Cyclosporine Biosynthesis in Tolypocladium inflatum Benefits Fungal Adaptation to the Environment

doi:10.1128/mBio.01211-18

	Cyclosporine Biosynthesis in Tolypocladium inflatum Benefits Fungal Adaptation to the Environment
	Yang, Xiuqing 1,2; Feng, Peng 1; Yin, Ying 1; Bushley, Kathryn 3; Spatafora, Joseph W.4; Wang, Chengshu1,5
	2018-09-01
发表期刊	MBIO (IF:5.1[JCR-2023],5.9[5-Year])
ISSN	2150-7511
卷号	9 期号:5
发表状态	已发表
DOI	10.1128/mBio.01211-18
摘要	The cycloundecapeptide cyclosporin A (CsA) was first isolated from the insect-pathogenic fungus Tolypocladium inflatum for its antifungal activity and later developed as an immunosuppressant drug. However, the full biosynthetic mechanism of CsA remains unknown and has puzzled researchers for decades. In this study, the biosynthetic gene cluster is suggested to include 12 genes encoding enzymes, including the nonribosomal peptide synthetase (NRPS) (SimA) responsible for assembling the 11 amino acid substrates of cyclosporine and a polyketide synthase (PKS) (SimG) to mediate the production of the unusual amino acid (4R)-4-[(E)-2butenyl]-4-methyl-L-threonine (Bmt). Individual deletion of 10 genes, isolation of intermediates, and substrate feeding experiments show that Bmt is biosynthesized by three enzymes, including SimG, SimI, and SimJ. The substrate D-alanine is catalyzed from L-alanine by alanine racemase SimB. Gene cluster transcription is regulated by a putative basic leucine zipper (bZIP)-type protein encoded by the cluster gene SimL. We also found that the cluster cyclophilin (SimC) and transporter (SimD) genes contribute to the tolerance of CsA in the CsA-producing fungus. We also found that cyclosporine production could enable the fungus to outcompete other fungi during cocultivation tests. Deletion of the CsA biosynthetic genes also impaired fungal virulence against insect hosts. Taking all the data together, in addition to proposing a biosynthetic pathway of cyclosporines, the results of this study suggest that CsA produced by this fungus might play important ecological roles in fungal environment interactions.
关键词	cyclosporine Tolypocladium inflatum antifungal activity biosynthetic pathway virulence
收录类别	SCI ; SCIE
语种	英语
资助项目	National Key R&D Program of China[2017YFD0200400]
WOS研究方向	Microbiology
WOS类目	Microbiology
WOS记录号	WOS:000449472200048
出版者	AMER SOC MICROBIOLOGY
WOS关键词	UNUSUAL AMINO-ACID ; ALANINE RACEMASE ; METARHIZIUM-ROBERTSII ; BEAUVERIA-BASSIANA ; GENE CLUSTERS ; IDENTIFICATION ; VIRULENCE ; DOMAIN ; CYCLOPHILIN ; METABOLISM
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/28687
专题	生命科学与技术学院_特聘教授组_王成树组
通讯作者	Wang, Chengshu
作者单位	1.Chinese Acad Sci, Shanghai Inst Plant Physiol & Ecol, CAS Ctr Excellence Mol Plant Sci, Key Lab Insect Dev & Evolutionary Biol, Shanghai, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China 3.Univ Minnesota, Dept Plant Biol, St Paul, MN 55108 USA 4.Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA 5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Yang, Xiuqing,Feng, Peng,Yin, Ying,et al. Cyclosporine Biosynthesis in Tolypocladium inflatum Benefits Fungal Adaptation to the Environment[J]. MBIO,2018,9(5).
APA	Yang, Xiuqing,Feng, Peng,Yin, Ying,Bushley, Kathryn,Spatafora, Joseph W.,&Wang, Chengshu.(2018).Cyclosporine Biosynthesis in Tolypocladium inflatum Benefits Fungal Adaptation to the Environment.MBIO,9(5).
MLA	Yang, Xiuqing,et al."Cyclosporine Biosynthesis in Tolypocladium inflatum Benefits Fungal Adaptation to the Environment".MBIO 9.5(2018).