Introducing co-review to .

now offers the option of co-review for our reviewers. Editors-in-Chief Russell J. Cox and Karen Faulds, and Executive Editor Laura Fisher, offer more detail on how this will work.

Comparing total chemical synthesis and total biosynthesis routes to fungal specialized metabolites.

Covering the period 1965-2024Total synthesis has been defined as the art and science of making the molecules of living Nature in the laboratory, and by extension, their analogues. At the extremes, specialised metabolites can be created by total chemical synthesis or by total biosynthesis. In this review we explore the advantages and disadvantages of these two approaches using quantitative methodology that combines measures of molecular complexity, molecular weight and fraction of sp centres for bioactive fungal metabolites.

Investigation of chain-length selection by the tenellin iterative highly-reducing polyketide synthase.

The programming of widely distributed iterative fungal hr-PKS is mysterious, yet it is central for generating polyketide natural product diversity by controlling the chain length, β-processing level and methylation patterns of fungal polyketides. For the iterative hr-PKS TENS, responsible for producing the pentaketide-tyrosine hybrid pretenellin A 1, the chain length programming is known to be determined by the KR domain. Structure prediction of the KR domain enabled the identification of a relevant substrate binding helix, which was the focus of swap experiments with corresponding sequences from the related hr-PKS DMBS and MILS that produce similar hexa- and heptaketides (2, 3).

Engineered and total biosynthesis of fungal specialized metabolites.

Filamentous fungi produce a very wide range of complex and often bioactive metabolites, demonstrating their inherent ability as hosts of complex biosynthetic pathways. Recent advances in molecular sciences related to fungi have afforded the development of new tools that allow the rational total biosynthesis of highly complex specialized metabolites in a single process. Increasingly, these pathways can also be engineered to produce new metabolites.

Reductive Release from a Hybrid PKS-NRPS during the Biosynthesis of Pyrichalasin H.

Three central steps during the biosynthesis of cytochalasan precursors, including reductive release, Knoevenagel cyclisation and Diels Alder cyclisation are not yet understood at a detailed molecular level. In this work we investigated the reductive release step catalysed by a hybrid polyketide synthase non-ribosomal peptide synthetase (PKS-NRPS) from the pyrichalasin H pathway. Synthetic thiolesters were used as substrate mimics for in vitro studies with the isolated reduction (R) and holo-thiolation (T) domains of the PKS-NRPS hybrid PyiS.

Total biosynthesis of fungal tetraketide pyrones.

Fungal tetraketide pyrones possess important and potent bioactivities, but their detailed biosynthetic pathways are unknown and synthetic routes to their production are lengthy. Here we investigated the fungal pathways to the multiforisins and compounds related to islandic acid. Heterologous expression experiments yield high titres of these compounds and pathway intermediates.

Sporothioethers: deactivated alkyl citrates from the fungus .

Submerged cultivation of MUCL 54604 resulted in formation of a stereoisomeric mixture of new sulfur-containing sporothriolide derivatives named sporothioethers A and B. The presence of the 2-hydroxy-3-mercaptopropanoic acid moiety attenuates the antimicrobial activity in comparison to the precursor sporothriolide suggesting a detoxification mechanism. However, moderate effects on biofilms of and were observed for sporothriolide and sporothioethers A and B at concentrations below their MICs.

Introducing transparent peer review to .

is introducing the option of transparent peer review for authors. Editors-in-Chief Russell J. Cox and Karen Faulds, and Executive Editor Laura C.

Decrypting the programming of β-methylation in virginiamycin M biosynthesis.

During biosynthesis by multi-modular trans-AT polyketide synthases, polyketide structural space can be expanded by conversion of initially-formed electrophilic β-ketones into β-alkyl groups. These multi-step transformations are catalysed by 3-hydroxy-3-methylgluratryl synthase cassettes of enzymes. While mechanistic aspects of these reactions have been delineated, little information is available concerning how the cassettes select the specific polyketide intermediate(s) to target.

Introduction to engineering the biosynthesis of fungal natural products.

Filamentous fungi are highly diverse eukaryotes that inhabit all known ecosystems on earth. Estimates suggest that more than 2 × 10 species are likely to exist, and analyses of typical fungal genomes suggest they harbour around 50 biosynthetic gene clusters on average. The biosynthetic potential of these organisms is thus vast.

Stereochemical and Biosynthetic Rationalisation of the Tropolone Sesquiterpenoids.

This review summarises the known structures, biological activities, and biosynthetic pathways of the tropolone sesquiterpenoid family of fungal secondary metabolites. Synthesis of this knowledge allows likely structural and stereochemical misassignments to be revised and shows how the compounds can be divided into three main biosynthetic classes based on the stereochemistry of key biosynthetic steps.

Maleidride biosynthesis - construction of dimeric anhydrides - more than just heads or tails.

Covering: up to early 2022Maleidrides are a family of polyketide-based dimeric natural products isolated from fungi. Many maleidrides possess significant bioactivities, making them attractive pharmaceutical or agrochemical lead compounds. Their unusual biosynthetic pathways have fascinated scientists for decades, with recent advances in our bioinformatic and enzymatic understanding providing further insights into their construction.

