Endogenous cross-talk of fungal metabolites

Abstract

Non-ribosomal peptide (NRP) synthesis in fungi requires a ready supply of proteogenic and non-proteogenic amino acids which are subsequently incorporated into the nascent NRP via a thiotemplate mechanism catalyzed by NRP synthetases. Substrate amino acids can be modified prior to or during incorporation into the NRP, or following incorporation into an early stage amino acid-containing biosynthetic intermediate. These post-incorporation modifications involve a range of additional enzymatic activities including but not exclusively, monooxygenases, methyltransferases, epimerases, oxidoreductases, and glutathione S-transferases which are essential to effect biosynthesis of the final NRP. Likewise, polyketide biosynthesis is directly by polyketide synthase megaenzymes and cluster-encoded ancillary decorating enzymes. Additionally, a suite of additional primary metabolites, for example: coenzyme A (CoA), acetyl CoA, S-adenosylmethionine, glutathione (GSH), NADPH, malonyl CoA, and molecular oxygen, amongst others are required for NRP and polyketide synthesis (PKS). Clearly these processes must involve exquisite orchestration to facilitate the simultaneous biosynthesis of different types of NRPs, polyketides, and related metabolites requiring identical or similar biosynthetic precursors or co-factors. Moreover, the near identical structures of many natural products within a given family (e.g., ergot alkaloids), along with localization to similar regions within fungi (e.g., conidia) suggests that cross-talk may exist, in terms of biosynthesis and functionality. Finally, we speculate if certain biosynthetic steps involved in NRP and PKS play a role in cellular protection or environmental adaptation, and wonder if these enzymatic reactions are of equivalent importance to the actual biosynthesis of the final metabolite.

Quantitative proteomics reveals the mechanism and consequence of gliotoxin-mediated dysregulation of the methionine cycle in Aspergillus niger

“…SAM is a methyl donor and one of the most interconnected metabolites of the cell. It is involved in sensing and stimulating its own biosynthesis [33] through the methionine cycle [34]. The use of SAM as a cofactor for trans-methylation reactions releases SAH, which, by SAH hydrolase, is degraded to Ado and Hcy.…”

Resistance is not futile: gliotoxin biosynthesis, functionality and utility

“…The gliotoxin-related metabolome Increasingly, examples of fungal secondary metabolite cross-talk, whereby abrogation or overproduction of one secondary metabolite may affect the production of another apparently unrelated metabolite are emerging, as reviewed in [53]. This phenomenon has been described in A. fumigatus in relation to gliotoxin biosynthesis, whereby overexpression of gliZ led to helvolic acid production at 378C which was not observed in wild type, while the production of multiple metabolites was altered by the loss or gain of gliZ, suggesting that gliZ may influence the biosynthesis of secondary metabolites other than gliotoxin [19].…”

Biosynthetic investigation of phomopsins reveals a widespread pathway for ribosomal natural products in Ascomycetes

“…Many other compounds produced by ascomycetes are toxic and are known as mycotoxins, which pose substantial threats to human food supplies and health (5). Major classes of natural products from Ascomycetes include alkaloids (6,7), terpenoids (8), polyketides (PKs) (9)(10)(11)(12), nonribosomal peptides (NRPs) (12)(13)(14), and PK-NRP hybrids (15,16). However, ribosomally synthesized and posttranslationally modified peptides (RiPPs), a rapidly growing class of natural products (17), have rarely been found in Ascomycetes.…”