Functional Genome Mining Reveals a Class V Lanthipeptide Containing a d-Amino Acid Introduced by an F 420 H 2 -Dependent Reductase

• Published in: Angewandte Chemie International Edition Vol. 59; no. 41; pp. 18029 - 18035
• Main Authors: Xu, Min, Zhang, Fei, Cheng, Zhuo, Bashiri, Ghader, Wang, Jing, Hong, Jiali, Wang, Yemin, Xu, Lijun, Chen, Xuefei, Huang, Sheng-Xiong, Lin, Shuangjun, Deng, Zixin, Tao, Meifeng
• Format: Journal Article
• Language: English
• Published: Germany 05.10.2020
• Subjects: Amino Acids - chemistry; Bacteriocins - chemistry; Genome; Oxidoreductases - chemistry; Peptides - chemistry; lexapeptide; F420H2 reductase; lanthipeptide; biosynthesis; class V lanthionine synthetase
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202008035

Lantibiotics are a type of ribosomally synthesized and post-translationally modified peptides (termed lanthipeptides) with often potent antimicrobial activity. Herein, we report the discovery of a new lantibiotic, lexapeptide, using the library expression analysis system (LEXAS) approach. Lexapeptide has rare structural modifications, including N-terminal (N,N)-dimethyl phenylalanine, C-terminal (2-aminovinyl)-3-methyl-cysteine, and d-Ala. The characteristic lanthionine moiety in lexapeptide is formed by three proteins (LxmK, LxmX, and LxmY), which are distinct from enzymes known to be involved in lanthipeptide biosynthesis. Furthermore, a novel F H -dependent reductase (LxmJ) from the lexapeptide biosynthetic gene cluster (BGC) is identified to catalyze the reduction of dehydroalanine to install d-Ala. Our findings suggest that lexapeptide is the founding member of a new class of lanthipeptides that we designate as class V. We also identified further class V lanthipeptide BGCs in actinomycetes and cyanobacteria genomes, implying that other class V lantibiotics await discovery.