Recent Advances in Search of Bioactive Secondary Metabolites from Fungi Triggered by Chemical Epigenetic Modifiers

Abstract

Genomic analysis has demonstrated that many fungi possess essential gene clusters for the production of previously unobserved secondary metabolites; however, these genes are normally reduced or silenced under most conditions. These cryptic biosynthetic gene clusters have become treasures of new bioactive secondary metabolites. The induction of these biosynthetic gene clusters under stress or special conditions can improve the titers of known compounds or the production of novel compounds. Among the inducing strategies, chemical-epigenetic regulation is considered a powerful approach, and it uses small-molecule epigenetic modifiers, which mainly act as the inhibitors of DNA methyltransferase, histone deacetylase, and histone acetyltransferase, to promote changes in the structure of DNA, histones, and proteasomes and to further activate cryptic biosynthetic gene clusters for the production of a wide variety of bioactive secondary metabolites. These epigenetic modifiers mainly include 5-azacytidine, suberoylanilide hydroxamic acid, suberoyl bishydroxamic acid, sodium butyrate, and nicotinamide. This review gives an overview on the method of chemical epigenetic modifiers to trigger silent or low-expressed biosynthetic pathways to yield bioactive natural products through external cues of fungi, mainly based on the research progress in the period from 2007 to 2022. The production of about 540 fungal secondary metabolites was found to be induced or enhanced by chemical epigenetic modifiers. Some of them exhibited significant biological activities such as cytotoxic, antimicrobial, anti-inflammatory, and antioxidant activity.

Epigenetic Induction of Secondary Metabolites Production in Endophytic Fungi Penicillium chrysogenum and GC-MS Analysis of Crude Metabolites with Anti-HIV-1 Activity

“…The crude extract of P03MB2 without treatment with epigenetic modifiers had weak anti-HIV activity compared to the treated crude extracts. Sodium butyrate is an epigenetic modifier which inhibits the histone deacetylase activity, leading to the differentiation of the eukaryotic cells [ 86 , 87 ]. Previous studies showed that sodium butyrate treatment had the highest induction rate of 22 cryptic secondary metabolites from endophytic Nigrospora sphaerica [ 88 ].…”

The Histone Deacetylase HstD Regulates Fungal Growth, Development and Secondary Metabolite Biosynthesis in Aspergillus terreus

“…It is noteworthy that sirtuin has not been identified in A. terreus or most other filamentous fungi. Previous results showed that nicotinamide, a potent inhibitor of sirtuins, significantly changed the metabolite profile of filamentous fungi [ 26 ]. Additionally, the effect was observed in A. terreus RA2905.…”

Strategies for the Enhancement of Secondary Metabolite Production via Biosynthesis Gene Cluster Regulation in Aspergillus oryzae

“…However, in the absence of these marks, the gene clusters are activated, altering the chromatin structure accordingly. Therefore, altering the histone modification state can regulate gene expression and induce numerous changes in metabolite spectra, ultimately activating the recessive secondary metabolite production [66,67].…”