A comprehensive overview on genomically directed assembly of aromatic polyketides and macrolide lactones using fungal megasynthases

Abstract

Fungal polyketide synthases (PKSs) catalyze a carbon-carbon bond forming reaction in an iterative manner using a variety of acyl-CoA molecules as substrates when biosynthesizing complex polyketides. Although most members from this class of natural products exhibit notable biological activities, often they are naturally produced in trace levels or cultivation of the analyteproducing organism is less than feasible. Appropriately, to contend with the former challenge, one must identify any translational bottleneck and perform functional analysis of the associated enzymes. In recent years, many gene clusters purportedly responsible for biosynthesizing polyketides have been identified and cataloged from a variety of fungal genomes including genes coding for iterative PKSs, particulary bikaverin, zearalenone and hypothemycin biosynthetic enzymes. Mounting appreciation of these highly specific codons and their translational consequence will afford scientists the ability to anticipate the fungal metabolite by correlating an organism's genomic cluster to an appropriate biosynthetic system. It was observed in recent reports, the successful production of these recombinant enzymes using an Escherichia coli expression system which in turn conferred the anticipated metabolite in vitro. This review will focus on iterative PKSs responsible for biosynthesizing bikaverin, zearalenone and hypothemycin, and expand on befitting enzymatic reaction mechanisms and development of a highly versatile system that could potentially generate biologically active compounds.

The structural role of the carrier protein – active controller or passive carrier

“…[294][295][296] Many fungal polyketides are formed through the iterative use of a single set of catalytic domains located on one polypeptide, and domain organisation is similar to that seen for the animal FAS. 297 In some cases both highly reducing and non-reducing PKSs cooperate to produce compounds such as zearalenone, 298 radicicol 299 and hypothemycin. 300 Similar interactions are also required from PKS/FAS hybrid synthases producing aflatoxin 301 and the related compound dothistromin, 302 while PKS/NRPS hybrid synthases 303 produce fusarin C, 304 lovastatin, 291 and tennelin.…”

Activation of the Dormant Secondary Metabolite Production by Introducing Gentamicin-Resistance in a Marine-Derived Penicillium purpurogenum G59

“…A significant number of natural product drugs and leads are of microbial origin [4,5,6,7], among which fungal secondary metabolites are of particular importance. Research on fungal secondary metabolites has attracted considerable attention [8,9,10,11,12,13,14,15] with particular interest in marine-derived fungi [10,11,12,13,14] and an increasing number of reports are related to the production of bioactive metabolites [13,14,15,16,17,18,19,20,21,22,23]. Secondary metabolites from uncultured microorganisms have now become accessible by the metagenomics method, bypassing the isolation and cultivation processes [24,25,26], or by new cultivation approaches [25,26].…”

“…The impact of microbial genomics on natural product research has yet to be taken into serious consideration [37,38]. The regulation of fungal secondary metabolism has also been explored to a certain extent, from genetic, genomic and biochemical perspectives, in transcriptional, translational and enzymatic levels [16,17,18,19,20,21,22,23]. Various genetic strategies have recently been developed to activate the silent gene clusters in order to obtain cryptic secondary metabolites [26,27,28,29].…”

Biochemical and Structural Characterization of Germicidin Synthase: Analysis of a Type III Polyketide Synthase That Employs Acyl-ACP as a Starter Unit Donor

“…Polyketides are ubiquitous secondary metabolites produced by bacteria, fungi, plants, and animals, 1–4 and constitute one of the largest sources for natural product-based pharmaceuticals (antibiotics, antiparasitics, antifungals, anticancer drugs, and immunosuppressants) and other commercial products (food additives, pigments and nutraceuticals). 5–7 Most polyketides are synthesized by three broad classes of polyketide synthases (PKSs), types I, II, and III, that share a common mechanism of sequential decarboxylative condensations of a wide range of acyl-coenzyme A (CoA) substrates.…”

“…Polyketides are ubiquitous secondary metabolites produced by bacteria, fungi, plants, and animals, − and they constitute one of the largest sources for natural product-based pharmaceuticals (antibiotics, antiparasitics, antifungals, anticancer drugs, and immunosuppressants) and other commercial products (food additives, pigments, and nutraceuticals). − Most polyketides are synthesized by three broad classes of polyketide synthases (PKSs), types I, II, and III, that share a common mechanism of sequential decarboxylative condensations of a wide range of acyl-coenzyme A (CoA) substrates. ,, Polyketide structural diversity is dictated by selectivity of starter and extender units, the number of condensation reactions, and the manner of off-loading or ring closure of the fully elaborated polyketide chains . Type I PKSs are multifunctional proteins made up of modules subdivisible into multiple discrete catalytic domains, all of which ultimately control the size and regio- and stereochemical characteristics of the polyketide scaffolds.…”