Acyl-CoA oxidases

Peroxisomal /3-Oxidation Requires FAD-Dependent Acyl-CoA Oxidase... 

In Candida sp., degradation of the CoA-alkanoic esters to the alkenoic acid esters is catalyzed by an acyl-CoA oxidase and results in the production of H2O2 that is converted into O2 by catalase activity. The enzyme from C. tropicalis contains FAD (Jiang and Thorpe 1983), and in C. lipolytica carries out a stereospecific antielimination of hydrogen (Kawagnchi et al. 1980). 

Jiang Z-Y, C Thorpe (1983) Acyl-CoA oxidase from Candida tropicalis. Biochemistry 22 3752-3758. 

Kawaguchi A, S Tsubotani, Y Seyama, T Yamakawa, T Osumi, T Hashimoto, Y Kikuchi, M Ando, S Okuda (1980) Stereochemistry of dehydrogenation catalyzed by acyl-CoA oxidase. J Biochem 88 1481-1486. 

The conversion of long-chain alkanoate CoA esters into the alkenoate CoA esters by acyl-CoA oxidase involves an anti elimination reaction. The stereochemistry of the reaction in Candida lipolytica was established using stearoyl-CoA-labeled with H at the 2 R)-, 3(R)-, and 3(5)-positions (Kawaguchi et al. 1980). 

The chain shortening pathway has not been characterized in detail at the enzymatic level in insects. It presumably is similar to the characterized pathway as it occurs in vertebrates. These enzymes are a partial P-oxidation pathway located in peroxisomes [29]. The key enzymes involved are an acyl-CoA oxidase (a multifunctional protein containing enoyl-CoA hydratase and 3-hy-droxyacyl-CoA dehydrogenase activities) and a 3-oxoacyl-CoA thiolase [30]. These enzymes act in concert to chain shorten acyl-CoAs by removing an acetyl group. A considerable amount of evidence in a number of moths has accumulated to indicate that limited chain shortening occurs in a variety of pheromone biosynthetic pathways. 

Acyl-CoA oxidase deficiency D-bifunctional protein deficiency Racemase deficiency Refsum s disease... 

Alkyl PAT, alkyl-dihydroxy phosphate synthase Bif, bifunctional enzyme DHAPAT, dihydroxyphosphate acyltransferase deficiency DHCA, dihydroxycholestanoic acid N, normal nd, not determined Ox, acyl-CoA oxidase Rac, 2-methylacyl-CoA racemase RCDP, rhizomelic chondrodysplasia punctata Ref, Refsum s disease THCA, trihydroxycholestanoic acid VLCFA, very-long-chain fatty acid. 

The initial oxidation reaction is unusual since it uses molecular oxygen. It is catalysed by the enzyme acyl-CoA oxidase. 

Ruyter B., O. Andersen, A. Dehli, A.-K. Ostlrmd Farrants, T. Gjoen, and M.S. Thomassen (1997). Peroxisome proliferator activated receptors in Atlantic salmon Salmo solar)-. Effects on PPAR transcription and acyl-CoA oxidase activity in hepatocytes by peroxisome proliferators and fatty acids. BBA-Lipids and Lipid Metabolism 1348 331-338. 

Finally, the yeast Yarrowia lipolytica is able to transform ricinoleic acid (12-hydroxy oleic acid) into y-decalactone, a desirable fruity and creamy aroma compound however, the biotransformation pathway involves fi-oxidation and requires the lactonisation at the CIO level. The first step of fi-oxidation in Y. lipolytica is catalysed by five acyl-CoA oxidases (Aox), some of which are long-chain-specific, whereas the short-chain-specific enzymes are also involved in the degradation of the lactone. Genetic constructions have been made to remove these lactone-degrading activities from the yeast strain [49, 50]. A strain displaying only Aox2p activity produced 10 times more lactone than the wild type in 48 h but still showed the same growth behaviour as the wild type. 

