title: Identification of Cyclic Depsipeptides and Their Dedicated Synthetase from Hapsidospora irregularis.
abstract: Seven cyclic depsipeptides were isolated from Hapsidospora irregularis and structurally characterized as the calcium channel blocker leualacin and six new analogues based on the NMR and HRESIMS data. These new compounds were named leualacins B-G. The absolute configurations of the amino acids and 2-hydroxyisocaproic acids were determined by recording the optical rotation values. Biological studies showed that calcium influx elicited by leualacin F in primary human lobar bronchial epithelial cells involves the TRPA1 channel. Through genome sequencing and targeted gene disruption, a noniterative nonribosomal peptide synthetase was found to be involved in the biosynthesis of leualacin. A comparison of the structures of leualacin and its analogues indicated that the A2and A4domains of the leualacin synthetase are substrate specific, while A1, A3, and A5can accept alternative precursors to yield new molecules.
authors.affiliation: Department of Biological Engineering, Utah State University , 4105 Old Main Hill, Logan, Utah 84322, United States.
authors.forename: Shuwei
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Biological Engineering, Utah State University , 4105 Old Main Hill, Logan, Utah 84322, United States.|TCM and Ethnomedicine Innovation & Development Laboratory, School of Pharmacy, Hunan University of Chinese Medicine , Changsha, Hunan 410208, People's Republic of China.
authors.forename: Yixing
authors.initials: Y
authors.lastname: Qiu
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Kakule
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Biological Engineering, Utah State University , 4105 Old Main Hill, Logan, Utah 84322, United States.
authors.forename: Fuchao
authors.initials: F
authors.lastname: Xu
authors.forename: John G
authors.initials: JG
authors.lastname: Lamb
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Reilly
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 501 Haike Road, Shanghai 202203, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Chemistry and Biochemistry, Utah State University , 0300 Old Main Hill, Logan, Utah 84322, United States.
authors.forename: Shing Wo Simon
authors.initials: SW
authors.lastname: Sham
authors.affiliation: TCM and Ethnomedicine Innovation & Development Laboratory, School of Pharmacy, Hunan University of Chinese Medicine , Changsha, Hunan 410208, People's Republic of China.
authors.forename: Wei
authors.identifier: 0000-0003-0876-2205
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 501 Haike Road, Shanghai 202203, People's Republic of China.
authors.forename: Lijiang
authors.identifier: 0000-0002-0593-3921
authors.initials: L
authors.lastname: Xuan
authors.forename: Eric W
authors.initials: EW
authors.lastname: Schmidt
authors.affiliation: Department of Biological Engineering, Utah State University , 4105 Old Main Hill, Logan, Utah 84322, United States.|TCM and Ethnomedicine Innovation & Development Laboratory, School of Pharmacy, Hunan University of Chinese Medicine , Changsha, Hunan 410208, People's Republic of China.
authors.forename: Jixun
authors.identifier: 0000-0003-0200-9183
authors.initials: J
authors.lastname: Zhan
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D002121:Calcium Channel Blockers / Q000737:chemistry; D047630:Depsipeptides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D006801:Humans; D006999:Hypocreales / Q000737:chemistry*; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010453:Peptide Synthases / Q000378:metabolism*; D010456:Peptides, Cyclic
chemical_list: D000596:Amino Acids; D002121:Calcium Channel Blockers; D047630:Depsipeptides; D010456:Peptides, Cyclic; C076086:leualacin; D010453:Peptide Synthases