Inhibition of Glyceraldehyde-3-phosphate Dehydrogenase by Pentalenolactone. 2. Identification of the Site of Alkylation by Tetrahydropentalenolactone

Cane, David E.; Sohng, Jae Kyung

doi:10.1021/bi00187a020

Cited by 42 publications

(26 citation statements)

References 49 publications

(66 reference statements)

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“…It is an inactivator of GAPDH and active against a wide range of microorganisms, including Gram-positive and Gram-negative bacteria, pathogenic and saprophytic fungi and protozoa. It also inhibits replication of DNA viruses such as HSV-1 and HSV-2, the causal agents of herpes simplex (Cane and Sohng 1994) Acoranes Acoranes are a family of spiro-sesquiterpenic compounds obtained from different sources. Trichoacorenol (171) (Fig.…”

Section: Heptelidic Acid and Derivativesmentioning

confidence: 99%

Secondary metabolites from species of the biocontrol agent Trichoderma

et al. 2007

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Trichoderma species are free-living fungi that are highly interactive in root, soil and foliar environments and have been used successfully in field trials to control many crop pathogens. Structural and biological studies of the metabolites isolated from Trichoderma species are reviewed. This review, encompassing all the literature in this field up to the present and in which 269 references are cited, also includes a detailed study of the biological activity of the metabolites, especially the role of these metabolites in biological control mechanisms. Some aspects of the biosynthesis of these metabolites and related compounds are likewise discussed.

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Section: Heptelidic Acid and Derivativesmentioning

confidence: 99%

Secondary metabolites from species of the biocontrol agent Trichoderma

et al. 2007

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“…Pentalenolactone inhibits glycolysis (9) by selectively inhibiting glyceraldehyde-3-phosphate dehydrogenase (10). The antibiotic was shown to irreversibly inactivate glyceraldehyde-3-phosphate dehydrogenase by alkylation of the active site cysteine residue (11). An inducible, pentalenolactone-insensitive glyceraldehyde-3-phosphate dehydrogenase isozyme that is part of the biosynthetic gene cluster confers self-resistance against the antibiotic in S. avermitilis and other Streptomyces strains (1,(12)(13)(14).…”

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confidence: 99%

Crystal Structure of the Non-heme Iron Dioxygenase PtlH in Pentalenolactone Biosynthesis

You

Ōmura

Ikeda

et al. 2007

Journal of Biological Chemistry

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The non-heme iron dioxygenase PtlH from the soil organism Streptomyces avermitilis is a member of the iron(II)/␣-ketoglutarate-dependent dioxygenase superfamily and catalyzes an essential reaction in the biosynthesis of the sesquiterpenoid antibiotic pentalenolactone. To investigate the structural basis for substrate recognition and catalysis, we have determined the x-ray crystal structure of PtlH in several complexes with the cofactors iron, ␣-ketoglutarate, and the non-reactive enantiomer of the substrate, ent-1-deoxypentalenic acid, in four different crystal forms to up to 1.31 Å resolution. The overall structure of PtlH forms a double-stranded barrel helix fold, and the cofactor-binding site for iron and ␣-ketoglutarate is similar to other double-stranded barrel helix fold enzymes. Additional secondary structure elements that contribute to the substrate-binding site in PtlH are not conserved in other double-stranded barrel helix fold enzymes. Binding of the substrate enantiomer induces a reorganization of the monoclinic crystal lattice leading to a disorder-order transition of a C-terminal ␣-helix. The newly formed helix blocks the major access to the active site and effectively traps the bound substrate. Kinetic analysis of wild type and site-directed mutant proteins confirms a critical function of two arginine residues in substrate binding, while simulated docking of the enzymatic reaction product reveals the likely orientation of bound substrate.Streptomyces avermitilis is a Gram-positive soil-dwelling organism that is used industrially for the production of the widely used anthelminthic avermectins. Recently, an S. avermitilis gene cluster for the biosynthesis of the sesquiterpenoid antibiotic pentalenolactone ( Fig. 1A) has been characterized (1). Pentalenolactone was first identified from Streptomyces roseogriseus (2) and is also produced by several Streptomyces strains (3-5). The antibiotic is active against Gram-positive and Gram-negative bacteria as well as fungi and protozoa (6). In addition, it has been shown to inhibit viral replication of herpes simplex virus 1 and herpes simplex virus 2 (7) and cell proliferation of rat vascular smooth muscle cells (8). Pentalenolactone inhibits glycolysis (9) by selectively inhibiting glyceraldehyde-3-phosphate dehydrogenase (10). The antibiotic was shown to irreversibly inactivate glyceraldehyde-3-phosphate dehydrogenase by alkylation of the active site cysteine residue (11). An inducible, pentalenolactone-insensitive glyceraldehyde-3-phosphate dehydrogenase isozyme that is part of the biosynthetic gene cluster confers self-resistance against the antibiotic in S. avermitilis and other Streptomyces strains (1,(12)(13)(14).We recently reported the molecular cloning and biochemical characterization of PtlH, an essential non-heme iron-dependent dioxygenase in the pentalenolactone biosynthesis pathway (15). The enzyme catalyzes the Fe(II)-and ␣-ketoglutarate-dependent hydroxylation of 1-deoxypentalenic acid to 11␤-hydroxy-1-deoxypentalenic acid (Fig. 1B). Non-heme...

