Acetyl-CoA carboxylase structure

Sasaki, Y., Nagano, Y. 2004. Plant acetyl-CoA carboxylase structure, biosynthesis, regulation, and gene manipulation for plant breeding. Biosci. Biotechnol. Biochem. 68 1175-1184. 

RW Brownsey, R Zhande, AN Boone. Isoforms of acetyl-CoA carboxylase structures, regulatory properties and metabohc functions. Biochem Soc Trans 25 1231-1238, 1997. 

Figure 3.4 Structure of two prosthetic groups (a) biotin (b) lipoate. Biotin functions as a carboxyl group carrier, e.g. in acetyl-CoA carboxylase. Lipoate is presented in its oxidised form (-S-S-). It is a cofactor for pyruvate dehydrogenase and oxoglu-tarate dehydrogenase.

Structure of A -carboxybiotin linked to biotin carboxyl carrier protein (BCCP). BCCP is one of the components of acetyl-CoA carboxylase isolated from E. coli. 

Takai, T., Yokoyama, C., Wada, K., and Tanabe, T. (1988). Primary structure of chicken liver acetyl-CoA carboxylase deduced from cDNA sequence./. Biol. Chem., 263, 2651-2657. 

Is a specific Inhibitor of type II fatty acid synthetase In higher plants and . coll 12401. The acetyl-CoA ACP S-acety1-transferase Is the apparent specific site of Inhibition 12411. Another antibiotic, cerulenin (structure not shown) Inhbits -ketococy1-ACP synthetase I In bacteria, fungi, and plants, but also Is Inhibitory to other sites such as polyketide and sterol biosynthesis 1242-2441. Cerulenin and thiolactomycin Inhibited CQ14W-acetate Incorporation Into fatty acids at 150 values of 50 and 4 uM, respectively 12451. Recently cydohexanedlone herbicides have been shown to Inhibit lipid biosynthesis by Inhibition of acetyl-CoA carboxylase 12461. 

Figure 16.26. Biotin-Binding Domain of Pyruvate Carboxylase. This likely structure is based on the structure of the homologous domain from the enzyme acetyl CoA carboxylase (Section 22.4.1). The biotin is on a flexible tether, allowing it to move between the ATP-bicarbonate site and the pyruvate site.

Biotin is a water-soluble vitamin. It is a cofactor for four ATP-dependent carboxylases acetyl-CoA carboxylase, pyruvate carboxylase, propionyl-CoA carboxylase, and p-methylcrotonyl-CoA carboxylase. Biotin occurs covalently bound to the enzymes via the terminal amino group of a lysine residue. With the normal and continual turnover of these enzymes in the body, the biotin is released, but then utilized again as a cofactor when the enzymes are re-synthesized. The structure of biotin is shown in Figure 9.32,... 

Enzymes. The structures of both acetyl-CoA carboxylase and fatty acid synthase in plants more closely resemble their counterparts in Escherichia coli than those in animal cells. For example, in E. coli and plants, each of the enzyme activities of fatty acid synthase is found on a separate protein. 

Fatty acid synthesis in plants differs from that in animals in the following ways location (plant fatty acid synthesis occurs mainly in the chloroplasts, whereas in animals fatty acid biosynthesis occurs in the cytoplasm), metabolic control (in animals the rate-limiting step is catalyzed by acetyl-CoA carboxylase, whereas in plants, this does not appear to be the case), enzyme structure (the structures of plant acetyl-CoA carboxylase and fatty acid synthetase are more closely related to similar enzymes in E. coli than to those in animals). 

Fig. 2. Acetyl-CoA carboxylase. (A) Eukaryotic ACCs contain -2300 residues organized into three functional domains — biotin carboxylase (BC), biotin carboxyl carrier protein (BCCP), and carboxyltransferase (CT). The role of the region between the biotin carboxyl carrier and carboxyltransferase domains is unknown. The biotin carboxyl carrier protein contains a typical conserved biotin attachment-site motif, VMKMV. The sites of phosphorylation are indicated by asterisks. (B) Electron micrograph of polymerized rat acetyl-CoA carboxylase (F. Ahmad, 1978). (C) Crystal structure of the biotin carboxylase domain of the yeast enzyme. In the presence of soraphen A, the biotin carboxyl carrier protein domain forms an inactive monomer the likely position of the modeled ATP-binding site is shown (adapted from Ref. [2]). (D) Crystal structure of the dimeric carboxyltransferase domain of the yeast enzyme. Although acetyl-CoA was included in the crystallization, density was observed only for CoA at one site and adenine at the other (adapted from Ref. [2]). (E) NMR structure of the biotin carboxyl carrier apoprotein domain of the human ACC2 The lysine attachment site for biotin is shown (RIKEN Structural Genomics/Proteomics Initiative, 2006). (See color plate section, plate no. 3.)...

Barber, M.C., Price, N.T., Travers, M.T. 2005. Structure and regulation of acetyl-CoA carboxylase genes of metazoa. Biochim. Biophys. Acta 1733 1-28. 

Figure 10 Chemical structures of acetyl-CoA carboxylase bisubstrate analog inhibitors.

Fig. 4.4). Acetyl-CoA carboxylase exists as an inactive dimer x 500 kDa) and a polymeric active form ( 20 X 500 kDa). The allosteric effector palmitoyl-CoA competes with citrate and causes depolymerisation of acetyl-CoA carboxylase and inhibits its activity. Phosphorylation of acetyl-CoA carboxylase also causes its inactivation. The primary structure of domestic fowl liver acetyl-CoA carboxylase has been deduced from its cDNA sequence (Takai et ai, 1988). 

