• Journal of Life Science
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• v.12 no.5
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• pp.632-648
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• 2002

The term polyketide defines a class of natural products synthesized through the successive condensation of small arboxylic acids, which results in products containing multiple carbonyl or hydroxyl groups, each separated by one arbon atom, as in the structural element CH$_2$C(=0)CH$_2$CH(OE)CH$_2$C(=0)-. Plant flavonoids, fungal aflatoxins, as well as undreds of compounds of different structures that can inhibit the growth of bacteria, viruses, fungi, parasites or human umor cells are included in this diverse group. Some of antifungal polyketides also have immunosuppresive activity. olyketides can vary widely in structure, and the diversity of polyketide structures reflects the wide variety of their iological properties. This review focuses on the biosynthesis of polyketides and recent progress in combinatorial iosynthesis of new hybrid polyketide compounds.

• Journal of Microbiology and Biotechnology
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• v.17 no.5
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• pp.830-839
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• 2007

Pradimicins are potent antifungal antibiotics having an unusual dihydrobenzo[$\alpha$]naphthacenequinone aglycone substituted with D-alanine and sugars. Pradimicins are polyketide antibiotics produced by Actinomadura hibisca P157-2. The gene cluster involved in the biosynthesis of pradimicins was cloned and sequenced. The pradimicin gene cluster was localized to a 39-kb DNA segment and its involvement in the biosynthesis of pradimicin was proven by gene inactivation of prmA and prmB(ketosynthases $\alpha\;and\;\beta$). The pradimicin gene cluster consists of 28 open reading frames(ORFs), encoding a type II polyketide synthase(PKS), the enzymes involved in sugar biosynthesis and tailoring enzymes as well as two resistance proteins. The deduced proteins showed strong similarities to the previously validated gene clusters of angucyclic polyketides such as rubromycin, griseorhodin, and fredericamycin. From the pradimicin gene cluster, prmP3 encoding a component of the acetyl-CoA carboxylase complex was disrupted. The production levels of pradimicins of the resulting mutants decreased to 62% of the level produced by the wild-type strain, which indicate that the acetyl-CoA carboxylase gene would have a significant role in the production of pradimicins through supplying the extender unit precursor, malonyl-CoA.

• The Plant Pathology Journal
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• v.24 no.1
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• pp.8-16
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• 2008

Aurofusarin is a polyketide pigment produced by some Fusarium species. The PKS12 and GIP1 genes, which encode a putative type I polyketide synthase (PKS) and a fungal laccase, respectively, are known to be required for aurofusarin biosynthesis in Gibberella zeae (anamorph: Fusarium graminearum). The ten additional genes, which are located within a 30 kb region of PKS12 and GIP1 and regulated by a putative transcription factor (GIP2), organize the aurofusarin biosynthetic cluster. To determine if they are essential for aurofusarin production in G. zeae, we have employed targeted gene deletion, complementation, and chemical analyses. GIP7, which encodes O-methyltransferase, is confirmed to be required for the conversion of norrubrofusarin to rubrofusarin, an intermediate of aurofusarin. GIP1-, GIP3-, and GIP8-deleted strains accumulated rubrofusarin, indicating those gene products are essential enzymes for the conversion of rubrofusarin to aurofusarin. Based on the phenotypic changes in the gene deletion strains examined, we propose a possible pathway for aurofusarin biosynthesis in G. zeae. Our results would provide important information for better understanding of naphthoquinone biosynthesis in other fdarnentous fungi as well as the aurofusarin biosynthesis in G. zeae.

