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Acyl-Carrier Protein

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John E Cronan – One of the best experts on this subject based on the ideXlab platform.

  • the bioc o methyltransferase catalyzes methyl esterification of malonyl acyl carrier Protein an essential step in biotin synthesis
    Journal of Biological Chemistry, 2012
    Co-Authors: Steven Lin, John E Cronan

    Abstract:

    Abstract Recent work implicated the Escherichia coli BioC Protein as the initiator of the synthetic pathway that forms the pimeloyl moiety of biotin (Lin, S., Hanson, R. E., and Cronan, J. E. (2010) Nat. Chem. Biol. 6, 682–688). BioC was believed to be an O-methyltransferase that methylated the free carboxyl of either malonyl-CoA or malonyl-acyl carrier Protein based on the ability of O-methylated (but not unmethylated) precursors to bypass the BioC requirement for biotin synthesis both in vivo and in vitro. However, only indirect proof of the hypothesized enzymatic activity was obtained because the activities of the available BioC preparations were too low for direct enzymatic assay. Because E. coli BioC Protein was extremely recalcitrant to purification in an active form, BioC homologues of other bacteria were tested. We report that the native form of Bacillus cereus ATCC10987 BioC functionally replaced E. coli BioC in vivo, and the Protein could be expressed in soluble form and purified to homogeneity. In disagreement with prior scenarios that favored malonyl-CoA as the methyl acceptor, malonyl-acyl carrier Protein was a far better acceptor of methyl groups from S-adenosyl-l-methionine than was malonyl-CoA. BioC was specific for the malonyl moiety and was inhibited by S-adenosyl-l-homocysteine and sinefungin. High level expression of B. cereus BioC in E. coli blocked cell growth and fatty acid synthesis.

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  • Diversity in enoyl-acyl carrier Protein reductases
    Cellular and Molecular Life Sciences, 2009
    Co-Authors: R. P. Massengo-tiassé, John E Cronan

    Abstract:

    The enoyl-acyl carrier Protein reductase (ENR) is the last enzyme in the fatty acid elongation cycle. Unlike most enzymes in this essential pathway, ENR displays an unusual diversity among organisms. The growing interest in ENRs is mainly due to the fact that a variety of both synthetic and natural antibacterial compounds are shown to specifically target their activity. The primary anti-tuberculosis drug, isoniazid, and the broadly used antibacterial compound, triclosan, both target this enzyme. In this review, we discuss the diversity of ENRs, and their inhibitors in the light of current research progress.

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  • Acyl Carrier Protein Phosphodiesterase (AcpH) of Escherichia coli Is a Non-Canonical Member of the HD Phosphatase/Phosphodiesterase Family†
    Biochemistry, 2007
    Co-Authors: Jacob Thomas, Daniel J. Rigden, John E Cronan

    Abstract:

    The Escherichia coli AcpH acyl carrier Protein phosphodiesterase (also called ACP hydrolyase) is the only enzyme known to cleave a phosphodiester-linked post-translational Protein modification. AcpH hydrolyzes the link between 4‘-phosphopanthetheine and the serine-36 side chain of acyl carrier Protein (ACP). Although the existence of this enzyme activity has long been known, study of the enzyme was hampered by its recalcitrant properties and scarcity. We recently isolated the gene encoding AcpH and have produced the recombinant enzyme in quantity (Thomas, J., and Cronan, J. E., (2005) J. Biol. Chem. 280, 34675−34683), thus allowing the first studies of its reaction mechanism. AcpH requires Mn2+ for activity, and thus, we focused on the metal binding ligands in order to locate the active site. Bioinformatic investigations indicated that AcpH and its homologues were weakly related to a phosphodiesterase of known structure, the hydrolyase domain of the bifunctional bacterial Protein, SpoT, suggesting that Ac…

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Michael D. Burkart – One of the best experts on this subject based on the ideXlab platform.

  • Molecular basis for interactions between an acyl carrier Protein and a ketosynthase.
    Nature Chemical Biology, 2019
    Co-Authors: Jacob C. Milligan, Michael D. Burkart, D. John Lee, David R. Jackson, Andrew J. Schaub, Joris Beld, Jesus F. Barajas, Joseph J. Hale, Ray Luo, Shiou-chuan Tsai

    Abstract:

    Fatty acid synthases are dynamic ensembles of enzymes that can biosynthesize long hydrocarbon chains efficiently. Here we visualize the interaction between the Escherichia coli acyl carrier Protein (AcpP) and β-ketoacyl-ACP-synthase I (FabB) using X-ray crystallography, NMR, and molecular dynamics simulations. We leveraged this structural information to alter lipid profiles in vivo and provide a molecular basis for how ProteinProtein interactions can regulate the fatty acid profile in E. coli. A combination of crosslinking, X-ray crystallography, NMR, and mutagenesis provide a detailed visualization of the interactions between an acyl carrier Protein and β-ketoacyl-ACP-synthase I in the Escherchia coli fatty acid synthase complex.