Independent of this discovery, in 1982 scientists from the same company were working on a project aimed at preparing novel Acetyl-CoA carboxylase inhibitors, based upon the typical cyclohexanedione structure known for this class. The first targeted compound (2), prepared as shown in Fig. 4.3.1, showed some herbicidal activity and they thus attempted preparation of a phenyl analogue in a similar manner. This led not to the expected product (3), but to the triketone (4). This compound was devoid of herbicidal activity, but (luckily ) in safener screens the compound showed antidotal effects in Soya for thiocarbamate herbicides. A further round of synthesis optimization was undertaken and it was found that the compound (5) with an ortho-chloro substituent showed reasonable herbicidal activity. Furthermore, they noticed that it exhibited the same unique bleaching symptomology observed for leptospermone (1, Fig. 4.3.1) [4]. Further optimiza-... 

The cause of acetyl-CoA carboxylase inactivation in partially purified enzyme preparations in the presence of ATP and Mg " " should he clarified at the outset. Because it has been reported that the carbox-ylated species of acetyl-CoA carboxylase is unstable and tends to de-polymerize in the absence of citrate (see Ref. 64), inactivation of acetyl-CoA carboxylase by ATP and Mg " has frequently been interpreted in terms of the formation of a carboxylated form of acetyl-CoA carboxylase 25,39, 64). According to this hypothesis, phosphorylation phenomena can be explained on the supposition that carboxylation of the enzyme results in changes in the structure of the carboxylase which make normally unavailable sites available for phosphorylation that is, phosphorylation is not the cause of enzyme inactivation, but a secondary result of carboxylation. 

It is interesting that fatty acid synthesis and the levels of acetyl-CoA carboxylase and fatty acid synthetase in transplantable hepatic tumors are not responsive to alterations in nutritional state [131-135]. However, carboxylase and synthetase levels in the livers of host animals are markedly depressed by fasting and are restored by refeeding a fat-free diet. A comparison of the purified carboxylases from hepatic tumors and host livers reveals no differences in structural [135], kinetic [135], or immunological [93] properties. One possible explanation which has been offered [135] is that the tumor may exhibit altered repressor control of enzyme level. 

The effects of citrate and isocitrate on the sedimentation behavior of the enzyme have been verified by direct electron microscopic examination. Electron microscopy of the avian liver acetyl-CoA carboxylase in the assay reaction mixture without tricarboxylic acid activator, in which the enzyme exists as the inactive 13 to 15 S species, reveals small protomeric forms having minimum and maximum dimensions of 70 A and 130 A, respectively (Fig. 7 4, reference [176]). Addition of either citrate or isocitrate, which activates the enzyme and leads to the rapidly sedimenting 47 to 50 S species, causes instantaneous polymerization (within 10 seconds) of the protomeric form giving rise to filamentous structures 70 to 100 A in width and up to 0.5// in length (Fig. IB, reference [176]). 

Using 4-courmaroyl-CoA (in most species) and three molecules of malonyl-CoA, chalcone synthase (CHS) carries out a series of sequential decarboxylation and condensation reactions, to produce a polyketide intermediate that then undergoes cyclization and aromatization reactions that form the A-ring and the resultant chalcone structure. The chalcone formed from 4-courmaroyl-CoA is naringenin chalcone. In a few species, caffeoyl-CoA and feruloyl-CoA may also be used as substrates for chalcone formation. Malonyl-CoA is formed from acetyl-CoA by acetyl-CoA carboxylase (ACC). Acetyl-CoA may be produced in mitochondria, plastids, peroxisomes, and the cytosol by a variety of routes. It is the cytosolic acetyl-CoA that is used for flavonoid biosynthesis, and it is produced by the multiple subunit enzyme ATP-citrate lyase that converts citrate, ATP, and CoA to acetyl-CoA, oxaloacetate, ADP, and inorganic phosphate [15]. 

Alban, C., Baldet, P. and Douce, R. (1994) Localization and characterization of two structurally different forms of acetyl-CoA carboxylase in young pea leaves, of which one is sensitive to aryloxyphenoxypropionate herbicides, Biochem. J. 300, 557-565. 

Ke, J., (Choi, J-K., Smith, M., Horner, H.T., Nikolau, B.J., and Wurtele, E.S. (1996) Structure and in situ characterization of the expression of CACh the Arabidopsis thaliana gene coding for the biotin-containing subunit of the plastidic acetyl-CoA carboxylase, submitted for publication. 

Comparison of Acetyl-CoA-Carboxylase (ACC) Inhibitors with Acetolactate Synthase (ALS) Inhibitors The response patterns from four chemically-unrelated herbicides are compared in Figure 4 The structural formulas of the compounds are given in Figure 6 These treatments have been carried out with different amounts of the active ingredients Therefore, one should not look at the bars too quantitatively the increase or decrease of metabolites is what is important ... 

Roesler KR, Shorrosh BS, Ohlrogge JB. Structure and expression of an Arabidopsis acetyl-CoA carboxylase gene. Plant Physiol 1994 105 611-617. 

Walid A-F, Subrahmanyan SC, Wakil SJ. Cloning of the yeast FAS3 gene and primary structure of yeast acetyl-CoA carboxylase. Proc Natl Acad Sci USA 1992 89 4534-4538. 

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