• Journal of Microbiology and Biotechnology
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• v.16 no.5
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• pp.764-770
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• 2006

Dihydrochalcomycin (GERI-155), produced by Streptomyces sp. KCTC-0041BP isolated from Korean soil, is a 16-membered macrolide antibiotic consisting of two deoxysugar moieties at C-5 and C-20 positions of a branched lactone ring. The cloning and sequencing of a gene cluster for dihydrochalcomycin biosynthesis revealed a 63-kb nucleotide region containing 25 open reading frames (ORFs). The products of all of these 25 ORFs playa role in dihydrochalcomycin biosynthesis and self-resistance against the compounds synthesized. At the core of this cluster lies a 39.6-kb polyketide synthase (PKS) region encoding eight modules in five giant multifunctional protein-coding genes (gerSI-SV). The genes responsible for the biosynthesis of deoxysugar moieties, D-chalcose and D-mycinose, and their modification and attachment were found on either side of this PKS region. The involvement of this gene cluster in dihydrochalcomycin biosynthesis was confirmed by disruption of the dehydratase (DH) domain in module 3 of the PKS gene and by metabolite analysis.

• Proceedings of the PSK Conference
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• 2003.10a
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• pp.75-78
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• 2003

Polyketides are a class of structurally diverse natural products which possess a wide range of biological activities. These compounds are used throughout medicine and agriculture as antimicrobials, immunosuppressants, antiparasitics, and anticancer agents. While structurally diverse, polyketides are assembled by a common mechanism of decarboxylative condensations of simple malonate derivatives by polyketide synthases (PKSs) in a manner very similar to fatty acid biosynthesis (Fig 1). (omitted)

• Molecules and Cells
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• v.38 no.12
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• pp.1105-1110
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• 2015

Phleichrome, a pigment produced by the phytopathogenic fungus Cladosporium phlei, is a fungal perylenequinone whose photodynamic activity has been studied intensively. To determine the biological function of phleichrome and to engineer a strain with enhanced production of phleichrome, we identified the gene responsible for the synthesis of phleichrome. Structural comparison of phleichrome with other fungal perylenequinones suggested that phleichrome is synthesized via polyketide pathway. We recently identified four different polyketide synthase (PKS) genes encompassing three major clades of fungal PKSs that differ with respect to reducing conditions for the polyketide product. Based on in silico analysis of cloned genes, we hypothesized that the non-reducing PKS gene, Cppks1, is involved in phleichrome biosynthesis. Increased accumulation of Cppks1 transcript was observed in response to supplementation with the application of synthetic inducer cyclo-(${_L}-Pro-{_L}-Phe$). In addition, heterologous expression of the Cppks1 gene in Cryphonectria parasitica resulted in the production of phleichrome. These results provide convincing evidence that the Cppks1 gene is responsible for the biosynthesis of phleichrome.

• Proceedings of the Korean Society for Applied Microbiology Conference
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• 2002.10a
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• pp.18-25
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• 2002

