Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.4.1.2 (acetyl-CoA carboxylase)
 2,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibition of acetyl-CoA carboxylase (ACC), with its resultant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation, has the potential to favorably affect, in a concerted manner, a multitude of the cardiometabolic risk factors associated with diabetes, obesity, and the metabolic syndrome. Studies in ACC2 knockout mice and in experimental animals treated with isozyme-specific antisense oligonucleotides or with isozyme-nonselective ACC inhibitors have demonstrated the potential for treating metabolic syndrome through this modality. Co-crystallization of the biotin carboxylase and carboxyltransferase domains of eukaryotic ACC in the presence of substrates and inhibitors has revealed characteristics of the catalytic center that can be exploited in drug discovery. A variety of structurally diverse, mechanistically distinct classes of ACC inhibitors have been disclosed in the scientific and patent literature. Isozyme-nonselective ACC inhibitors may provide the optimal therapeutic potential. However, demonstration of the full potential of isozyme-selective inhibitors, once identified, should reveal advantages and liabilities associated with single isozyme inhibition.
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PMID:Inhibitors of mammalian acetyl-CoA carboxylase. 1822 Nov 16

Acetyl-CoA carboxylase (ACC) catalyzes the first step in fatty acid biosynthesis: the synthesis of malonyl-CoA from acetyl-CoA. As essential regulators of fatty acid biosynthesis and metabolism, ACCs are regarded as therapeutic targets for the treatment of metabolic diseases such as obesity. In ACC, the biotinoyl domain performs a critical function by transferring an activated carboxyl group from the biotin carboxylase domain to the carboxyl transferase domain, followed by carboxyl transfer to malonyl-CoA. Despite the intensive research on this enzyme, only the bacterial and yeast ACC structures are currently available. To explore the mechanism of ACC holoenzyme function, we determined the structure of the biotinoyl domain of human ACC2 and analyzed its characteristics and interaction with the biotin ligase, BirA using NMR spectroscopy. The 3D structure of the hACC2 biotinoyl domain has a similar folding topology to the earlier determined domains from E. coli and P. shermanii. However, the local structures near the biotinylation sites have notable differences that include the geometry of the consensus "Met-Lys-Met" (MKM) motif and the absence of "thumb" structure in the hACC2 biotinoyl domain. Observations of the NMR signals upon the biotinylation indicate that the biotin group of hACC2 does not affect the structure of the biotinoyl domain, while the biotin group for E. coli ACC interacts directly with the thumb residues that are not present in the hACC2 structure. These results imply that, in the E. coli ACC reaction, the biotin moiety carrying the carboxyl group from BC to CT can pause at the thumb of the BCCP domain. The human biotinoyl domain, however, lacks the thumb structure and does not have additional noncovalent interactions with the biotin moiety; thus, the flexible motion of the biotinylated lysine residue must underlie the "swinging arm" motion. The chemical shift perturbation and the cross saturation experiments of the human ACC2 holo-biotinoyl upon the addition of the biotin ligase (BirA) showed the interaction surface near the MKM motif, the two glutamic acids (Glu 926, Glu 953), and the positively charged residues (several lysine and arginine residues). This study provides insight into the mechanism of ACC holoenzyme function and supports the swinging arm model in human ACCs.
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PMID:Biotinoyl domain of human acetyl-CoA carboxylase: Structural insights into the carboxyl transfer mechanism. 1824 44

Biotin carboxylase catalyzes the ATP-dependent carboxylation of biotin and is one component of the multienzyme complex acetyl-CoA carboxylase that catalyzes the first committed step in fatty acid synthesis in all organisms. Biotin carboxylase from Escherichia coli, whose crystal structures with and without ATP bound have been determined, has served as a model system for this component of the acetyl-CoA carboxylase complex. The two crystal structures revealed a large conformational change of one domain relative to the other domains when ATP is bound. Unfortunately, the crystal structure with ATP bound was obtained with an inactive site-directed mutant of the enzyme. As a consequence the structure with ATP bound lacked key structural information such as for the Mg2+ ions and contained altered conformations of key active-site residues. Therefore, nanosecond molecular dynamics studies of the wild-type biotin carboxylase were undertaken to supplant and amend the results of the crystal structures. Specifically, the protein-metal interactions of the two catalytically critical Mg2+ ions bound in the active site are presented along with a reevaluation of the conformations of active-site residues bound to ATP. In addition, the regions of the polypeptide chain that serve as hinges for the large conformational change were identified. The results of the hinge analysis complemented a covariance analysis that identified the individual structural elements of biotin carboxylase that change their conformation in response to ATP binding.
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PMID:Molecular dynamics simulations of biotin carboxylase. 1827 71

