Structure of the biotin carboxylase subunit of pyruvate carboxylase from<i>Aquifex aeolicus</i>at 2.2 Å resolution

Kondo, Satoshi; Nakajima, Yoshitaka; Sugio, Shigetoshi; Yong-Biao, Jin; Sueda, Shinji; Kondo, Hiroki

doi:10.1107/s0907444904000423

Cited by 32 publications

(49 citation statements)

References 15 publications

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“…The crystal structure of the BC subunit of Aquifex aeolicus PC is highly homologous to that of the E. coli enzyme [119]. The only structures of a eukaryotic BC domain are for the yeast ACC, both the free enzyme and the complex with the potent natural product inhibitor soraphen A [107].…”

Section: Bcmentioning

confidence: 99%

Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery

Tong

2005

CMLS, Cell. Mol. Life Sci.

426

340

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Acetyl-coenzyme A carboxylases (ACCs) have crucial roles in fatty acid metabolism in most living organisms. Mice deficient in ACC2 have continuous fatty acid oxidation and reduced body fat and body weight, validating this enzyme as a target for drug development against obesity, diabetes and other symptoms of the metabolic syndrome. ACC is a biotin-dependent enzyme and catalyzes the carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is a multi-subunit enzyme in most prokaryotes, whereas it is a large, multi-domain enzyme in most eukaryotes. The activity of the enzyme can be controlled at the transcriptional level as well as by small molecule modulators and covalent modification. This review will summarize the structural information that is now available for both the BC and CT enzymes, as well as the molecular mechanism of action of potent ACC inhibitors. The current intense research on these enzymes could lead to the development of novel therapies against metabolic syndrome and other diseases.

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Section: Bcmentioning

confidence: 99%

Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery

Tong

2005

CMLS, Cell. Mol. Life Sci.

426

340

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“…Methanobacterium sp, Methanococcus sp and Methanosarcina sp [94, 95, 96] and certain bacteria i.e. Aquifex aeolicus [97], Pseudomonas spp [98, 99]. Interestingly, the majority of α 4 -type PCs are subject to allosteric regulation.…”

Section: Structurementioning

confidence: 99%

Structure, mechanism and regulation of pyruvate carboxylase

Jitrapakdee

Maurice

Rayment

et al. 2008

Biochemical Journal

369

337

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Synopsis Pyruvate carboxylase (PC) is a biotin-containing enzyme that catalyses the HCO3−- and MgATP-dependent carboxylation of pyruvate to form oxaloacetate. This is a very important anaplerotic reaction, replenishing oxaloacetate withdrawn from the Krebs cycle for various pivotal biochemical pathways. PC is therefore considered as an enzyme that is crucial for intermediary metabolism, controlling fuel partitioning toward gluconeogenesis, lipogenesis and insulin secretion. The enzyme was discovered in 1959 and over the last decade there has been much progress in understanding its structure and function. PC from most organisms is a tetrameric protein that is allosterically regulated by acetyl CoA and aspartate. High resolution crystal structures of the holoenzyme with various ligands bound have recently been determined, and have revealed details and the relative positions of the biotin carboxylase, carboxyltransferase and biotin carboxyl carrier domains, and also a unique allosteric effector domain. In the presence of the allosteric effector, acetyl CoA, the biotin moiety transfers the carboxyl group intermediate between the biotin carboxylase domain active site on one polypeptide chain and the carboxyltransferase active site on the adjacent antiparallel polypeptide chain. In addition, the bona fide role of PC in the non-gluconeogenic tissues has been studied using a combination of classical biochemistry and genetic approaches. The first cloning of the promoter of the PC gene in mammals and subsequent transcriptional studies reveal some key cognate transcription factors regulating tissue-specific expression. This review summarizes these advances and also offers some prospects in terms of future directions for the study of this important enzyme.

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“…However, there are some PCs that have an α 4 β 4 quaternary structure where the α subunits (~ 55 kDa) contain the BC domain, whilst the β subunits (~ 70 kDa) contain the CT and BCCP domains. The α 4 β 4 PCs are generally found in archaea, such as Methanococcus jannaschii [5], and in some bacteria, such as Aquifex aeolicus [6] and Pseudomonas aeruginosa [7]. While the α 4 PCs are activated, to varying degrees, by acetyl CoA, those with α and β subunits are unaffected by acetyl CoA [5, 6].…”

Section: Effects Of Acetyl Coa On the Structure Of Pcmentioning

confidence: 99%

Regulation of the structure and activity of pyruvate carboxylase by acetyl CoA

Adina-Zada

Zeczycki

Attwood³

2012

Archives of Biochemistry and Biophysics

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In this review we examine the effects of the allosteric activator, acetyl CoA on both the structure and catalytic activities of pyruvate carboxylase. We describe how the binding of acetyl CoA produces gross changes to the quaternary and tertiary structures of the enzyme that are visible in the electron microscope. These changes serve to stabilize the tetrameric structure of the enzyme. The main locus of activation of the enzyme by acetyl CoA is the biotin carboxylation domain of the enzyme where ATP-cleavage and carboxylation of the biotin prosthetic group occur. As well as enhancing reaction rates, acetyl CoA also enhances the binding of some substrates, especially HCO3−, and there is also a complex interaction with the binding of the cofactor Mg2+. The activation of pyruvate carboxylase by acetyl CoA is generally a cooperative processes, although there is a large degree of variability in the degree of cooperativity exhibited by the enzyme from different organisms. The X-ray crystallographic holoenzyme structures of pyruvate carboxylases from Rhizobium etli and Staphylococcus aureus have shown the allosteric acetyl CoA binding domain to be located at the interfaces of the biotin carboxylation and carboxyl transfer and the carboxyl transfer and biotin carboxyl carrier protein domains.

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Structure of the biotin carboxylase subunit of pyruvate carboxylase fromAquifex aeolicusat 2.2 Å resolution

Cited by 32 publications

References 15 publications

Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery

Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery

Structure, mechanism and regulation of pyruvate carboxylase

Regulation of the structure and activity of pyruvate carboxylase by acetyl CoA

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