Characterization of the Bafilomycin Biosynthetic Gene Cluster from <i>Streptomyces lohii</i>

Zhang, Wei; Fortman, Jeffrey L.; Carlson, Jacob C.; Yan, Jinyong; Liu, Yi; Bai, Fengwu; Guan, Wenna; Jia, Jun; Matainaho, Teatulohi; Sherman, David H.; Li, Shengying

doi:10.1002/cbic.201200743

Cited by 39 publications

(42 citation statements)

References 46 publications

(48 reference statements)

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“…Bafilomycins were produced by various Actinomycetales microorganisms including two genera, Streptomyces and Kitasatospora species. Two biosynthetic gene clusters of S. lohii JCM 14114 14 and S. griseus DSM 2608 15 were very similar to each other. As the deduced amino acid sequence similarity of each ORF (Table 1) was in the range of 89% (identity)/91% (similarity) to 97% (identity)/98% (similarity), these two gene clusters may have recently evolved.…”

Section: Characterization Of Bafilomycin Biosynthesismentioning

confidence: 67%

“…The third gene cluster consisted of non-ribosomal peptide synthetases and type-I PKSs, and was estimated to be involved in factumycin biosynthesis. The last gene cluster showed a strong resemblance in the features of gene organization and deduced amino acid sequences of each open reading frame (ORF) to the biosynthetic gene clusters for bafilomycin of S. lohii JCM 14114 14 and S. griseus DSM 2608 15 ( Figure 2 and Table 1). …”

Section: Resultsmentioning

confidence: 99%

“…The final step, the conversion of bafilomycin C 1 to B 1 , is performed by BfmL using 2-amino-3-hydroxy-cyclopenta-2-enone, which is generated from glycine and succinyl-CoA through 5-aminolevulinate by BfmK and BfmM. The discovery of gene clusters for bafilomycin biosynthesis from many Streptomyces [14][15][16] and Kitasatospora 3,12,13 species suggests that the broad distribution of this gene cluster by horizontal transfer may frequently occur in Actinomycetales microorganisms.…”

Section: Characterization Of Bafilomycin Biosynthesismentioning

confidence: 99%

“…Vacuolar-type ATPases are involved in bone resorption processes in osteoclasts and thus these macrolides have potential in the treatment of osteoporosis. 10,11 Bafilomycins were previously reported to be produced by various Actinomycetales microorganisms including K. setae KM-6054, 3 K. griseola MK730-N6, 12 K. cheerisanensis KCTC 2395, 13 S. lohii JCM 14114, 14 S. griseus DSM 2608 15 and Streptomyces sp. M10.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of bafilomycin biosynthesis in Kitasatospora setae KM-6054 and comparative analysis of gene clusters in Actinomycetales microorganisms

et al. 2017

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(setamycin) produced by Kitasatospora setae KM-6054 belong to the plecomacrolide family, which exhibit antibacterial, antifungal, antineoplastic and immunosuppressive activities. An analysis of gene clusters from K. setae KM-6054 governing the biosynthesis of bafilomycins revealed that it contains five large open reading frames (ORFs) encoding the multifunctional polypeptides of bafilomycin polyketide synthases (PKSs). These clustered PKS genes, which are responsible for bafilomycin biosynthesis, together encode 11 homologous sets of enzyme activities, each catalyzing a specific round of polyketide chain elongation. The region contains an additional 13 ORFs spanning a distance of 73 287 bp, some of which encode polypeptides governing other key steps in bafilomycin biosynthesis. Five ORFs, BfmB, BfmC, BfmD, BfmE and BfmF, were involved in the formation of methoxymalonyl-acyl carrier protein (ACP). Two possible regulatory genes, bfmR and bfmH, were found downstream of the above genes. A gene-knockout analysis revealed that BfmR was only a transcriptional regulator for the transcription of bafilomycin biosynthetic genes. Two genes, bfmI and bfmJ, were found downstream of bfmH. An analysis of these gene-disruption mutants in addition to an enzymatic analysis of BfmI and BfmJ revealed that BfmJ activated fumarate and BfmI functioned as a catalyst to form a fumaryl ester at the C21 hydroxyl residue of bafilomycin A 1 . A comparative analysis of bafilomycin gene clusters in K. setae KM-6054, Streptomyces lohii JCM 14114 and Streptomyces griseus DSM 2608 revealed that each ORF of both gene clusters in two Streptomyces strains were quite similar to each other. However, each ORF of gene cluster in K. setae KM-6054 was of lower similarity to that of corresponding ORF in the two Streptomyces species.

