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Polyketide

Polyketides are a structurally diverse class of secondary metabolites produced by bacteria, fungi, plants, and other organisms through the catalytic action of polyketide synthases (PKSs), multifunctional enzyme complexes that assemble simple carboxylic acid precursors such as malonyl-CoA into complex carbon chains.^[1]^[2] This biosynthesis process mirrors fatty acid synthesis but features programmable variations in chain elongation, β-keto group processing (including optional reductions, dehydrations, and methylations), and cyclizations, resulting in polyketides with a vast array of architectures ranging from linear polyketide chains to macrolides, polyenes, and aromatic compounds.^[1]^[2] PKSs are classified into three main types based on their architecture and mechanism: type I PKSs, which are large multifunctional proteins operating in either iterative or modular (assembly-line) fashions, predominantly in bacteria and fungi; type II PKSs, consisting of discrete enzymes that iteratively build aromatic polyketides, mainly in bacteria; and type III PKSs, homodimeric chalcone synthase-like enzymes that produce simple polyketides such as flavonoids in plants and some bacteria.^[2]^[3] Modular type I PKSs, in particular, feature repeating modules each containing core domains like ketosynthase (KS) for condensation, acyltransferase (AT) for extender unit loading, and acyl carrier protein (ACP) for thioester tethering, with optional modifying domains that dictate the final product's functional groups and stereochemistry.^[1] This modularity enables the production of over 60,000 type I polyketide gene clusters identified in public microbial genomes as of 2024, many of which remain uncharacterized ("orphan" clusters), highlighting the untapped chemical diversity.^[2]^[4] Polyketides play crucial ecological roles in producer organisms, such as defense against predators, competition with other microbes, and signaling in symbioses, while their biomedical significance stems from potent bioactivities that have led to numerous clinically approved drugs.^[2] Notable examples include the macrolide antibiotic erythromycin, biosynthesized by the modular type I 6-deoxyerythronolide B synthase (DEBS) in Saccharopolyspora erythraea; the polyene antifungal amphotericin; the cholesterol-lowering statin lovastatin from fungal iterative type I PKS; and anticancer agents like epothilone.^[1]^[2] Advances in genetic engineering of PKS pathways in heterologous hosts have further expanded their potential for generating novel therapeutics, underscoring polyketides' enduring importance in medicine and biotechnology.^[5]^[6]

Overview

Definition and Characteristics

Polyketides are a diverse class of secondary metabolites produced by bacteria, fungi, plants, and some animals through the catalytic action of polyketide synthases (PKSs), multifunctional enzyme complexes that assemble carbon chains from simple precursor units. These precursors primarily consist of acetate (C2) derived from acetyl-CoA or malonyl-CoA, and propionate (C3) derived from propionyl-CoA or methylmalonyl-CoA, with malonyl-CoA serving as the predominant extender unit after decarboxylation during condensation.^[2]^[7] The core biosynthetic process involves iterative decarboxylative Claisen-like condensations between acyl thioesters bound to acyl carrier protein (ACP) domains, generating linear chains of β-ketoacyl intermediates that extend the polyketide backbone.^[2] These β-ketoacyl units form the foundational structural motif of polyketides, characterized by repeating patterns of ketone (C=O) and methylene (CH2) groups along the chain, often represented in simplified form as derived from n units of malonyl-CoA, yielding a poly-β-ketone structure like -\left( \ce{CH2-C(O)} \right)_n - after reductions or eliminations. The chains can undergo programmed modifications, including optional β-carbon reductions (via ketoreductase, dehydratase, and enoylreductase domains), intramolecular cyclizations, or aromatizations, leading to backbones that may incorporate alternating ketone-methylene sequences. Further tailoring, such as glycosylation, alkylation, or halogenation, enhances structural complexity without altering the core polyketide scaffold.^[2]^[8]^[9] In distinction from other natural products, polyketides differ from fatty acids—also derived from acetate units via fatty acid synthases—in their incomplete reduction of β-keto groups and frequent formation of cyclic or aromatic rings, yielding compact, bioactive molecules rather than long, linear hydrocarbon chains. Unlike terpenoids, which construct their carbon skeletons from isoprene (C5) units via the mevalonate or methylerythritol phosphate pathways, polyketides rely exclusively on C2/C3 carboxylic acid building blocks, resulting in acetate-propionate-derived frameworks without the branched, isoprenoid branching patterns.^[10]^[2]^[11] Polyketides generally exhibit lipophilicity owing to their predominantly hydrocarbon-based chains and reduced polar groups, which influences their solubility in organic solvents and interactions with biological membranes. Many also display characteristic UV absorption in the 230–300 nm range due to conjugated ketone or double-bond systems, particularly in aromatized or unsaturated variants, aiding in their detection and structural analysis.^[12]^[13]