The pikromycin biosynthetic system in Streptomyces venezuleae is unique for its ability to produce two groups of antibiotics that include the 12-membered ring macrolides methymycin and neomethymycin, and the 14-membered ring macrolides narbomycin and pikromycin. The metabolic pathway also contains two post polyketide-modification enzymes, a glycosyltransferase and P450 hydroxylase that have unusually broad substrate specificities. In order to explore further the substrate flexibility of these enzymes a series of hybrid polyketide synthases were constructed and their metabolic products characterized. The plasmid-based replacement of the multifunctional protein subunits of the pikromycin PKS in S. venezuelae by the corresponding subunits from heterologous modular PKSs resulted in recombinant strains that produce both 12- and 14-membered ring macrolactones with predicted structural alterations. In all cases, novel macrolactones were produced and further modified by the DesVII glycosyltransferase and PikC hydroxylase leading to biologically active macrolide structures. These results demonstrate that hybrid PKSs in S. venezuelae can produce a multiplicity of new macrolactones that are modified further by the highly flexible DesVII glycosyltransferase and PikC hydroxylase tailoring enzymes. This work demonstrates the unique capacity of the S. venezuelae pikromycin pathway to expand the toolbox of combinatorial biosynthesis and to accelerate the creation of novel biologically active natural products. The polyketide backbone of rifamycin B is assembled through successive condensation and ${\beta}$-carbonyl processing of the extender units by the modular rifamycin PKS. The eighth module, in the RifD protein, contains nonfunctional DH domain and functional KR domain, which specify the reduction of the ${\beta}$-carbonyl group resulting in the C-21 bydroxyl of rifamycin B. A four amino acid substitution and one amino acid deletion were introduced in the putative NADPH binding motif in the proposed KR domain encoded by rifD. This strategy of mutation was based on the amino acid sequences of the corresponding motif of the KR domain of module 3 in the RifA protein, which is believed dysfunctional, so as to introduce a minimum alteration and retain the reading frame intact, yet ensure loss of function. The resulting strain produces linear polyketides, from tetraketide to octaketide, which are also produced by a rifD disrupted mutant as a consequence of premature termination of polyketide assembly. Much of the structural diversity within the polyketide superfamily of natural products is due to the ability of PKSs to vary the reduction level of every other alternate carbon atom in the backbone. Thus, the ability to introduce heterologous reductive segments such as ketoreductase (KR), dehydratase (DH), and enoylreductase (ER) into modules that naturally lack these activities would increase the power of the combinatorial biosynthetic toolbox. The dehydratase domain of module 7 of the rifamycin PKS, which is predicted to be nonfunctional in view of the sequence of the apparent active site, was replaced with its functional homolog from module 7 of rapamycin-producing polyketide synthase. The resulting mutant strain behaved like a rifC disrupted mutant, i.e., it accumulated the heptaketide intermediate and its precursors. This result points out a major difficulty we have encountered with all the Amycolatopsis mediterranei strain containing hybrid polyketide synthases: all the engineered strains prepared so far accumulate a plethora of products derived from the polyketide chain assembly intermediates as major products instead of just analogs of rifamycin B or its ansamycin precursors.

• Genomics & Informatics
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• v.6 no.4
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• pp.227-230
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• 2008

Compounds of polyketide origin possess a wealth of pharmacological effects, including antibacterial, antifungal, antiparasitic, anticancer and immunosuppressive activities. Many of these compounds and their semisynthetic derivatives are used today in the clinic. Most of the gene clusters encoding commercially important drugs have also been cloned and sequenced and their biosynthetic mechanisms studied in great detail. The area of biosynthetic engineering of the enzymes involved in polyketide biosynthesis has recently advanced and been transferred into the industrial arena. In this work, we introduce a computational system to provide the user with a wealth of information that can be utilized for biosynthetic engineering of enzymes involved in post-PKS tailoring steps. Post-PKS tailoring steps are necessary to add functional groups essential for the biological activity and are therefore important in polyketide biosynthesis.

• Proceedings of the PSK Conference
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• 2003.10a
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• pp.79-80
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• 2003

A lot of polyketide antibiotics have been isolated from natural sources like microorganism, fungi and plant. The polyketide natural products have biologically and medically important activities, including antibacterial, anticancer, antiparasitic, and immunosuppressant properties. The diversified activities of polyketides are originated from their structural variety of which have been took advantage by several research groups for development of new drugs. (omitted)

• Biomolecules & Therapeutics
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• v.27 no.2
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• pp.127-133
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• 2019

The study of the genus Streptomyces is of particular interest because it produces a wide array of clinically important bioactive molecules. The genomic sequencing of many Streptomyces species has revealed unusually large numbers of cytochrome P450 genes, which are involved in the biosynthesis of secondary metabolites. Many macrolide biosynthetic pathways are catalyzed by a series of enzymes in gene clusters including polyketide and non-ribosomal peptide synthesis. In general, Streptomyces P450 enzymes accelerate the final, post-polyketide synthesis steps to enhance the structural architecture of macrolide chemistry. In this review, we discuss the major Streptomyces P450 enzymes research focused on the biosynthetic processing of macrolide therapeutic agents, with an emphasis on their biochemical mechanisms and structural insights.