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“…Based on data available for S. avermitilis, we postulate the following pentalenolactone synthesis pathway in S. collinus Tü 365 ( Table 3): The first step in the biosynthesis of pentalenolactone is the cyclization of the precursor farnesyl diphosphate (FPP) to the sesquiterpene hydrocarbon pentalenene [9], catalyzed by a pentalenene synthase, in S. collinus Tü 365 encoded by B446_29695. The oxidative conversion of pentalenene to pentalenolactone requires the presence of four redox enzymes such as cytochrome P450 B446_29700, the non-heme iron, α-ketoglutarate-dependent hydroxylase analog, encoded by gene B446_29665, the 1-deoxy-11-beta-hydroxypentalenate dehydrogenase B446_29675, the flavin-dependent monooxygenase B446_29680 and the dioxygenase B446_29685.…”

Section: Pentalenolactonementioning

confidence: 99%

Identification and activation of novel biosynthetic gene clusters by genome mining in the kirromycin producer Streptomyces collinus Tü 365

Iftime

Kulik

Härtner

et al. 2016

Journal of Industrial Microbiology and Biotechnology

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Streptomycetes are prolific sources of novel biologically active secondary metabolites with pharmaceutical potential. S. collinus Tü 365 is a Streptomyces strain, isolated 1972 from Kouroussa (Guinea). It is best known as producer of the antibiotic kirromycin, an inhibitor of the protein biosynthesis interacting with elongation factor EF-Tu. Genome Mining revealed 32 gene clusters encoding the biosynthesis of diverse secondary metabolites in the genome of Streptomyces collinus Tü 365, indicating an enormous biosynthetic potential of this strain. The structural diversity of secondary metabolisms predicted for S. collinus Tü 365 includes PKS, NRPS, PKS-NRPS hybrids, a lanthipeptide, terpenes and siderophores. While some of these gene clusters were found to contain genes related to known secondary metabolites, which also could be detected in HPLC-MS analyses, most of the uncharacterized gene clusters are not expressed under standard laboratory conditions. With this study we aimed to characterize the genome information of S. collinus Tü 365 to make use of gene clusters, which previously have not been described for this strain. We were able to connect the gene clusters of a lanthipeptide, a carotenoid, five terpenoid compounds, an ectoine, a siderophore and a spore pigment-associated gene cluster to their respective biosynthesis products.

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Inhibition of Glyceraldehyde-3-phosphate Dehydrogenase by Pentalenolactone. 2. Identification of the Site of Alkylation by Tetrahydropentalenolactone

Cited by 42 publications

References 49 publications

Secondary metabolites from species of the biocontrol agent Trichoderma

Secondary metabolites from species of the biocontrol agent Trichoderma

Crystal Structure of the Non-heme Iron Dioxygenase PtlH in Pentalenolactone Biosynthesis

Identification and activation of novel biosynthetic gene clusters by genome mining in the kirromycin producer Streptomyces collinus Tü 365

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