Sources and Diversity

Polyketides are a vast class of secondary metabolites, with thousands of distinct structures identified to date, many of which originate from microbial sources, particularly actinomycete bacteria such as Streptomyces species.^[2] These soil-dwelling bacteria are prolific producers, contributing compounds like the antibiotic erythromycin and the pigment actinorhodin.^[14] Fungi also serve as significant microbial sources, yielding polyketides such as the toxin aflatoxin, while plants and marine organisms, including actinomycetes like Salinispora from ocean sediments, add to the repertoire with unique variants adapted to their environments.^[15]^[16] The structural diversity of polyketides spans a wide range of sizes and complexities, from simple aromatic molecules featuring 6-membered rings, such as those produced by type II polyketide synthases, to elaborate macrocyclic lactones like tylactone and extended polyenes exemplified by nystatin.^[17] This variability arises from differences in biosynthetic programming, allowing for linear chains, cyclic scaffolds, and fused ring systems that confer distinct physicochemical properties.^[2] Genomic studies have identified over 60,000 type I polyketide gene clusters as of 2024, many remaining uncharacterized ("orphan" clusters).^[4] Ecologically, polyketides often function as adaptive tools for microbial survival, serving as antibiotics to inhibit competitors, pigments for protection against UV radiation or signaling, and toxins to deter predators or pathogens.^[18]^[19]^[5] Beyond actinomycetes, non-bacterial sources highlight the evolutionary breadth of polyketide production, with emerging discoveries of type III polyketide synthase (PKS) products in fungi that generate compact aromatic compounds like resorcylic acids.^[20] In plants, chalcone synthase, a canonical type III PKS, catalyzes the formation of chalcones, which are precursors to flavonoids involved in UV protection and pollinator attraction.^[21] These non-actinomycete PKS systems underscore polyketides' role as versatile adaptive metabolites, evolved for defense against biotic stresses and intercellular signaling across kingdoms.^[22]^[2]

Historical Development

Early Discoveries

The early conceptual foundations for polyketides were laid in the late 19th century by British chemist John Norman Collie, who in 1893 proposed that the structure of orcinol, a phenolic compound derived from lichens, could be explained by the head-to-tail condensation of acetate units, foreshadowing the acetate origin of many natural products. Collie further advanced this idea in 1907 by coining the term "polyketone" to describe compounds formed through the polymerization of ketene-like units (-CH2CO-), drawing parallels to the synthesis of fatty acids and aromatic compounds. These insights, though speculative at the time, marked the initial recognition of polyketides as a distinct biosynthetic class, albeit without experimental validation due to the limitations of analytical techniques. The first experimental isolations of polyketides occurred in the 1920s to 1940s, primarily from microbial sources, as researchers screened soil actinomycetes for bioactive pigments and antibiotics amid the rising demand for antimicrobial agents during World War II. For instance, the red pigment actinorhodin was isolated in the late 1940s from Streptomyces coelicolor, a soil bacterium, highlighting the antibiotic potential of these colored metabolites produced by streptomycetes.^[23] Similarly, the polyketide antibiotic aureomycin (chlortetracycline) was discovered in 1948 from Streptomyces aureofaciens through soil screening efforts at Lederle Laboratories, representing one of the earliest clinically viable polyketides and ushering in the tetracycline class.^[24] These isolations were often serendipitous, driven by bioassay-guided fractionation rather than targeted biosynthesis studies. Pioneering work in the 1950s by Australian chemist Arthur J. Birch solidified the polyketide hypothesis through isotopic labeling experiments, demonstrating that aromatic polyketides such as 6-methylsalicylic acid incorporate multiple acetate units in a manner akin to fatty acid chain elongation and cyclization. Birch's 1953 and 1955 publications provided direct evidence using ^{14}C-labeled acetate fed to fungi like Penicillium patulum, confirming the head-to-tail assembly and aromatization processes Collie had theorized decades earlier. This hypothesis linked polyketide formation to polyketide synthase enzymes, analogous to fatty acid synthases, and spurred further investigations into microbial secondary metabolism. Initial structural elucidations posed significant challenges, relying on laborious degradation studies and classical chemical methods before the advent of nuclear magnetic resonance (NMR) spectroscopy in the mid-1950s.^[25] For example, the complex polycyclic structure of tetracyclines was unraveled through oxidative degradation and UV spectroscopy, delaying full characterization until the late 1950s. The first polyketide antibiotic approval came with aureomycin in 1948 for human use, followed by tetracycline itself in 1953 (patented) and 1954 (FDA approval), which became a cornerstone of broad-spectrum therapy due to its oral efficacy and low toxicity. These milestones underscored the therapeutic promise of polyketides amid post-war infectious disease outbreaks. By the 1960s, polyketides were formally recognized as a major class of natural products in scientific literature and symposia, with the terminology "polyketide" standardized to encompass acetate-derived metabolites from bacteria, fungi, and plants, distinct from terpenoids or alkaloids.^[26] This era saw compilations of biosynthetic data from isotope experiments, establishing polyketides' diversity and paving the way for deeper mechanistic studies, though genetic tools remained unavailable until later decades.