Biotin carboxylase from Escherichia coli catalyzes the ATP-dependent carboxylation of biotin and is one component of the multienzyme complex acetyl-CoA carboxylase, which catalyzes the committed step in long-chain fatty acid synthesis. Comparison of the crystal structures of biotin carboxylase in the absence and presence of ATP showed a central B-domain closure when ATP was bound. Peptidic NH groups from two active site glycine residues (Gly165 and Gly166) that form hydrogen bonds to the phosphate oxygens of ATP were postulated to act as a "trigger" for movement of the B-domain. The function of these two glycine residues in the catalytic mechanism was studied by disruption of the hydrogen bonds using site-directed mutagenesis. Both single (G165V) and (G166V) and double mutants (G165V-G166V) were constructed. The mutations did not affect the maximal velocity of a partial reaction, the bicarbonate-dependent ATPase activity. This suggests that the peptidic NH groups of Gly165 and Gly166 are not triggers for domain movement. However, the K(m) values for ATP for each of the mutants was increased over 40-fold when compared with wild-type indicating the peptidic NH groups of Gly165 and Gly166 play a role in binding ATP. Consistent with ATP binding, the maximal velocity for the biotin-dependent ATPase activity (i.e. the complete reaction) was decreased over 100-fold suggesting the mutations have misaligned the reactants for optimal catalysis. Molecular dynamics studies confirm perturbation of the hydrogen bonds from the mutated residues to ATP, whereas the double mutant exhibits antagonistic effects such that hydrogen bonding from residues 165 and 166 to ATP is similar to that in the wild-type. Consistent with the site-directed mutagenesis results the molecular dynamics studies show that ATP is misaligned in the mutants.
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PMID:The utility of molecular dynamics simulations for understanding site-directed mutagenesis of glycine residues in biotin carboxylase. 1870 41

Bacterial acetyl-CoA carboxylase is a multifunctional biotin-dependent enzyme that consists of three separate proteins: biotin carboxylase (BC), biotin carboxyl carrier protein (BCCP), and carboxyltransferase (CT). Acetyl-CoA carboxylase is a potentially attractive target for novel antibiotics because it catalyzes the first committed step in fatty acid biosynthesis. In the first half-reaction, BC catalyzes the ATP-dependent carboxylation of BCCP. In the second half-reaction, the carboxyl group is transferred from carboxybiotinylated BCCP to acetyl-CoA to produce malonyl-CoA. A series of structures of BC from several bacteria crystallized in the presence of various ATP analogs is described that addresses three major questions concerning the catalytic mechanism. The structure of BC bound to AMPPNP and the two catalytically essential magnesium ions resolves inconsistencies between the kinetics of active-site BC mutants and previously reported BC structures. Another structure of AMPPNP bound to BC shows the polyphosphate chain folded back on itself, and not in the correct (i.e., extended) conformation for catalysis. This provides the first structural evidence for the hypothesis of substrate-induced synergism, which posits that ATP binds nonproductively to BC in the absence of biotin. The BC homodimer has been proposed to exhibit half-sites reactivity where the active sites alternate or "flip-flop" their catalytic cycles. A crystal structure of BC showed the ATP analog AMPPCF(2)P bound to one subunit while the other subunit was unliganded. The liganded subunit was in the closed or catalytic conformation while the unliganded subunit was in the open conformation. This provides the first structural evidence for half-sites reactivity in BC.
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PMID:Structural evidence for substrate-induced synergism and half-sites reactivity in biotin carboxylase. 1872 55

