)95274-9","article-title":"Two labdane diterpenoids from Nicotiana raimondii","volume":"21","author":"Noma","year":"1982","journal-title":"Phytochemistry"},{"key":"2021032716191044100_CR31"},{"key":"2021032716191044100_CR32","doi-asserted-by":"publisher","first-page":"113","DOI":"10.7164\/antibiotics.44.113","article-title":"Lactacystin, a novel microbial metabolite, induces neuritogenesis of neuroblastoma cells","volume":"44","author":"Omura","year":"1991","journal-title":"J Antibiot"},{"key":"2021032716191044100_CR33","doi-asserted-by":"publisher","first-page":"6050","DOI":"10.1128\/JB.186.18.6050-6058.2004","article-title":"Targeted mutagenesis of the Mycobacterium smegmatis mca gene, encoding a mycothiol-dependent detoxification protein","volume":"186","author":"Rawat","year":"2004","journal-title":"J Bacteriol"},{"key":"2021032716191044100_CR34","doi-asserted-by":"publisher","first-page":"13543","DOI":"10.1073\/pnas.231313098","article-title":"Structure of trichodiene synthase from Fusarium sporotrichioides provides mechanistic inferences on the terpene cyclization cascade","volume":"98","author":"Rynkiewicz","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021032716191044100_CR35","doi-asserted-by":"publisher","first-page":"7681","DOI":"10.1021\/ja026058q","article-title":"Pentalenene synthase. Analysis of active site residues by site-directed mutagenesis","volume":"124","author":"Seemann","year":"2002","journal-title":"J Am Chem Soc"},{"key":"2021032716191044100_CR36","doi-asserted-by":"publisher","first-page":"1815","DOI":"10.1126\/science.277.5333.1815","article-title":"Structural basis for cyclic terpene biosynthesis by tobacco 5-epi-aristolochene synthase","volume":"277","author":"Starks","year":"1997","journal-title":"Science"},{"key":"2021032716191044100_CR37","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.gene.2011.01.005","article-title":"Pleiotropic effect of a null mutation in the cvn1 conservon of Streptomyces coelicolor A3(2)","volume":"477","author":"Takano","year":"2001","journal-title":"Gene"},{"key":"2021032716191044100_CR38","doi-asserted-by":"publisher","first-page":"6179","DOI":"10.1021\/bi060419n","article-title":"A gene cluster for biosynthesis of the sesqui-terpenoid antibiotic pentalenolactone in Streptomyces avermitilis","volume":"45","author":"Tetzlaff","year":"2006","journal-title":"Biochemistry"},{"key":"2021032716191044100_CR39","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/B978-0-12-394290-6.00007-0","article-title":"Diversity and analysis of bacterial terpene synthases","volume-title":"Chapter seven, Natural product biosynthesis by microorganisms and plants, part A, methods in enzymology","author":"Yamada","year":"2012"},{"key":"2021032716191044100_CR40","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1073\/pnas.1422108112","article-title":"Terpene synthases are widely distributed in bacteria","volume":"112","author":"Yamada","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021032716191044100_CR41","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1038\/ja.2014.171","article-title":"Novel terpenes generated by heterologous expression of bacterial terpene synthase genes in an engineered Streptomyces host","volume":"68","author":"Yamada","year":"2015","journal-title":"J Antibiot"}],"container-title":["Journal of Industrial Microbiology and Biotechnology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10295-015-1694-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s10295-015-1694-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/academic.oup.com\/jimb\/article-pdf\/43\/2-3\/325\/36751976\/jimb0325.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jimb\/article-pdf\/43\/2-3\/325\/36751976\/jimb0325.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T11:45:43Z","timestamp":1676375143000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimb\/article\/43\/2-3\/325\/5995762"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,1]]},"references-count":41,"journal-issue":{"issue":"2-3","published-print":{"date-parts":[[2016,3,1]]}},"URL":"https:\/\/doi.org\/10.1007\/s10295-015-1694-6","relation":{},"ISSN":["1476-5535","1367-5435"],"issn-type":[{"value":"1476-5535","type":"electronic"},{"value":"1367-5435","type":"print"}],"subject":[],"published-other":{"date-parts":[[2016,3,1]]},"published":{"date-parts":[[2016,3,1]]}}}