Key Advances in Understanding

In the 1970s, isotopic labeling experiments using 13C-enriched acetate precursors, analyzed via 13C NMR spectroscopy, provided definitive evidence for the polyketide origin of macrolide antibiotics from sequential acetate units. For instance, studies on leucomycin A3 demonstrated the incorporation of labeled acetate into specific carbon positions, confirming the head-to-tail assembly typical of polyketide biosynthesis. These techniques marked a shift from radioisotope methods to more precise stable isotope approaches, enabling detailed mapping of biosynthetic pathways in complex macrolides. By the 1980s, the first polyketide synthase (PKS) genes were isolated through cloning efforts in Streptomyces species, with the complete actinorhodin biosynthetic gene cluster from Streptomyces coelicolor representing a landmark achievement that revealed the genetic basis of aromatic polyketide production.^[27] The 1990s brought transformative insights into modular PKS architecture, exemplified by the sequencing of the erythromycin gene cluster in Saccharopolyspora erythraea, which uncovered a collinear organization of enzymatic modules analogous to fatty acid synthases (FAS). This discovery by Donadio et al. in 1991 established the modular type I PKS paradigm, where discrete domains for chain extension and modification operate in an assembly-line fashion.^[28] Building on foundational work from the 1964 Nobel Prize in Physiology or Medicine awarded to Konrad Bloch and Feodor Lynen for elucidating FAS mechanisms, these findings integrated polyketide models with FAS principles, highlighting shared evolutionary origins and catalytic strategies. Entering the 2000s, the genomic era facilitated complete sequencing of PKS clusters, such as the 6-deoxyerythronolide B synthase (DEBS) for erythromycin, enabling detailed annotation of domain functions and paving the way for engineering efforts. Concurrently, the identification of trans-acyltransferase (trans-AT) PKS systems expanded the known diversity, with the 2002 cloning of the pederin gene cluster from an uncultured bacterial symbiont revealing discrete acyltransferase enzymes acting in trans, distinct from the integrated cis-AT systems in actinomycetes. These advances underscored the prevalence of trans-AT PKS in non-actinobacterial producers, broadening the scope of polyketide structural variation. From the 2010s onward, metagenomics has unveiled PKS diversity from uncultured microbial sources, such as soil and marine environments, identifying novel clusters inaccessible through traditional culturing. Recent 2025 developments in metabologenomics, integrating metabolomics with genome mining, have accelerated the discovery of modular type I polyketide-derived compounds by correlating gene clusters with detected metabolites, as demonstrated in targeted analyses of bacterial consortia.^[29] This approach has yielded unprecedented insights into silent biosynthetic potential, fostering the isolation of bioactive polyketides from previously unexplored ecosystems.

Biosynthesis

Polyketide Synthase Enzymes

Polyketide synthases (PKSs) are large, multi-domain enzymatic complexes that catalyze the biosynthesis of polyketide natural products through iterative chain elongation and optional reduction steps. These enzymes assemble carbon chains by repeatedly adding two-carbon units derived primarily from malonyl-CoA, analogous to fatty acid biosynthesis but with greater structural variability. The core process involves decarboxylative Claisen condensation reactions, where a growing polyketide chain is extended by an activated acyl unit, forming β-keto thioester intermediates that can undergo partial or complete reduction to introduce diversity in functional groups.^[30] The general mechanism of PKSs begins with the loading of a starter unit, such as acetyl-CoA or propionyl-CoA, onto the acyl carrier protein (ACP) domain via an acyltransferase (AT) domain. Subsequent elongation cycles involve the AT domain transferring malonyl-CoA to the ACP, forming malonyl-ACP. The ketosynthase (KS) domain then catalyzes the decarboxylative Claisen condensation between the acyl chain tethered to ACP (R-C(O)-S-ACP) and malonyl-ACP, yielding a β-ketoacyl-ACP intermediate and releasing CO₂. This reaction can be simplified as:

\ce{R-C(O)-S-ACP + malonyl-S-ACP ->[KS] R-C(O)-CH2-C(O)-S-ACP + CO2}

The KS domain forms a covalent thioester intermediate with the growing chain, facilitating nucleophilic attack by the enolate from decarboxylated malonyl-ACP. The ACP domain, equipped with a phosphopantetheine arm, tethers substrates and intermediates, enabling their delivery to active sites across the enzyme. AT domains ensure specificity by selecting appropriate extender units, such as malonyl-CoA for standard acetate-derived extensions or methylmalonyl-CoA for branched chains.^[30]^[31]^[32] In comparison to fatty acid synthases (FAS), which produce fully saturated linear chains through complete reduction of β-keto intermediates to methylene groups in every cycle, PKSs exhibit programmable reduction patterns that retain keto, hydroxy, or enoyl functionalities, thereby generating diverse polyketide structures rather than uniform fatty acids. This flexibility arises from the presence or absence of reductive domains (ketoreductase, dehydratase, enoylreductase) in each module, contrasting with the invariant full reductive loop in FAS. Energy for PKS catalysis includes NADPH as the cofactor for optional β-keto and enoyl reductions, with one equivalent consumed per reduction step, and ATP required upstream for priming via activation of starter and extender units (e.g., carboxylation of acetyl-CoA to malonyl-CoA by acetyl-CoA carboxylase). For a typical polyketide like 6-deoxyerythronolide B, synthesis demands approximately six equivalents each of NADPH and ATP equivalents alongside substrate inputs.^[25]^[30]^[33]

