Genomics-driven discovery of the pneumocandin biosynthetic gene cluster in the fungus Glarea lozoyensis

BMC Genomics

Research Article

Yongsheng Che¹  Francisco Javier Ortiz-López²  Gerald F Bills³  Chengshu Wang⁴  Xinyu Zhang⁵  Xingzhong Liu⁵  Qun Yue⁵  Shaojie Li⁵  Meichun Xiang⁵  Li Chen⁶  Zhiqiang An⁷ 

[1] Beijing Institute of Pharmacology & Toxicology, 100850, Beijing, People’s Republic of China;Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, 18100, Granada, Spain;Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, 18100, Granada, Spain;Texas Therapeutics Institute, the Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, 77030, Houston, TX, USA;Key Laboratory of Insect Developmental and Evolutionary Biology, Institute of Plant physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200032, Shanghai, People’s Republic of China;State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, People’s Republic of China;State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, People’s Republic of China;University of Chinese Academy of Sciences, 100049, Beijing, People’s Republic of China;Texas Therapeutics Institute, the Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, 77030, Houston, TX, USA;

关键词: Polyketide;    Cyclic Hexapeptide;    Orsellinic Acid;    Tolypocladium Inflatum;    Dimethylallyl Tryptophan;   

DOI  :  10.1186/1471-2164-14-339

 received in 2012-12-19, accepted in 2013-05-09,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundThe antifungal therapy caspofungin is a semi-synthetic derivative of pneumocandin B0, a lipohexapeptide produced by the fungus Glarea lozoyensis, and was the first member of the echinocandin class approved for human therapy. The nonribosomal peptide synthetase (NRPS)-polyketide synthases (PKS) gene cluster responsible for pneumocandin biosynthesis from G. lozoyensis has not been elucidated to date. In this study, we report the elucidation of the pneumocandin biosynthetic gene cluster by whole genome sequencing of the G. lozoyensis wild-type strain ATCC 20868.ResultsThe pneumocandin biosynthetic gene cluster contains a NRPS (GLNRPS4) and a PKS (GLPKS4) arranged in tandem, two cytochrome P450 monooxygenases, seven other modifying enzymes, and genes for L-homotyrosine biosynthesis, a component of the peptide core. Thus, the pneumocandin biosynthetic gene cluster is significantly more autonomous and organized than that of the recently characterized echinocandin B gene cluster. Disruption mutants of GLNRPS4 and GLPKS4 no longer produced the pneumocandins (A0 and B0), and the Δglnrps4 and Δglpks4 mutants lost antifungal activity against the human pathogenic fungus Candida albicans. In addition to pneumocandins, the G. lozoyensis genome encodes a rich repertoire of natural product-encoding genes including 24 PKSs, six NRPSs, five PKS-NRPS hybrids, two dimethylallyl tryptophan synthases, and 14 terpene synthases.ConclusionsCharacterization of the gene cluster provides a blueprint for engineering new pneumocandin derivatives with improved pharmacological properties. Whole genome estimation of the secondary metabolite-encoding genes from G. lozoyensis provides yet another example of the huge potential for drug discovery from natural products from the fungal kingdom.

【 授权许可】

Unknown   
© Chen et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.