Enhancing Nonribosomal Peptide Biosynthesis in Filamentous Fungi

Abstract

Filamentous fungi are historically known as rich sources for production of biologically active natural products, so-called secondary metabolites. One particularly pharmaceutically relevant chemical group of secondary metabolites is the nonribosomal peptides synthesized by nonribosomal peptide synthetases (NRPSs). As most of the fungal NRPS gene clusters leading to production of the desired molecules are not expressed under laboratory conditions, efforts to overcome this impediment are crucial to unlock the full chemical potential of each fungal species. One way to activate these silent clusters is by overexpressing and deleting global regulators of secondary metabolism. The conserved fungal-specific regulator of secondary metabolism, LaeA, was shown to be a valuable target for sleuthing of novel gene clusters and metabolites. Additionally, modulation of chromatin structures by either chemical or genetic manipulation has been shown to activate cryptic metabolites. Furthermore, NRPS-derived molecules seem to be affected by cross talk between the specific gene clusters and some of these metabolites have a tissue- or developmental-specific regulation. This chapter summarizes how this knowledge of different tiers of regulation can be combined to increase production of NRPS-derived metabolites in fungal species.

The Putative Methyltransferase TlLAE1 Is Involved in the Regulation of Peptaibols Production in the Biocontrol Fungus Trichoderma longibrachiatum SMF2

“…were increased 2.5-and 2-fold, respectively, as a result of constitutive overexpression of Tllae1. These findings support that overexpression of LaeA/LAE1 serves as an effective strategy to improve production of biologically active secondary metabolites and even to discover new metabolites via activating silent gene clusters in fungi (Soukup et al, 2016), which are rich resources for valuable secondary metabolites that have great potentials in agriculture, industry, and pharmaceutics.…”

“…For example, several PKS (polyketide synthetase) and NRPS encoding genes have been shown to be upregulated in the lae1-overexpressing T. reesei (Karimi-Aghcheh et al, 2013); overexpression of LaeA in A. fumisynnematus significantly increased the production of cyclopiazonic acid, which was previously known as mycotoxin (Hong et al, 2015); and in P. citrinum, overexpression of LaeA enhanced mevastatin production (Zheng et al, 2014). More strikingly, overexpression of LaeA has even led to synthesis of new metabolites that have not been detected in the WT strain (Karimi-Aghcheh et al, 2013;Hong et al, 2015;Jiang et al, 2016;Soukup et al, 2016). In our study, constitutive overexpression of Tllae1 markedly enhanced the peptaibols yield in T. longibrachiatum SMF2.…”

Distribution and Evolution of Nonribosomal Peptide Synthetase Gene Clusters in the Ceratocystidaceae

“…These building blocks play a role in both the structural adaptability and diversity of biological activities present among NRPs [5]. In filamentous fungi, the genes required for biosynthesis of these NRPs are often clustered together in the genome [6,7]. In such a cluster, one of the genes encode a large mono- or multimodular enzyme, referred to as a nonribosomal peptide synthetase (NRPS), which is responsible for producing the NRP backbone [3,4].…”

“…In such a cluster, one of the genes encode a large mono- or multimodular enzyme, referred to as a nonribosomal peptide synthetase (NRPS), which is responsible for producing the NRP backbone [3,4]. Other genes in the cluster encode proteins involved in modifying the NRP and regulating its production and function [7].…”

CORRELATION BETWEEN NON-RIBOSOMAL PEPTIDE SYNTHETASE (NRPS) PRODUCTION AND VIRULENCE OF Ganoderma boninense PER71 ON OIL PALM (Elaeis guineensis)

“…Instead, proteinogenic and non-proteinogenic amino acids are serially incorporated (Sayari et al, 2019). These enzymes are multi-modular and most NRPS modules consist of three conserved domains: adenylation (A) (identification and substrate activation), thiolation (T) or peptidyl carrier protein (PCP) (covalent binding and transmission) and condensation (C) (formation of peptide bond) which when grouped together are referred to as a single module (Martínez Núñez and López, 2016;Soukup et al, 2016). Each module is responsible for recognition and incorporation of amino acids into the extending peptide backbone depending on the complexity of the peptide.…”