Types of Polyketide Synthases

Polyketide synthases (PKSs) are categorized into distinct types based on their architectural organization and mode of iteration during polyketide chain assembly. Type I PKSs are modular systems composed of large, multifunctional proteins that contain dedicated domains for each step of the biosynthetic cycle. These enzymes assemble polyketides in an assembly-line fashion, where each module typically handles one round of chain elongation and processing. A classic example is the 6-deoxyerythronolide B synthase (DEBS) from Saccharopolyspora erythraea, which produces the core structure of the antibiotic erythromycin through three multidomain polypeptides. Fungal iterative Type I PKSs, such as the lovastatin synthase (LovB with trans-acting enoyl reductase LovC that selectively reduces three of eight possible enoyl groups), produce reduced polyketides with decoupled reductive activities. Similarly, the pks15 PKS in the entomopathogenic fungus Beauveria bassiana, interacting with an associated enoyl reductase, regulates virulence factors; a 2025 study showed mutants downregulate 36 secondary metabolite clusters and exhibit impaired cell wall modulation, enhancing insect immune evasion.^[34]^[35]^[36] Type I PKSs are further subdivided into cis-acyltransferase (cis-AT) and trans-acyltransferase (trans-AT) subtypes, differing in how malonyl-CoA extender units are loaded. In cis-AT systems, the acyltransferase (AT) domain is integrated within each module, whereas trans-AT systems employ discrete, standalone AT proteins that serve multiple modules, enabling greater structural flexibility. Recent 2024 studies have highlighted the extraordinary diversity of trans-AT PKS modules, with over 150 architectural variants identified, often involving hybrid systems that incorporate non-canonical domains for novel polyketide scaffolds; evolution-guided engineering has successfully reprogrammed these systems to produce 22 designer variants with high efficiency in bacterial hosts.^[37]^[2] Type II PKSs operate iteratively using a set of dissociated, monofunctional enzymes that are reused for multiple rounds of chain extension, contrasting the modular nature of Type I systems. These enzymes, commonly found in bacteria, include a core ketosynthase-chain length factor (KS-CLF) heterodimer responsible for chain initiation and elongation, along with accessory proteins for tailoring. Type II PKSs primarily synthesize aromatic polyketides, such as anthracyclines and tetracyclines, through folding and cyclization of poly-β-ketoacyl intermediates. They can be grouped into aromatic subgroups, which produce polycyclic aromatic compounds via C7-C12 or C9-C14 aldol condensations, and alicyclic subgroups, which yield non-aromatic, partially reduced products like angucyclines through alternative cyclization mechanisms.^[38]^[39] Type III PKSs are homodimeric enzymes resembling chalcone synthase, primarily occurring in plants and fungi, and catalyze the synthesis of simple, often aromatic polyketides using a single active site for both priming and iterative elongation without carrier proteins. These enzymes typically produce 2-4 elongation cycles, yielding products like chalcones, phloroglucinols, and pyrans, with specificity determined by starter unit selection and cyclization mode. In fungi, Type III PKSs contribute to ecological and medicinal compounds, such as antimicrobials and pigments. A 2025 study functionally characterized 42 novel fungal Type III PKSs (T3PKSs) from 2,096 genomes, revealing broad substrate promiscuity— with one enzyme accepting 10 of 12 tested CoA starters—and novel quinolone formation, tripling the known functional diversity and enabling synthesis of unnatural 2-pyrones with alkyne or heterocyclic moieties.^[40]

Post-Synthetic Modifications

Post-synthetic modifications encompass a suite of enzymatic transformations that diversify the polyketide scaffold after its release from the polyketide synthase (PKS) complex, often introducing functional groups essential for biological activity. These tailoring steps typically occur post-chain release but can also proceed co-PKS on protein-bound intermediates, enabling the addition of hydroxyl, sugar, or halogen moieties to enhance solubility, target specificity, or stability. In many cases, the initial chain release is facilitated by thioesterase (TE) domains, which catalyze macrolactonization to form cyclic structures; for instance, the pikromycin TE adopts a curled substrate conformation via a hydrophilic barrier, directing efficient 12-membered ring formation from the linear polyketide precursor.^[41] Common modifications include cyclizations such as Dieckmann condensation, which generates β-keto ester rings through intramolecular Claisen-like reactions. A representative example is the off-loading Dieckmann cyclase NcmC in nocamycin biosynthesis, where it catalyzes tetramate heterocyclization on the hybrid polyketide/nonribosomal peptide chain, as revealed by 1.6 Å crystal structures and mutagenesis studies. Reductions, mediated by ketoreductase (KR) domains, convert β-keto groups to alcohols, with stereoselectivity determined by active-site residues like Tyr or Ser; these can occur post-release in discrete enzymes, though often integrated during elongation. Oxidations, frequently catalyzed by flavoprotein monooxygenases (FPMOs), introduce hydroxylations or Baeyer-Villiger rearrangements; in hitachimycin biosynthesis, HitM3 (a P450-like oxygenase) adds an oxygen at C10 post-macrolactonization, while HitM4 dehydrogenates C11-OH, establishing a sequential modification pathway confirmed by gene inactivation experiments.^[42]^[43] Key tailoring enzymes include cytochrome P450 monooxygenases for regioselective hydroxylation, as in stambomycin where P450-catalyzed oxidation at a terminal carbon provides the hydroxyl group required for subsequent TE-mediated macrolactonization. Glycosyltransferases (GTs) append sugars to improve pharmacokinetics; notably, in pactamycin, the GT PtmJ acts co-PKS on an ACP-tethered 3-(3-aminophenyl)-3-oxopropionyl intermediate, marking the first reported glycosylation of a small-molecule polyketide while protein-bound. Halogenases enable chlorination for enhanced reactivity; the flavin-dependent ChlA halogenase in DIF-1 biosynthesis dichlorinates the trihydroxyphenyl hexanone precursor via a lysine-chloramine intermediate, as demonstrated in vitro with FADH₂ and Cl⁻. These enzymes often function post-PKS, with timing coordinated by substrate availability after TE release.^[44]^[45]^[46] Recent insights from 2024–2025 highlight atypical cyclizations and oxidations in trans-AT PKS systems, where discrete trans-acting enzymes expand structural diversity. In the leinamycin family, divergent tandem ACPs necessitate in-series processing with cryptic transacylation prior to off-loading and cyclization, enabling complex ring formations beyond canonical modules. For example, genome mining of trans-AT clusters has revealed FPMO oxidation modules producing lobatamides with broader chemo- and regioselectivity in on-line α-hydroxylations and epoxidations during late-stage tailoring. These advances underscore the modular flexibility of trans-AT systems for generating bioactive variants.^[47]^[48]^[49]

