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.
Highlights
Non-ribosomal peptides (NRP) and polyketides are produced by both fungi and bacteria, via non-ribosomal peptide synthesis (NRPS) and polyketide synthesis (PKS), respectively, and are often associated with aiding the organisms to adapt to, or survive in, a hostile environment such as the presence of competing microorganisms, nutrient limitation, and protection against insect immune systems (Meier and Burkart, 2009; Wiemann and Keller, 2014)
Polyketides are biosynthesized from acyl coenzyme A (CoA) precursors by multi-modular enzymes consisting of essential ketosynthase, acyl carrier protein and acyltransferase, amongst other, domains (Weissman, 2014)
It is produced by A. fumigatus, and its biosynthesis is mediated by the products of the gli gene cluster, with the NRP synthetase GliP starting the pathway through the fusion of L-phenylalanine and L-serine (Balibar and Walsh, 2006), while many of the other genes encode decorating enzymes
Summary
Non-ribosomal peptides (NRP) and polyketides are produced by both fungi and bacteria, via non-ribosomal peptide synthesis (NRPS) and polyketide synthesis (PKS), respectively, and are often associated with aiding the organisms to adapt to, or survive in, a hostile environment such as the presence of competing microorganisms, nutrient limitation, and protection against insect immune systems (Meier and Burkart, 2009; Wiemann and Keller, 2014). Primary metabolism is required to provide the essential biosynthetic precursors for NRPS, many NRPs share substrate amino acids and additional co-substrates, chromatin structure apparently controls much SM gene cluster expression, and evidence is emerging that NRPS pathways interact such that alterations in the biosynthesis of specific NRPs may impact on the production of apparently unrelated metabolites (O’Keeffe et al, 2014; Wiemann et al, 2014).
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