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  • Resin supported acyl carrier Protein labeling strategies
    RSC Adv., 2014
    Co-Authors: Michael Rothmann, Nicolas M. Kosa, Michael D. Burkart

    Abstract:

    The post-translational modifying enzymes phophopantetheinyl transferase and acyl carrier Protein hydrolase show utility in the functional modification of acyl carrier Proteins. Here we develop these tools as immobilized biocatalysts on agarose supports. New utility is imparted through these methods, enabling rapid and label-independent Protein purification. Immobilization of acyl carrier Protein is also demonstrated for rapid activity assays of these 4′-phosophopantetheine modifying enzymes, displaying a particular advantage in the case of phosphopantetheine removal, where few orthogonal techniques have been demonstrated. These tools further enrich the suite of functional utility of 4′-phosophopantetheine chemistry, with applications to Protein functionalization, materials, and natural product biosynthetic studies.

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  • Binding and pKa Modulation of a Polycyclic Substrate Analogue in a Type II Polyketide Acyl Carrier Protein
    ACS Chemical Biology, 2011
    Co-Authors: Robert W. Haushalter, Fabian V. Filipp, Stanley J. Opella, Michael D. Burkart

    Abstract:

    Type II polyketide synthases are biosynthetic enzymatic pathways responsible for the production of complex aromatic natural products with important biological activities. In these systems, biosynthetic intermediates are covalently bound to a small acyl carrier Protein that associates with the synthase enzymes and delivers the bound intermediate to each active site. In the closely related fatty acid synthases of bacteria and plants, the acyl carrier Protein acts to sequester and protect attached intermediates within its helices. Here we investigate the type II polyketide synthase acyl carrier Protein from the actinorhodin biosynthetic pathway and demonstrate its ability to internalize the tricyclic, polar molecule emodic acid. Elucidating the interaction of acyl carrier Proteins with bound analogues resembling late-stage intermediates in the actinorhodin pathway could prove valuable in efforts to engineer these systems toward rational design and biosynthesis of novel compounds.

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Matthew P. Crump – One of the best experts on this subject based on the ideXlab platform.

  • preliminary kinetic analysis of acyl carrier Protein ketoacylsynthase interactions in the actinorhodin minimal polyketide synthase
    Molecular BioSystems, 2009
    Co-Authors: Pedro Beltranalvarez, Christopher J. Arthur, Matthew P. Crump, John Crosby, Russell J Cox, Thomas J. Simpson

    Abstract:

    Interactions between the acyl carrier Protein (ACP) and ketoacylsynthase (KS) components of the actinorhodinpolyketide synthase have been investigated using kinetic assays. These indicate that for three different quantifiable interactions (acceleration of self-malonylation, initiation and extension) mutations of E47 and E53 residues located on ACP helix II have different effects. Initiation clearly involves interaction between KSβ and ACP helix II, but self-malonylation acceleration and extension by KSα appear not to be affected strongly by the same mutations.

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  • Self-malonylation is an intrinsic property of a chemically synthesized type II polyketide synthase acyl carrier Protein.
    Biochemistry, 2005
    Co-Authors: Christopher J. Arthur, Anna E. Szafranska, Simon Evans, Stuart C. Findlow, Steven G. Burston, Philip Owen, Ian Clark-lewis, Thomas J. Simpson, John Crosby, Matthew P. Crump

    Abstract:

    During polyketide biosynthesis, malonyl groups are transferred to the acyl carrier Protein (ACP) component of the polyketide synthase (PKS), and it has been shown that a number of type II polyketide ACPs undergo rapid self-acylation from malonyl-CoA in the absence of a malonyl-CoA:holo-acyl carrier Protein transacylase (MCAT). More recently, however, the observation of self-malonylation has been ascribed to contamination with Escherichia coli MCAT (FabD) rather than an intrinsic property of the ACP. The wild-type apo-ACP from the actinorhodin (act) PKS of Streptomyces coelicolor (synthetic apo-ACP) has therefore been synthesized using solid-state peptide methods and refolded using the GroEL/ES chaperone system from E. coli. Correct folding of the act ACP has been confirmed by circular dichroism (CD) and 1H NMR. Synthetic apo-ACP was phosphopantetheinylated to 100% by S. coelicolor holo-acyl carrier Protein synthase (ACPS), and the resultant holo-ACP underwent self-malonylation in the presence of malonyl-C…

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  • conserved secondary structure in the actinorhodin polyketide synthase acyl carrier Protein from streptomyces coelicolor a3 2 and the fatty acid synthase acyl carrier Protein from escherichia coli
    FEBS Letters, 1996
    Co-Authors: Matthew P. Crump, John Crosby, Christopher E Dempsey, Martin Murray, David A Hopwood, Thomas J. Simpson

    Abstract:

    Abstract The acyl carrier Protein (ACP) of Streptomyces coelicolor A3(2) functions as a molecular chaperone during the biosynthesis of the polyketide actinorhodin ( act ). Here we compare structural features of the polyketide synthase (PKS) ACP, determined by two-dimensional 1 H-NMR, with the Escherichia coli fatty acid synthase (FAS) ACP. The PKS ACP contains four helices (residues 7–16 [A], 42–53 [B], 62–67 [C], 72–86 [D]), and a large loop (residues 17–41) having no defined secondary structure with the exception of a turn between residues 21 and 24. The act ACP shows 47% sequence similarity with the E. coli FAS ACP and the results demonstrate that the sequence homology is extended to the secondary structure of the Proteins.

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