Classification

By Biosynthetic Machinery

Polyketides are classified by the type of polyketide synthase (PKS) machinery responsible for their biosynthesis, which determines the structural diversity and complexity of the resulting products. Type I PKS systems, characterized by large multifunctional enzymes with modular domains, assemble polyketide chains through sequential elongation cycles, leading to linear or macrocyclic structures. Type II PKSs consist of discrete, iterative enzymes that build aromatic scaffolds via repeated condensations followed by cyclization. Type III PKSs, simpler homodimeric enzymes, perform iterative condensations without carrier proteins, predominantly in eukaryotic organisms. Hybrid systems integrate PKS modules with nonribosomal peptide synthetases (NRPS), yielding chimeric molecules that combine polyketide and peptide elements. Type I PKS products include macrolide antibiotics such as erythromycin, produced by the 6-deoxyerythronolide B synthase (DEBS) in Saccharopolyspora erythraea, which features dedicated modules for each chain extension step to generate a 14-membered lactone ring.^[50] Polyene antifungals like amphotericin B, biosynthesized by Streptomyces nodosus, exemplify the modular assembly yielding linear polyene chains with conjugated double bonds and a macrolactone core.^[51] This modular architecture allows for precise control over chain length and functionalization, resulting in structurally complex, non-aromatic polyketides often used in therapeutics. Type II PKS products are predominantly aromatic compounds, such as the tetracycline antibiotics from Streptomyces species, where iterative chain extension by ketosynthase and malonyl-CoA:ACP transacylase enzymes produces linear polyketide chains that undergo folding and aromatization to form fused ring systems.^[52] Anthraquinones, including those from Photorhabdus luminescens, arise from similar iterative processes involving discrete enzymes that facilitate decarboxylative condensation and subsequent cyclization into polycyclic aromatic frameworks.^[53] The dissociation of enzyme subunits after each cycle enables the formation of multiring aromatics, distinguishing these products from the linear outputs of other PKS types. Type III PKSs generate flavonoids and pyrone derivatives through straightforward Claisen condensations of acyl-CoA starters with malonyl-CoA extenders, primarily in plants and fungi. In plants, chalcone synthase catalyzes the formation of chalcones, the precursors to flavonoids like naringenin, via three condensation steps leading to a tetraketide intermediate that cyclizes into an aromatic ring.^[3] Fungal type III PKSs produce triketide or tetraketide pyrones, such as 6-pentyl-α-pyrone in Trichoderma atroviride, through iterative condensations without thioester intermediates, yielding simple cyclic polyketides with ecological roles.^[54] Hybrid NRPS-PKS systems fuse polyketide and peptide assembly lines to create mixed scaffolds, as seen in phytotoxins like coronatine where NRPS and PKS modules assemble the peptide (coronamic acid) and polyketide (coronafacic acid) portions, respectively.^[55]^[56] Recent genomic mining efforts in 2025 have uncovered over 60 novel biosynthetic gene clusters (BGCs) integrating PKS, NRPS, and polyunsaturated fatty acid synthase-like modules, revealing diverse hybrid polyketides in bacterial genomes.^[57] These hybrids expand structural diversity by alternating polyketide chain extensions with peptide condensations, often post-modified for bioactivity.

