Gene mining and efficient biosynthesis of a fungal peptidyl alkaloid

Chen Zhang; Bing-Yu Liu; Jia-Wang Liu; Dao-Jiang Yan; Jian Bai; Ya-Long Zhang; Yan-Hua Mou; You-Cai Hu

doi:10.1016/j.chmed.2020.11.003

Gene mining and efficient biosynthesis of a fungal peptidyl alkaloid

Chin Herb Med. 2020 Dec 1;13(1):98-104. doi: 10.1016/j.chmed.2020.11.003. eCollection 2021 Jan.

Authors

Chen Zhang¹, Bing-Yu Liu¹, Jia-Wang Liu¹, Dao-Jiang Yan¹, Jian Bai¹, Ya-Long Zhang¹, Yan-Hua Mou², You-Cai Hu¹

Affiliations

¹ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
² School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.

Abstract

Objective: Peptidyl alkaloids, a series of important natural products can be assembled by fungal non-ribosomal peptide synthetases (NRPSs). However, many of the NRPSs associated gene clusters are silent under laboratory conditions, and the traditional chemical separation yields are low. In this study, we aim to discovery and efficiently prepare fungal peptidyl alkaloids assembled by fungal NRPSs.

Methods: Bioinformatics analysis of gene cluster containing NRPSs from the genome of Penicillium thymicola, and heterologous expression of the putative gene cluster in Aspergillus nidulans were performed. Isolation, structural identification, and biological evaluation of the product from heterologous expression were carried out.

Results: The putative tri-modular NRPS AncA was heterologous-expressed in A. nidulans to give anacine (1) with high yield, which showed moderate and selective cytotoxic activity against A549 cell line.

Conclusion: Heterologous expression in A. nidulans is an efficient strategy for mining fungal peptidyl alkaloids.

Keywords: anacine; biosynthesis; non-ribosomal peptide synthetase; peptidyl alkaloid.