Woodyatt, N.J., Lambe, K.G, Myers, K.A., Tugwood, J.D. Roberts, R.A. (1999) The peroxisome proliferator (PP) response element upstream of the human acyl CoA oxidase gene is inactive among a sample human population significance for species differences in response to PPs. Carcinogenesis, 20, 369-372... 

Group 2 contains the single peroxisomal enzyme deficiencies [14]. This group is also subdivided in different classes, including the peroxisomal beta-oxidation deficiencies (X-linked adrenoleucodystrophy, X-ALD), acyl-CoA oxidase 1 deficiency... 

Unfortunately, a minority of the patients with peroxisomal dysfunction cannot be diagnosed using plasma parameters. In the authors laboratory, patients have been seen with peroxisome biogenesis defects, D-bifunctional protein deficiency, and acyl-CoA oxidase deficiency in whom no abnormalities of plasma VLCFA, phytanic acid, pristanic acid or bile acids could be established. Hence, a strong clinical suspicion of peroxisomal disease should always be verified by fibroblast investigation, regardless of the outcome of plasma analyses. 

Fatty acids Acyl-CoA synthetase + Acyl-CoA oxidase... 

However, peroxisomal-proliferating chemicals do not appear to cause the phenomenon in all species, and humans are believed to be a nonresponsive species. Thus, guinea pigs are refractory, and with humans given ciprofibrate, only limited peroxisomal proliferation was seen, and there was no increase in acyl CoA oxidase. 

Acyl CoA oxidase, which is induced up to at least 15 X normal levels, catalyzes a specific step characteristic of jl-oxidation in the peroxisome-producing hydrogen peroxide as a byproduct (Fig. 7.10). Other oxidases may also lead to increased hydrogen peroxide. Normally, this is removed and detoxified by the enzyme catalase, which breaks hydrogen peroxide down to water and oxygen. However, catalase is only increased about twofold after treatment with peroxisomal proliferators. 

Figure 7.10 Part of the peroxisomal 3-oxidation pathway showing the production of hydrogen peroxide by acyl CoA oxidase. Hydrogen peroxide can be detoxified by catalase to water and oxygen. However, in the absence of sufficient enzyme, it can be broken down to the highly reactive hydroxyl radical in the presence of metal ions such...

Refractory species such as guinea pig seem to have fewer PPARa receptors in the liver, and observations suggest there are significant differences between rodents and humans in a number of aspects of the response. Recent studies in cynomologous monkeys treated with ciprofibrate have detected peroxisomal proliferation but only found slight changes in certain parameters [e.g., messenger RNA (mRNA) induction for acyl CoA oxidase] of minimal oxidative stress, and despite hypertrophy, cell proliferation was not detected. 

One difference between the peroxisomal and mitochondrial pathways is in the chemistry of the first step. In peroxisomes, the flavoprotein acyl-CoA oxidase that introduces the double bond passes electrons directly to 02, producing H202 (Fig. 17-13). This strong and potentially damaging oxidant is immediately cleaved to H20 and 02 by catalase. Recall that in mitochondria, the electrons removed in the first oxidation step pass through the respiratory chain to 02 to produce H20, and this process is accompanied by ATP synthesis. In peroxisomes, the energy released in the first oxidative step of fatty acid breakdown is not conserved as ATP, but is dissipated as heat. 

Tugwood,J. D., Issemann, I., Anderson, R. G., Bundell, K. R., McPheat, W. L., and Green, S. (1992). The mouse peroxisome proliferator activated receptor recognizes a response element in the 5 flanking sequence of the rat acyl CoA oxidase gene. EMBOJ. 11, 433-439. 

Fan C-Y, Pan J, Usuda N, et al. 1998. Steatohepatitis, spontaneous peroxisome proliferation and liver tumors inmice lacking peroxisomal fatty acyl-CoA oxidase. J Biol Chem273(25) 15639-15645. 

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