By Chemical Structure

Polyketides are classified by chemical structure into several major categories based on their molecular architectures, which reflect the folding and cyclization patterns of the polyketide chain independent of the underlying biosynthetic enzymes. This structural taxonomy highlights the diversity of scaffolds, from planar aromatic systems to complex three-dimensional motifs, enabling distinct chemical properties and reactivities.^[58] Aromatic polyketides feature planar, polycyclic ring systems derived from the aromatization of linear poly-β-ketone precursors, often resulting in phenolic or quinone-containing structures. Simpler examples include phenolic compounds such as orsellinic acid and its derivatives, which possess a single or fused benzene rings with hydroxyl substituents, contributing to their stability and redox properties. More complex variants, like anthracyclines, exhibit linear fused tetracyclic aglycones with a characteristic 7,8,9,10-tetrahydrotetracene-5,12-quinone core; daunorubicin, for instance, incorporates this scaffold linked to a daunosamine sugar, exemplifying the linear fused ring arrangement typical of this subclass. These aromatic structures are prevalent in bacterial secondary metabolites and often display vibrant pigmentation due to extended conjugation.^[59]^[60]^[61] Macrocyclic polyketides are characterized by large cyclic frameworks, typically 12- to 20-membered rings, formed by ester or ether linkages that confer rigidity and conformational specificity. Macrolactones, such as those in the erythromycin family, feature a lactone ring connecting a hydroxyl and carboxylic acid terminus of the polyketide chain, enabling membrane permeability and binding interactions. Depsipeptides represent hybrid motifs where ester bonds alternate with amide linkages, often incorporating polyketide-derived segments in mixed scaffolds. Polyether ionophores, like monensin, incorporate multiple tetrahydrofuran and tetrahydropyran rings fused into a macrocycle, creating ion-binding cavities through oxygen-rich ether bridges. These structures are predominantly microbial in origin and facilitate functions like ion transport due to their preorganized cavities.^[58]^[62]^[63] Linear and aliphatic polyketides lack extensive cyclization or aromatization, retaining extended carbon chains with functional groups like double bonds or unstable moieties. Polyenes, such as amphotericin B, contain conjugated double bonds along a linear backbone, forming rigid, amphipathic structures that interact with lipid membranes. Enediynes feature a distinctive (Z)-enediyne warhead—a labile bicyclic system with two triple bonds separated by a double bond—capable of generating DNA-cleaving radicals upon activation; calicheamicin exemplifies this with its linear polyene-derived core attached to a carbohydrate and enediyne unit, where the warhead's instability underlies its potency. These acyclic or minimally cyclic forms emphasize chain flexibility and reactive unsaturation.^[64]^[65] Other structural motifs in polyketides include highly fused or spirocyclic systems that arise from intricate folding. Spirotetronates possess a central spiro[4.4]nonane core with an embedded tetronate ring, often decorated with sugar moieties, as in chlorothricin and nomimicin, where the spiro junction imparts three-dimensional complexity and stereochemical diversity. Meroterpenoids integrate polyketide-derived aromatic or aliphatic segments with terpenoid chains, yielding hybrid scaffolds like hongoquercin A, which combines a naphthoquinone polyketide with a farnesyl terpene unit for enhanced lipophilicity. Recent discoveries from 2024–2025 have unveiled novel trans-AT polyketide variants, such as those identified through genome-based mining, revealing unprecedented scaffolds like tricyclic aromatics with flexible chain lengths in underexplored actinomycetes. These motifs underscore the evolving structural repertoire of polyketides.^[66]^[67]^[68]^[69]

Applications

Medicinal Applications

Polyketides represent a major class of natural products with significant therapeutic value in human medicine, particularly as antibiotics and anticancer agents. Among antibiotics, macrolides such as erythromycin, first approved by the FDA in 1952, are produced by modular polyketide synthases in bacteria like Saccharopolyspora erythraea and exert their antibacterial effects by binding to the 50S subunit of the bacterial ribosome, thereby inhibiting protein synthesis during the elongation phase.^[70] Tetracyclines, including the semi-synthetic derivative doxycycline, originate from polyketide biosynthesis pathways in Streptomyces species and similarly target the 30S ribosomal subunit to prevent aminoacyl-tRNA accommodation, blocking polypeptide chain elongation and providing broad-spectrum activity against Gram-positive and Gram-negative bacteria.^[71] These compounds have been foundational in treating respiratory, skin, and other infections, with doxycycline remaining a key option for conditions like acne and Lyme disease due to its favorable pharmacokinetics.^[72] In oncology, polyketide-derived anthracyclines like doxorubicin, approved by the FDA in 1974, are widely used for treating leukemias, lymphomas, and solid tumors through DNA intercalation, which disrupts replication and transcription while also generating reactive oxygen species to induce cell death.^[73] Enediynes, such as esperamicin, represent another potent subclass of polyketide antitumor agents isolated from actinomycetes; they function by abstracting hydrogen atoms from DNA sugars, triggering double-strand breaks via their reactive enediyne core, which contributes to their exceptional cytotoxicity against cancer cells.^[74] Overall, approximately 20 polyketide-based drugs have received FDA approval, underscoring their clinical impact across infectious and neoplastic diseases, though formulations like liposomal doxorubicin (Doxil, approved 1995) have mitigated toxicity issues such as cardiotoxicity.^[75] Beyond antibiotics and anticancer therapies, polyketides serve as immunosuppressants and antiparasitics. Rapamycin (sirolimus), a macrocyclic polyketide from Streptomyces hygroscopicus, acts as an mTOR inhibitor by forming a complex with FKBP12 that allosterically blocks kinase activity, thereby suppressing T-cell proliferation and cytokine signaling; it is FDA-approved for preventing organ transplant rejection and treating lymphangioleiomyomatosis.^[76] Avermectin derivatives, notably ivermectin—a hydrogenated product of avermectins produced by Streptomyces avermitilis—target glutamate-gated chloride channels in invertebrates, causing paralysis in parasites; approved in 1987, ivermectin has revolutionized treatment for onchocerciasis and other neglected tropical diseases, earning its discoverers the 2015 Nobel Prize in Physiology or Medicine.^[77]^[78] Despite their efficacy, polyketide therapeutics face challenges from antimicrobial resistance, such as in methicillin-resistant Staphylococcus aureus (MRSA), where erm and msr genes confer resistance to erythromycin via ribosomal methylation or efflux pumps, reducing binding affinity and complicating treatment of skin and soft tissue infections.^[79] To address such issues, recent advances include the discovery of novel antioxidant polyketides through cocultivation of bacteria and fungi, which activates silent biosynthetic gene clusters to yield compounds with potential to combat oxidative stress-related pathologies; for instance, a 2024 study on fungal-bacterial co-cultures has identified polyketides exhibiting radical-scavenging activity, offering leads for adjunctive therapies in antibiotic-resistant infections.^[80]