Acetyl-CoA carboxylase (ACC) catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA, a key metabolite in the fatty acid synthetic and oxidation pathways. The present study describes the steady-state kinetic analysis of a purified recombinant human form of the enzyme, namely ACC2, using a novel LC/MS/MS assay to directly measure malonyl-CoA formation. Four dimensional matrices, in which bicarbonate (HCO(3)(-)), ATP, acetyl-CoA, and citrate were varied, and global data fitting to appropriate steady-state equations were used to generate kinetic constants. Product inhibition studies support the notion that the enzyme proceeds through a hybrid (two-site) random Ter Ter mechanism, one that likely involves a two-step reaction at the biotin carboxylase domain. Citrate, a known activator of animal forms of ACC, activates both by increasing k(cat) and k(cat)/K(M) for ATP and acetyl-CoA.
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PMID:Characterization of recombinant human acetyl-CoA carboxylase-2 steady-state kinetics. 1923 60

Malonyl-CoA is an essential precursor for fatty acid biosynthesis that is generated from the carboxylation of acetyl-CoA. In this work, a gene coding for acetyl-CoA carboxylase (ACC) was isolated from an oleaginous fungus, Mucor rouxii. According to the amino acid sequence homology and the conserved structural organization of the biotin carboxylase, biotin carboxyl carrier protein, and carboxyl transferase domains, the cloned gene was characterized as a multi-domain ACC1 protein. Interestingly, a 40% increase in the total fatty acid content of the non-oleaginous yeast Hansenula polymorpha was achieved by overexpressing the M. rouxii ACC1. This result demonstrated a significant improvement in the production of fatty acids through genetic modification in this yeast strain.
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PMID:Overexpression of acetyl-CoA carboxylase gene of Mucor rouxii enhanced fatty acid content in Hansenula polymorpha. 1926 51

BODIPY-labeled Soraphen A derivative 4 was synthesized and characterized as an acetyl-CoA carboxylase (ACC) binder. Biophysical measurements indicate that the molecule binds in the biotin carboxylase domain where Soraphen A has been shown to bind. The fluorescent label of the BODIPY can be used to biophysically identify a compound that binds to the Soraphen A site of the biotin carboxylase domain versus the carboxytransferase domain of ACC.
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PMID:Synthesis and characterization of a BODIPY-labeled derivative of Soraphen A that binds to acetyl-CoA carboxylase. 1935 68

Acetyl-CoA carboxylases (ACCs) have been highlighted as therapeutic targets for obesity and diabetes, as they play crucial roles in fatty acid metabolism. ACC activity is regulated through the short-term mechanism of inactivation by reversible phosphorylation. Here, we report the crystal structures of the biotin carboxylase (BC) domain of human ACC2 phosphorylated by AMP-activated protein kinase (AMPK). The phosphorylated Ser222 binds to the putative dimer interface of BC, disrupting polymerization and providing the molecular mechanism of inactivation by AMPK. We also determined the structure of the human BC domain in complex with soraphen A, a macrocyclic polyketide natural product. This structure shows that the compound binds to the binding site of phosphorylated Ser222, implying that its inhibition mechanism is the same as that of phosphorylation by AMPK.
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PMID:Molecular mechanism for the regulation of human ACC2 through phosphorylation by AMPK. 1990 Apr 10

Acetyl-CoA Carboxylase catalyzes the first committed step in fatty acid synthesis. Escherichia coli acetyl-CoA carboxylase is composed of biotin carboxylase, carboxyltransferase and biotin carboxyl carrier protein functions. The accA and accD genes that code for the alpha- and beta-subunits, respectively, are not in an operon, yet yield an alpha(2)beta(2) carboxyltransferase. Here, we report that carboxyltransferase regulates its own translation by binding the mRNA encoding its subunits. This interaction is mediated by a zinc finger on the beta-subunit; mutation of the four cysteines to alanine diminished nucleic acid binding and catalytic activity. Carboxyltransferase binds the coding regions of both subunit mRNAs and inhibits translation, an inhibition that is relieved by the substrate acetyl-CoA. mRNA binding reciprocally inhibits catalytic activity. Preferential binding of carboxyltransferase to RNA in situ was shown using fluorescence resonance energy transfer. We propose an unusual regulatory mechanism by which carboxyltransferase acts as a 'dimmer switch' to regulate protein production and catalytic activity, while sensing the metabolic state of the cell through acetyl-CoA concentration.
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PMID:A tale of two functions: enzymatic activity and translational repression by carboxyltransferase. 1996 70


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