Terpenoids from Kiwi endophytic fungus sp. and their antibacterial activity against pv. .

A chemical investigation on the kiwi endophytic fungus sp. Resulted in the isolation of eight new terpenoids (-) and five known analogues (-). Compounds - are novel sativene sesquiterpenoids containing three additional skeletal carbons, while compounds and are rare dimers.

Antroxazole A, an oxazole-containing chamigrane dimer from the fungus with immunosuppressive activity.

Antroxazole A (1), a chamigrane type sesquiterpene dimer containing an oxazole moiety, has been characterized from cultures of the fungus . The structure with absolute configuration was determined by extensive spectroscopic methods and single crystal X-ray diffraction. A plausible biosynthetic pathway for 1 was proposed.

Curiouser and curiouser: progress in understanding the programming of iterative highly-reducing polyketide synthases.

Covering: 1996-2022Investigations over the last 2 decades have begun to reveal how fungal iterative highly-reducing polyketide synthases are programmed. Both and experiments have revealed the interplay of intrinsic and extrinsic selectivity of the component catalytic domains of these systems. Structural biology has begun to provide high resolution structures of hr-PKS that can be used as the basis for their engineering and reprogramming, but progress to-date remains rudimentary.

Heterologous Expression of Secondary Metabolite Genes in for Waste Valorization.

() was developed as a microbial cell factory for the heterologous expression of fungal secondary metabolites. This was achieved by inactivation of sorbicillinoid biosynthesis and construction of vectors for the rapid cloning and expression of heterologous fungal biosynthetic genes. Two types of megasynth(et)ases were used to test the strain and vectors, namely a non-reducing polyketide synthase (nr-PKS, ) from and a hybrid highly-reducing PKS non-ribosomal peptide synthetase (hr-PKS-NRPS, ) from .

studies of maleidride-forming enzymes.

assays of enzymes involved in the biosynthesis of maleidrides from polyketides in fungi were performed. The results show that the enzymes are closely related to primary metabolism enzymes of the citric acid cycle in terms of stereochemical preferences, but with an expanded substrate selectivity. A key citrate synthase can react both saturated and unsaturated acyl CoA substrates to give solely substituted citrates.

Engineering for the Heterologous Expression of a Bacterial Modular Polyketide Synthase.

Microbial natural products have had phenomenal success in drug discovery and development yet form distinct classes based on the origin of their native producer. Methods that enable metabolic engineers to combine the most useful features of the different classes of natural products may lead to molecules with enhanced biological activities. In this study, we modified the metabolism of the fungus to enable the synthesis of triketide lactone (TKL), the product of the modular polyketide synthase DEBS1-TE engineered from bacteria.

Contains a Biosynthetic Gene Cluster That Encodes the Antifungal Agent Ilicicolin H.

The biosynthetic gene cluster (BGC) from the well-studied organism was studied by heterologous expression in the fungal host . Coexpression of and produces two new acyl tetramic acids. Addition of the ring-expanding cytochrome P450 encoded by then yields a known pyridone intermediate to ilicicolin H and a new chain-truncated shunt metabolite.

Stereochemical characterisation of the non-canonical α-humulene synthase from .

The non-canonical fungal α-humulene synthase was investigated through isotopic labelling experiments for its stereochemical course regarding inversion or retention at C-1, the face selectivity at C-11, and the stereoselectivity of the final deprotonation. A new and convenient desymmetrisation strategy was developed to enable a full stereochemical analysis of the catalysed steps to the achiral α-humulene product from stereoselectively labelled farnesyl diphosphate.

Understanding and Engineering the Stereoselectivity of Humulene Synthase.

The non-canonical terpene cyclase AsR6 is responsible for the formation of 2E,6E,9E-humulene during the biosynthesis of the tropolone sesquiterpenoid (TS) xenovulene A. The structures of unliganded AsR6 and of AsR6 in complex with an in crystallo cyclized reaction product and thiolodiphosphate reveal a new farnesyl diphosphate binding motif that comprises a unique binuclear Mg -cluster and an essential K289 residue that is conserved in all humulene synthases involved in TS formation. Structure-based site-directed mutagenesis of AsR6 and its homologue EupR3 identify a single residue, L285/M261, that controls the production of either 2E,6E,9E- or 2Z,6E,9E-humulene.

The sporothriolides. A new biosynthetic family of fungal secondary metabolites.

The biosynthetic gene cluster of the antifungal metabolite sporothriolide was identified from three producing ascomycetes: MUCL 54604, CLL 205 and DAOMC 242471. A transformation protocol was established, and genes encoding a fatty acid synthase subunit and a citrate synthase were simultaneously knocked out which led to loss of sporothriolide and sporochartine production. reactions showed that the sporochartines are derived from non-enzymatic Diels-Alder cycloaddition of and trienylfuranol A during the fermentation and extraction process.