Agricultural and Industrial Applications

Polyketides have found significant applications in agriculture, particularly as insecticides and antifungals for crop protection. The spinosyn family, including spinosad, represents a prominent class of polyketide-derived insecticides produced by the actinomycete Saccharopolyspora spinosa. Spinosad was first registered for agricultural use in the United States in 1997 and targets a broad spectrum of insect pests by disrupting nicotinic acetylcholine receptors in the insect nervous system, leading to hyperexcitation and paralysis.^[81]^[82] This mode of action provides selective toxicity, sparing many beneficial insects and reducing environmental impact compared to conventional synthetic insecticides. In antifungal applications, polyketides such as the polyene nystatin, biosynthesized by type I polyketide synthases in Streptomyces noursei, inhibit fungal cell membrane function by binding ergosterol, offering control against soil-borne and foliar pathogens in crops like fruits and vegetables.^[83] Herbicidal polyketides and hybrids have also emerged as sustainable alternatives for weed management. Phosphonothrixin, a herbicidal phosphonate natural product from Saccharothrix sp. ST-888, features a branched carbon skeleton assembled via a nonribosomal peptide synthetase–polyketide synthase (NRPS–PKS) hybrid system, inhibiting plant growth through disruption of metabolic pathways.^[84] This compound exemplifies how polyketide-derived structures can contribute to broad-spectrum weed control with lower persistence in soil than traditional herbicides. In industrial contexts, polyketide pigments like actinorhodin, a blue benzoisochromanequinone produced by Streptomyces coelicolor via type II polyketide synthases, serve as natural dyes in textiles and potentially in antibacterial fabrics due to their antimicrobial properties.^[85] Actinorhodin exhibits pH-dependent color changes, enabling applications in indicators and coloring agents for non-food industries. For biofuels, engineered modular polyketide synthases have been utilized to produce fuel precursors such as fatty acid-derived alkanes and alkenes from microbial hosts, offering a renewable route to drop-in biofuels with tunable chain lengths.^[86] Polyketides also show promise in environmental roles, particularly bioremediation, through siderophore-like structures. Certain bacterial siderophores, such as those incorporating polyketide moieties via NRPS-PKS hybrids (e.g., yersiniabactin-like compounds), chelate heavy metals like iron, lead, and cadmium, enhancing their bioavailability for microbial degradation and reducing soil toxicity.^[87] Recent advances in 2024 highlight the optimization of polyketide-based pesticides like milbemycins, macrocyclic lactones from Streptomyces species, for sustainable agrochemicals, improving efficacy against resistant pests while minimizing ecological footprints through semi-synthetic modifications.^[88]

Biotechnology and Engineering

Natural Product Optimization

Natural product optimization strategies for polyketides focus on enhancing yields and generating analogs through modifications to native producer strains and cultivation processes, without redesigning biosynthetic pathways de novo. Fermentation optimization plays a central role, involving adjustments to media composition and nutrient supplementation to improve precursor availability and metabolic flux. For instance, in the production of the macrolide antibiotic erythromycin by Saccharopolyspora erythraea, supplementation with propionate or n-propanol as precursors for propionyl-CoA has been shown to increase titers by up to 100%, as these additives boost the incorporation of extender units into the polyketide chain during the growth-dissociated production phase.^[89] Media engineering further refines this by balancing carbon sources like glucose with nitrogen inputs, such as ammonium sulfate fed at controlled rates (e.g., 0.02 g/L/h after 60 hours of fermentation), which enhances erythromycin synthesis by optimizing precursor pools and reducing byproduct accumulation.^[90] Strain improvement via mutagenesis complements these efforts by generating variants with upregulated biosynthetic genes or reduced feedback inhibition. Random mutagenesis, often using UV irradiation or chemical agents like N-methyl-N'-nitro-N-nitrosoguanidine, followed by screening for higher yields, has been a cornerstone of industrial optimization for S. erythraea. Multiple rounds of such mutagenesis have historically elevated erythromycin A production in commercial strains, with improvements attributed to mutations enhancing methylmalonyl-CoA node efficiency and minimizing pathway bottlenecks.^[91] For example, transposon mutagenesis in S. erythraea identified genotypes that increase erythromycin output by altering regulatory elements, demonstrating the empirical power of this approach despite its labor-intensive nature.^[92] Precursor-directed biosynthesis extends optimization by supplying non-native starter or extender units to the polyketide synthase (PKS), yielding structural analogs with potentially improved properties. In S. erythraea, engineering a genetic block in the initial condensation step of the 6-deoxyerythronolide B pathway allows exogenous synthetic diketides to be incorporated, producing multimilligram quantities of novel macrolides processed into antibacterial analogs comparable in potency to erythromycin. A representative case is the generation of 7-deoxyerythromycin, where altered propionyl-CoA analogs serve as starters, resulting in desmethyl variants that evade resistance mechanisms while retaining ribosomal binding affinity.^[93] This method's selectivity stems from the PKS loading module's tolerance for structural variations, enabling rational analog diversification directly in native hosts.^[94] Heterologous expression transfers PKS gene clusters to more amenable hosts like Escherichia coli or yeast, achieving higher titers through optimized cellular machinery and reduced native interference. In E. coli, expression of the full erythromycin pathway, including 17 heterologous genes, has produced erythromycin C at up to 50 mg/L, surpassing native yields in early shake-flask cultures by leveraging the host's rapid growth and genetic tractability.^[95] Similarly, Saccharomyces cerevisiae serves as a chassis for modular type I PKSs, with codon-optimized clusters yielding polyketides like 6-methylsalicylic acid at titers exceeding 1 g/L after pathway refactoring.^[96] Recent advancements include the 2025 development of Streptomyces aureofaciens J1-022 as a versatile chassis for type II polyketides; after deleting endogenous biosynthetic gene clusters, it produced oxytetracycline at a record 8.53 g/L and chlortetracycline at over 5 g/L without further engineering, highlighting its innate precursor abundance for tetracycline-class compounds.^[97] Despite these advances, challenges persist in heterologous systems, including polyketide toxicity to host cells, which disrupts growth and reduces titers, and the large size of PKS clusters (often >100 kb), complicating cloning and stable expression.^[5] Toxicity arises from intermediate accumulation or membrane perturbation, necessitating chaperone co-expression or compartmentalization strategies, while cluster size limits vector capacity in non-actinomycete hosts, often requiring multi-plasmid assemblies that lower efficiency.^[98] These hurdles underscore the need for host-specific tailoring to balance productivity and stability.

