Anti-inflammatory and Neuroprotective α-Pyrones from a Marine-Derived Strain of the Fungus <i>Arthrinium arundinis</i> and Their Heterologous Expression
Yiwei Hu, Xiaoyang Zhao, Yue Song, Jiahui Jiang, Ting Yu Long, Mengjing Cong, Yuhua Miao, Yonghong Liu, Zhiyou Yang, Yiguang Zhu, Junfeng Wang
Abstract
Fungal linear polyketides, such as α-pyrones with a 6-alkenyl chain, have been a rich source of biologically active compounds. Two new ( 1 and 2 ) and four known ( 3 – 6 ) 6-alkenylpyrone polyketides were isolated from a marine-derived strain of the fungus Arthrinium arundinis . Their structures were determined based on extensive spectroscopic analysis. The biosynthetic gene cluster ( alt ) for alternapyrones was identified from A. arundinis ZSDS-F3 and validated by heterologous expression in Aspergillus nidulans A1145 ΔSTΔEM, which revealed that the cytochrome P450 monooxygenase Alt2′ could convert the methyl group 26-CH 3 to a carboxyl group to produce 4 from 3 . Another cytochrome P450 monooxygenase, Alt3′, catalyzed successive hydroxylation, epoxidation, and oxidation steps to produce 1, 2, 5, and 6 from 4 . Alternapyrone G ( 1 ) not only suppressed M1 polarization in lipopolysaccharide (LPS)-stimulated BV2 microglia but also stimulated dendrite regeneration and neuronal survival after Aβ treatment, suggesting alternapyrone G may be utilized as a privileged scaffold for Alzheimer’s disease drug discovery.