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T1 - The shikimic acid pathway and polyketide biosynthesis

T1 - Vinylogous Dehydration by a Polyketide Dehydratase Domain in Curacin Biosynthesis

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Polyketides and nonribosomal peptides

Natural products, produced chiefly by microorganisms and plants, can be large and structurally complex molecules. These molecules are manufactured by cellular assembly lines, in which enzymes construct the molecules in a stepwise fashion. The means by which enzymes interact and work together in a modular fashion to create diverse structural features has been an active area of research; the work has provided insight into the fine details of biosynthesis.

terreus as examples, focusing on 13 polyketide synthase (PKS) genes in A.

Abhirup Das received his M.S. degree from Indian Institute of Technology, Kanpur, India, in the year 2004. He is currently a Ph.D. student in Chemistry. His research interest includes semisynthesis and biosynthesis of medicinally useful aromatic polyketides.

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BT - Complex Enzymes in Microbial Natural Product Biosynthesis, Part B

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The individual steps involved in the biosynthesis of DHCHC from shikimic acid in Streptomyces hygroscopicus var ascomyceticus has been delineated and shown to be stereochemically and enzymatically distinct from the CHC pathway.

Polyketide Biosynthesis - ResearchGate

KW - Polyketide

N2 - The shikimic acid pathway, ubiquitous in microorganisms and plants, provides precursors for the biosynthesis of primary metabolites such as the aromatic amino acids and folic acid. Several branchpoints from the primary metabolic pathway also provide aromatic and, in some unusual cases, nonaromatic precursors for the biosynthesis of secondary metabolites. We report herein recent progress in the analysis of two unusual branches of the shikimic acid pathway in streptomycetes the formation of the cyclohexanecarboxylic acid (CHC)-derived moiety of the antifungal agent ansatrienin and the dihydroxycyclohexanecarboxylic acid (DHCHC) starter unit for the biosynthesis of the immunosuppressant ascomycin. A gene for 1-cyclohexenylcarbonyl-CoA reductase, chcA, which plays a role in catalyzing three of the reductive steps leading from shikimic acid to CHC has been characterized from Streptomyces collinus. A cluster of six open reading frames (ORFs) has been identified by sequencing in both directions from chcA and the putative role of these in CHC biosynthesis is discussed. The individual steps involved in the biosynthesis of DHCHC from shikimic acid in Streptomyces hygroscopicus var ascomyceticus has been delineated and shown to be stereochemically and enzymatically distinct from the CHC pathway. A dehydroquinate dehydratase gene (dhq) likely Involved in providing shikimic acid for both DHCHC biosynthesis and primary metabolism has been cloned, sequenced and characterized.

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  • Polyketides Biosynthesis - an overview | ScienceDirect …

    Aspergillus terreus is an outstanding producer of many bioactive agents, and a large part of them are polyketides.

  • Learn more about Polyketides Biosynthesis

    Polyketide synthases ..

  • Biosynthesis Polyketides are ..

    Polyketide biosynthesis has been well studied and there are several ..

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Polyketide | Alkene | Biosynthesis

Nearly a quarter-century ago, the advent of molecular genetic tools in the field of natural product biosynthesis led to the remarkable revelation that the genes responsible for the biosynthesis, regulation, and self-resistance of complex polyketide antibiotics were clustered in the genomes of the bacteria that produced these compounds. This in turn facilitated rapid cloning and sequencing of genes encoding a number of polyketide synthases (PKSs). By now, it is abundantly clear that, notwithstanding extraordinary architectural and biocatalytic diversity, all PKSs are evolutionarily related enzyme assemblies. As such, understanding the molecular logic for the biosynthesis of literally thousands of amazing polyketide natural products made by nature can benefit enormously from detailed investigations into a few “model systems”. For nearly the past two decades, our laboratory has focused its efforts on two such PKSs. One of them synthesizes two polyketides in approximately equal ratios, SEK4 and SEK4b, and both shunt products from the pathway that leads to the biosynthesis of the pigmented antibiotic actinorhodin. The other synthesizes 6-deoxyerythronolide B, the first isolable intermediate in the biosynthetic pathway for the widely used antibacterial agent erythromycin. Our present-day knowledge of the structures and mechanisms of these two PKSs is summarized here.

Polyketide Biosynthesis Department of ..

Chaitan Khosla is a professor of Chemical Engineering, Chemistry, and (by courtesy) Biochemistry at Stanford University. He received his Ph.D. in 1990 at the California Institute of Technology and joined Stanford University in 1992 after completing his postdoctoral studies at the John Innes Centre, U.K. Since the beginning of his independent career, he and his students have investigated polyketide synthases in an effort to understand and exploit their modular architectures and mechanisms for practical biocatalysis. He is especially interested in the anti-infective properties of polyketide natural products.

been the cornerstone of the polyketide pathway ..

KEGG COMPOUND, as well as KEGG GLYCAN, is a resource for understanding such biosynthetic codes and for inferring chemical repertoires of these diverse substances from genomic information [1-3].

Biosynthesis of the salinosporamide A polyketide …

AB - Polyketide synthase (PKS) enzymes continue to hold great promise as synthetic biology platforms for the production of novel therapeutic agents, biofuels, and commodity chemicals. Dehydratase (DH) catalytic domains play an important role during polyketide biosynthesis through the dehydration of the nascent polyketide intermediate to provide olefins. Our understanding of the detailed mechanistic and structural underpinning of DH domains that control substrate specificity and selectivity remains limited, thus hindering our efforts to rationally re-engineer PKSs. The curacin pathway houses a rare plurality of possible double bond permutations containing conjugated olefins as well as both cis- and trans-olefins, providing an unrivaled model system for polyketide dehydration. All four DH domains implicated in curacin biosynthesis were characterized in vitro using synthetic substrates, and activity was measured by LC-MS/MS analysis. These studies resulted in complete kinetic characterization of the all-trans-trienoate-forming CurK-DH, whose kcat of 72 s-1 is more than 3 orders of magnitude greater than that of any previously reported PKS DH domain. A novel stereospecific mechanism for diene formation involving a vinylogous enolate intermediate is proposed for the CurJ and CurH DHs on the basis of incubation studies with truncated substrates. A synthetic substrate was co-crystallized with a catalytically inactive Phe substitution in the His-Asp catalytic dyad of CurJ-DH to elucidate substrate-enzyme interactions. The resulting complex suggested the structural basis for dienoate formation and provided the first glimpse into the enzyme-substrate interactions essential for the formation of olefins in polyketide natural products. This examination of both canonical and non-canonical dehydration mechanisms reveals hidden catalytic activity inherent in some DH domains that may be leveraged for future applications in synthetic biology.

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