Synthetic Biology Approaches

Synthetic biology approaches to polyketide production leverage genetic engineering techniques to generate novel structures beyond those found in nature, enabling the creation of hybrid enzymes and diversified biosynthetic pathways. These methods address limitations in natural polyketide diversity by modularly reassembling polyketide synthase (PKS) components, such as ketosynthase (KS) and acyltransferase (AT) domains, to produce variants with altered chain lengths, stereochemistry, or functional groups. For instance, domain swapping between KS and AT domains from different modular PKSs has been used to engineer hybrid products like 6-deoxyerythromycin, where the substitution of the erythromycin PKS loading module with one from a rapamycin PKS resulted in a simplified macrolide scaffold in the 1990s, paving the way for subsequent optimizations into the 2020s.^[99]^[100] Such swaps minimize disruptions to the overall PKS architecture while introducing specificity for alternative extender units, as demonstrated in engineering the AT domain of epothilone PKS to incorporate methylmalonyl-CoA, yielding new epothilone analogs with potential anticancer activity.^[101] CRISPR-based editing of PKS gene clusters has emerged as a precise tool for targeted mutations that diversify polyketide outputs, particularly by modifying docking domains to enhance inter-module communication and assembly efficiency. In 2025, CRISPR-based insertion of docking domains into modular PKS genes from bacteria improved metabolite titers by 5–13-fold through better mRNA integrity and functional assembly line production.^[102] Similarly, CRISPR/Cas9-mediated knockout of the EgPKS gene in the fungus Edenia gomezpompae confirmed its role in preussomerin biosynthesis, enabling cluster refactoring to produce truncated polyketide variants with antifungal properties.^[103] These edits facilitate rapid diversification by introducing point mutations or deletions in biosynthetic clusters, contrasting with traditional optimization by focusing on structural novelty rather than yield enhancement.^[104] Combinatorial biosynthesis employs plug-and-play modular systems to generate libraries of polyketide variants, often integrating modules from genomically mined clusters to access new scaffolds. Platforms like BioBricks enable the assembly of type I PKS variants, such as constructing 125 pentaketide synthases from standardized modules, which produced a diverse set of aromatic polyketides in Escherichia coli hosts.^[105] Genomic mining, including metagenomic approaches (metabologenomics), has identified novel PKS modules from uncultured bacteria, which are then incorporated into synthetic pathways; for example, a 2024 study demonstrated plug-and-play engineering of modular type I PKSs to produce custom polyketides with varied starter and extender units.^[106] This strategy expands the chemical space by mixing ketoreductase-inactive modules with tailoring enzymes, generating hundreds of analogs from a single scaffold without relying on full cluster refactoring.^[107]^[108] Looking ahead, AI-driven prediction of PKS architectures promises to accelerate the design of custom synthases, with tools integrating machine learning to forecast module compatibility and product profiles based on sequence-structure relationships.^[109] In parallel, studies on bacterial type III PKSs highlight their untapped potential as targets for pathogenesis inhibitors; a 2025 investigation revealed that a type III PKS in Mycobacterium tuberculosis contributes to virulence factor production, suggesting engineered inhibitors could disrupt infections by blocking these pathways.^[110] These innovations position synthetic biology at the forefront of polyketide engineering, bridging computational design with therapeutic applications.

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Assembling a plug-and-play production line for combinatorial ...
Jul 18, 2019 · This work enables plug-and-play combinatorial biosynthesis of aromatic polyketides using bacterial type II PKSs in E. coli, providing full access to its many ...Missing: mining | Show results with:mining
[107]
Application of Synthetic Biology to the Biosynthesis of Polyketides
Aug 14, 2024 · This paper first introduces polyketides from different sources and classifications, then the reconstruction of biosynthetic pathways is described.
[108]
Natural products, synthetic biology and artificial intelligence for next ...
Jan 24, 2025 · Collaboration across synthetic biology, AI, and clinical research is essential to translating these breakthroughs into next‐generation treatments.
[109]
Functional flexibility of a type III polyketide synthase in ... - NIH
Jul 16, 2025 · Our study is the first report of the involvement of a T3PKS in bacterial pathogenesis and provides exciting insights for future therapeutics.Missing: inhibitors | Show results with:inhibitors