Acetyl Coenzyme A Carboxylase System of Escherichia coli

Polakis, S. Efthimios; Guchhait, Ras B.; Zwergel, Eberhard E.; Lane, M. Daniel; Cooper, Terrance G.

doi:10.1016/s0021-9258(19)42205-9

Cited by 99 publications

(25 citation statements)

References 22 publications

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“…This residue is located in strand ␤7BЈ of the C domain, whose main Our attempts at demonstrating this pattern of inhibition were not successful, due to the high K m (around 10 mM) chain is in direct contact with the CP-640186 inhibitor (Figure 2A). Our binding studies confirm this prediction of the biotin substrate (Polakis et al, 1974).…”

Section: Isolated Ct Domain (See Below) the Structural Informa-supporting

confidence: 86%

Crystal Structure of the Carboxyltransferase Domain of Acetyl-Coenzyme A Carboxylase in Complex with CP-640186

Zhang

Tweel

et al. 2004

Structure

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Acetyl-coenzyme A carboxylases (ACCs) are important targets for the development of therapeutic agents against obesity, diabetes, and other diseases. CP-640186 is a potent inhibitor of mammalian ACCs and can reduce body weight and improve insulin sensitivity in test animals. It is believed to target the carboxyltransferase (CT) domain of these enzymes. Here we report the crystal structure of the yeast CT domain in complex with CP-640186. The inhibitor is bound in the active site at the interface of a dimer of the CT domain. CP-640186 has tight interactions with the putative biotin binding site in the CT domain and demonstrates a distinct mode of inhibiting the CT activity as compared to the herbicides that inhibit plant ACCs. The affinity of inhibitors for the CT domain has been assessed using kinetic and fluorescence anisotropy binding studies. The structural information identifies three regions for drug binding in the active site of CT.

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Section: Isolated Ct Domain (See Below) the Structural Informa-supporting

confidence: 86%

Crystal Structure of the Carboxyltransferase Domain of Acetyl-Coenzyme A Carboxylase in Complex with CP-640186

Zhang

Tweel

et al. 2004

Structure

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“…The first partial reaction involves the formation of the enzymecarboxybiotin complex, most probably via the formation of a very labile carboxyphosphate intermediate [66]. Evidence in support of this comes from studies demonstrating that the biotin carboxylase subunit from E. coli ACC can phosphorylate ADP from carbamoyl phosphate, which is an analogue of carboxyphosphate, to form ATP [68]. The observation that PCs from sheep kidney and chicken liver are also capable of catalysing the phosphorylation of ADP from carbamoyl phosphate provides further support for such an intermediate [69,70].…”

Section: Reaction Mechanismmentioning

confidence: 99%

Structure, function and regulation of pyruvate carboxylase

JITRAPAKDEE¹,

Wallace²

1999

Biochem. J.

114

103

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Pyruvate carboxylase (PC; EC 6.4.1.1), a member of the biotin-dependent enzyme family, catalyses the ATP-dependent carboxylation of pyruvate to oxaloacetate. PC has been found in a wide variety of prokaryotes and eukaryotes. In mammals, PC plays a crucial role in gluconeogenesis and lipogenesis, in the biosynthesis of neurotransmitter substances, and in glucose-induced insulin secretion by pancreatic islets. The reaction catalysed by PC and the physical properties of the enzyme have been studied extensively. Although no high-resolution three-dimensional structure has yet been determined by X-ray crystallography, structural studies of PC have been conducted by electron microscopy, by limited proteolysis, and by cloning and sequencing of genes and cDNA encoding the enzyme. Most well characterized forms of active PC consist of four identical subunits arranged in a tetrahedron-like structure. Each subunit contains three functional domains: the biotin carboxylation domain, the transcarboxylation domain and the biotin carboxyl carrier domain. Different physiological conditions, including diabetes, hyperthyroidism, genetic obesity and postnatal development, increase the level of PC expression through transcriptional and translational mechanisms, whereas insulin inhibits PC expression. Glucocorticoids, glucagon and catecholamines cause an increase in PC activity or in the rate of pyruvate carboxylation in the short term. Molecular defects of PC in humans have recently been associated with four point mutations within the structural region of the PC gene, namely Val145-->Ala, Arg451-->Cys, Ala610-->Thr and Met743-->Thr.

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“…This sequence has been supported by kinetic studies , by partial exchange reactions (Northrop and Wood, 1969), and by the isolation and subsequent reutilization of the carboxybiotinyl-enzyme intermediate (Wood et al, 1963). As with other biotin carboxylases [e.g., bacterial acetyl-CoA carboxylase (Polakis et al, 1974)], it is reasoned that acyl-CoA substrates bind to regions of the active site distinct from regions where keto acid substrates bind (quite probably on distinct subunits) with the biotinyl carrier protein serving as a swinging arm mechanism .…”

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confidence: 99%

Stereochemistry of propionyl-coenzyme A and pyruvate carboxylations catalyzed by transcarboxylase

Cheung¹,

Fung²,

Walsh³

1975

Biochemistry

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The stereochemistry of the two half-reactions catalyzed by the biotin-containing enzyme, transcarboxy-lase from Propionobacteria shermanii, has been determined. The pro-R hydrogen at C-2 of propionyl-coenzyme A is replaced by CO2 in formation of the S isomer of methylmalonyl-CoA, defining the process as retention of configuration. This C-2 hydrogen is abstracted at a rate identical with product formation. For the other half-reaction, pyruvate to oxalacetate, the chiral methyl group methodology of Rose (I. A. Rose (1970), J. Biol. Chem. 245, 6052) was employed. First, it was determined with [3-2-He]pyruvate that a kinetic deuterium isotope effect of 2.1 occurs at Vmax in this carboxyl transfer, indicating that the necessary requirement for discrimination against heavy isotopes of hydrogen existed. Then, 3(S)-[3-2-H,3-H]pyruvate, generated from 3(S)-]E-2-H,3-H]phosphoglycerate, was carboxylated and the oxalacetate trapped as [3030H]malate using malate dehydrogenase. Exhaustive incubation of the tritiated malate (3-H/14-C = 1.95) with fumarase to labilize the pro-R hydrogen at C-3 resulted in release of 65% of the tritium into water. Reisolation of the malate after fumarase action yielded a 30H/14-C ration of 0.67, indicating 34% retention as expected. The theoretical enantiotopic distribution for the observed k1H/k2H of 2.1 is 68:32. Selective enrichment of tritium in the pro-R position at C-3 of malate indicates enzymatic carboxylation of pyruvate with retention of configuration in this half-reaction also.

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Acetyl Coenzyme A Carboxylase System of Escherichia coli

Cited by 99 publications

References 22 publications

Crystal Structure of the Carboxyltransferase Domain of Acetyl-Coenzyme A Carboxylase in Complex with CP-640186

Crystal Structure of the Carboxyltransferase Domain of Acetyl-Coenzyme A Carboxylase in Complex with CP-640186

Structure, function and regulation of pyruvate carboxylase

Stereochemistry of propionyl-coenzyme A and pyruvate carboxylations catalyzed by transcarboxylase

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