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Section: Characterization Of Bafilomycin Biosynthesismentioning

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Characterization Of Bafilomycin Biosynthesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Characterization of bafilomycin biosynthesis in Kitasatospora setae KM-6054 and comparative analysis of gene clusters in Actinomycetales microorganisms

et al. 2017

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“…Indeed, screening of actinobacterial extracts has been successful in yielding hygrolide congeners with differing functional groups. After more than 30 years of investigation, the production of a hygrolide was definitively linked to a biosynthetic gene cluster (BGC) in 2012 [42–44]. Armed with this knowledge, genome mining can allow prioritization of strains for investigation.…”

Section: Introductionmentioning

confidence: 99%

Biological characterization of the hygrobafilomycin antibiotic JBIR-100 and bioinformatic insights into the hygrolide family of natural products

Molloy

Tietz

Blair

et al. 2016

Bioorganic & Medicinal Chemistry

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The hygrolides, a family of 16-member-ring-containing plecomacrolides produced by Actinobacteria, exhibit numerous reported bioactivities. Using HR-MS/MS, nucleophilic 1,4-addition-based labeling, NMR, and bioinformatic analysis, we identified Streptomyces varsoviensis as a novel producer of JBIR-100, a fumarate-containing hygrolide, and elucidated the previously unknown stereochemistry of the natural product. We investigated the antimicrobial activity of JBIR-100, with preliminary insight into mode of action indicating that it perturbs the membrane of Bacillus subtilis. S. varsoviensis is known to produce compounds from multiple hygrolide sub-families, namely hygrobafilomycins (JBIR-100 and hygrobafilomycin) and bafilomycins (bafilomycin C1 and D). In light of this, we identified the biosynthetic gene cluster for JBIR-100, which, to our knowledge, represents the first reported for a hygrobafilomycin. Finally, we performed a bioinformatic analysis of the hygrolide family, describing clusters from known and predicted producers. Our results indicate that potential remains for the Actinobacteria to yield novel hygrolide congeners, perhaps with differing biological activities.

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Somalactams A–D: Anti‐inflammatory Macrolide Lactams with Unique Ring Systems from an Arctic Actinomycete Strain

Yang

Sang

et al. 2023

Angewandte Chemie

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Four new PKS‐NRPS‐derived macrolide lactams with three unique ring fusion types were discovered from the Arctic sponge associated actinomycete Streptomyces somaliensis 1107 using a genome mining strategy. Their structures were elucidated by a combination of MS, NMR spectroscopic analysis, and single‐crystal X‐ray diffraction. Biosynthetically, a novel gene cluster sml consisting of three polyketide synthases and one hybrid polyketide synthase‐nonribosomal peptide synthetase together with cytochrome P450s and flavin‐containing monooxygenases and oxidoreductases was demonstrated to assemble the unique skeleton. Pharmacological studies revealed that compound 1 displayed a potent anti‐inflammatory effect without cytotoxicity. It inhibited IL‐6 and TNF‐α release in the serum of LPS‐stimulated RAW264.7 macrophage cells with IC50 values of 5.76 and 0.18 μM, respectively, and modulated the MAPK pathway. Moreover, compound 1 alleviated LPS‐induced systemic inflammation in our transgenic fluorescent zebrafish model.

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Characterization of the Bafilomycin Biosynthetic Gene Cluster from Streptomyces lohii

Cited by 39 publications

References 46 publications

Characterization of bafilomycin biosynthesis in Kitasatospora setae KM-6054 and comparative analysis of gene clusters in Actinomycetales microorganisms

Characterization of bafilomycin biosynthesis in Kitasatospora setae KM-6054 and comparative analysis of gene clusters in Actinomycetales microorganisms

Biological characterization of the hygrobafilomycin antibiotic JBIR-100 and bioinformatic insights into the hygrolide family of natural products

Somalactams A–D: Anti‐inflammatory Macrolide Lactams with Unique Ring Systems from an Arctic Actinomycete Strain

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