Elucidation of Biosynthetic Pathways of Natural Products

Abstract

During the last decade, we have revealed biosynthetic pathways responsible for the formation of important and chemically complex natural products isolated from various organisms through genetic manipulation. Detailed in vivo and in vitro characterizations enabled elucidation of unexpected mechanisms of secondary metabolite biosynthesis. This personal account focuses on our recent efforts in identifying the genes responsible for the biosynthesis of spirotryprostatin, aspoquinolone, Sch 210972, pyranonigrin, fumagillin and pseurotin. We exploit heterologous reconstitution of biosynthetic pathways of interest in our study. In particular, extensive involvement of oxidation reactions is discussed. Heterologous hosts employed here are Saccharomyces cerevisiae, Aspergillus nidulans and A. niger that can also be used to prepare biosynthetic intermediates and product analogs by engineering the biosynthetic pathways using the knowledge obtained by detailed characterizations of the enzymes. (998 char.).

Safety of the fungal workhorses of industrial biotechnology: update on the mycotoxin and secondary metabolite potential of Aspergillus niger, Aspergillus oryzae, and Trichoderma reesei

“…Pseurotins are NRP polyketide hybrid secondary metabolites that have neuritogenic (Komagata et al 1996 ), antibiotic (Mehedi et al 2010 ; Pinheiro et al 2013 ), anti-inflammatory (Shi et al 2015 ), chitin-synthase inhibitor (Wenke et al 1993 ), and antileishmanial and anticancer (Martinez-Luis et al 2012 ) characteristics. Pseurotin A & D was reported to be produced together with chlovalicin (Uchoa et al 2017 ) probably coded by an intertwined gene clusters, as is the case for Aspergillus fumigatus , where pseurotin A and fumagillin, chemically closely related to chlovalicin, are coded by an intertwined gene cluster (Wiemann et al 2013 ; Kishimoto et al 2017 ). However, psurotins have not been reported from any other isolate of A. niger (Nielsen et al 2009 ), so the two metabolites may be produced by another species in Aspergillus section Nigri .…”

“…The pyranonigrins A–K are NRP-PK derived antioxidant secondary metabolites from A. niger (Hiort et al 2004 ; Miyake et al 2007 ; Kishimoto et al 2017 ). There are several pyranonigrins isolated from Aspergillus niger , including pyranonigrin A–K (Kishimoto et al 2017 ).…”

Identification of the pyranonigrin A biosynthetic gene cluster by genome mining in Penicillium thymicola IBT 5891

“…Pyranonigrins are a family of antioxidative compounds that are reported to be secondary metabolites produced by Aspergillus niger , all featuring a unique pyrano[2,3‐c]pyrrole bicyclic skeleton, which is rarely found in nature . Of this family, pyranonigrin A (Figure ) was shown to have the activity as a 1,1‐diphenyl‐2‐picrylhydrazyl radical scavenging reagent .…”

Infection Process and Genome Assembly Provide Insights into the Pathogenic Mechanism of Destructive Mycoparasite Calcarisporium cordycipiticola with Host Specificity

“…Six proteins encoded by the genes of cluster 8 showed high sequence identity (31-52%) with a cluster of Aspergillus niger CBS 513.88 being responsible for pyranonigrins (Figure S13A) [80]. Pyranonigrins are a family of antioxidative compounds that are reported to be produced by A. niger, all featuring a unique pyrano [2,3-c] pyrrole core structure which is rarely found in nature [81]. Transcriptome data showed that these genes were moderately expressed in the mycelia (Table S15), indicating C. cordycipiticola might produce pyranonigrins-related compounds.…”