Abstract
Fungal secondary metabolites are renowned toxins as well as valuable sources of antibiotics, cholesterol-lowering drugs, and immunosuppressants; hence, great efforts were levied to understand how these compounds are genetically regulated. The genes encoding for the enzymes required for synthesizing secondary metabolites are arranged in biosynthetic gene clusters (BGCs). Often, BGCs contain a pathway specific transcription factor (PSTF), a valuable tool in shutting down or turning up production of the BGC product. In this review, we present an in-depth view of PSTFs by examining over 40 characterized BGCs in the well-studied fungal species Aspergillus nidulans and Aspergillus fumigatus. Herein, we find BGC size is a predictor for presence of PSTFs, consider the number and the relative location of PSTF in regard to the cluster(s) regulated, discuss the function and the evolution of PSTFs, and present application strategies for pathway specific activation of cryptic BGCs.
Highlights
Secondary metabolites (SMs) in fungi, known as natural products, are present and synthesized in ecologically diverse species [1]
The dotted black arrow indicates the process of protein translation by the pathway specific transcription factor (PSTF) gene; the solid black arrow indicates the process of SM(s) production by the biosynthetic gene clusters (BGCs); the dotted red arrow indicates the positive regulation by the PSTF for all the other biosynthetic genes in the cluster; the solid red arrow indicates positive regulation by the PSTF for the specific gene; the solid blue arrow with a stop end indicates the negative regulation by the PSTF for the specific gene
By examining characterized BGCs and their PSTFs in A. nidulans and A. fumigatus, we find that the majority of in-cluster PSTFs are positive regulators of BGCs, and overexpression of these PSTFs leads to increased titers of specific BGC products
Summary
Secondary metabolites (SMs) in fungi, known as natural products, are present and synthesized in ecologically diverse species [1]. Recent advances shed light on hierarchical levels of SM transcriptional elements by highlighting the role of global regulators (e.g., the Velvet complex [20,21]), stress response regulators (e.g., PacC mediating fungal response to pH [22]), epigenetic regulators (e.g., the COMPASS complex in A. nidulans [23,24]), as well as a variety of TFs including pathway specific transcription factors (PSTFs). Whereas all of these elements are utilized for genome mining of fungal BGCs, the use of PSTFs presents the most mechanistically clear approach. We examine these two model fungi and identify which BGCs contain PSTFs, characterize known regulatory mechanisms of each PSTF, and present recommendations on how to better utilize PSTFs for the discovery of novel SMs
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