Liver acyl dehydrogenases

FIGURE 24.13 The subunit structure of medium chain acyl-CoA dehydrogenase from pig liver mitochondria. Note the location of the bound FAD (red). (Adapted from Kim, J-T., and Wiz, J., 1988. Structure of the medium-chain acyl-CoA clchyclro-genase from pig liver mitochonciria at 3-A resolution. Proceedings of the National Academy of Sciences, USA 85 6671-668. )... 

Fatty liver, encephalopathy, and sudden unexpected death in early childhood due to medium-chain acyl-coenzyme A dehydrogenase deficiency. 

Diagnosis of medium-chain acyl-CoA dehydrogenase deficiency in lymphocytes and liver by a gas chromatographic method the effect of oral riboflavin supplementation. 

Each of the forms of ETF isolated from the different sources contain FAD as coenzyme and form an anionic semiquinone on one-electron reduction. Stopped-flow kinetic studies on the pig liver ETF showed the anionic flavin semiquinone to be formed at times faster than catalytic turnover and thus demonstrate the participation of the anionic FAD semiquinone as an intermediate in the acceptance of reducing equivalents from the dehydrogenase. These studies would also imply the intermediacy of the semiquinone form of the acyl CoA dehydrogenase which would have been expected to form a neutral flavin semiquinone at the time the studies of Hall and Lambeth were performed, however, no spectral evidence for its formation were found. Recent studies have shown that the binding of CoA analogs to the dehydrogenase results in the perturbation of the pKa of the FAD semiquinone such that an anionic (red) rather than the neutral (blue) semiquinone is formed. This perturbation was estimated to reduce the pKa by at least 2.5 units to a value of... 

For every step of the P oxidation sequence there is a small family of enzymes with differing chain length preferences.6 7 For example, in liver mitochondria one acyl-CoA dehydrogenase acts most rapidly on M-butyryl and other short-chain acyl-CoA a second prefers a substrate of medium chain length such as n-octanoyl-CoA a third prefers long-chain substrates such as pal-mitoyl-CoA and a fourth, substrates with 2-methyl branches. A fifth enzyme acts specifically on isovaleryl-CoA. Similar preferences exist for the other enzymes of the P oxidation pathway. In Escherichia coli... 

Veitch K, Draye JP, Van Hoof F, and Sherratt HS (1988) Effects of riboflavin deficiency and clofibrate treatment on the five acyl-CoA dehydrogenases in rat liver mitochondria. 

VLCAD deficiency 201475 Very long-chain acyl-CoA dehydrogenase >1 75,000 Spectrurn from early onset cardiomyopathy, coma, liver disease to adult onset myopathy ... 

MCAD deficiency 201450 Medium-chain acyl-CoA dehydrogenase >1 25,000 Liver disease HELLP syndrome... 

Fig. 1. The structures of key retinoids and their precursors. Fish convert retinyl esters (e.g. retinyl palmitate (RP)) and carotenoids (e.g. /3-carotene) to retinol in the gut lumen prior to intestinal absorption. Retinyl esters (e.g. RP) stored in the liver are synthesized from retinol by lecithin retinol acyltransferase (LRAT) and acyl CoAiretinol acyltransferase (ARAT). The retinyl esters are mobilized through their conversion to retinol by retinyl ester hydrolase (REH), which is then transported in the circulation to various sites in the body. Retinol is further metabolized within specific tissues to retinal by alcohol dehydrogenases (ADH) or short-chain dehydrogenase/reductase. Retinal is converted to the two major biologically active forms of retinoic acid (RA) (all-trans and 9-cis RA). Retinaldehyde dehydrogenase 2 (Raldh2) synthesizes all-trans RA from all-trans precursors and 9-cis RA form 9-cis precursors.

As noted above, there have been reports that link some cases of APLP with a defect in fatty acid metabolism in the fetus. These include fetal deficiencies of long chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD), carnitine-palmitoyl transferase 1 (CPT 1), and medium chain acyl-coenzyme A dehydrogenase (MCAD). The mechanism by which defective fetal fatty acid oxidation causes maternal illness is not known. However, since the fetus uses primarily glucose metabolism for its energy needs, it is likely that toxic products from the placenta, which does use fatty acid oxidation, cause the maternal liver failure. 

The control of fatty-acid oxidation is related to the availability of circulating fatty acids and the activity of palmitoyl carnitine transferase 1. When circulating fatty acids are elevated, considerable fatty-acyl CoA is formed in a number of tissues, including the liver, which is sufficient to inhibit both acetyl CoA carboxylase in the cytosol and, indirectly, pyruvate dehydrogenase in the mitochondrion. Under this condition, neither malonyl CoA nor citrate would accumulate thus, there would be a diminution of fatty-acid synthesis. When large amounts of fatty... 

Qi, C., Zhu, Y., Pan, J., Usuda, N., Maeda, N., Yeldandi, A. V., Rao, M. S., Hashimoto, T., and Reddy, J. K. Absence of spontaneous peroxisome proliferation in enoyl-CoA Hydratase/L-3-hydroxyacyl-CoA dehydrogenase-deficient mouse liver. Further support for the role of fatty acyl CoA oxidase in PPARalpha ligand metabolism. J Biol Chem 274 (1999) 15775-15780. 

Ikeda, Y., Tanaka, K. 1990. Purification and characterization of five acyl-CoA dehydrogenases from rat liver mitochondria. In Fatty Acid Oxidation. Clinical, Biochemical and Molecular Aspects. K. Tanaka,... 

Izai, K., Uchida, Y, Orii, T., Yamamoto, S., Hashimoto, T. 1992. Novel fatty acid -oxidation enzymes in rat liver mitochondria. I. Purification and properties of very-long-chain acyl coenzyme A dehydrogenase. J. Biol. Chem. 267 1027-1033. 

Mitochondrial elongation occurs by successive addition and reduction of acetyl units in a reversal of fatty acid oxidation. Although fatty acid P-oxidation and mitochondrial chain elongation have the same organelle location, reversal of a tra/ii-2-enoyl-CoA reductase P-oxidation is not feasible the FAD-dependent acyl-CoA dehydrogenase of P-oxidation is substituted by a more thermodynamically favorable enzyme reaction, catalyzed by NADPH-dependent enoyl-CoA reductase, to produce overall negative free-energy for the sequence. Enoyl-CoA reductase firom liver mitochondria is distinct from... 

Although hypoglycin causes hypoglycemia, it acts by inhibiting an acyl CoA dehydrogenase involved in (3-oxidation that has specificity for short- and medium-chain fatty acids. Because more glucose must be oxidized to compensate for the decreased ability of fatty acids to serve as fuel, blood glucose levels may fall to extremely low levels. Fatty acid levels, however, rise because of decreased (3-oxidation. As a result of the increased fatty acid levels, a-oxidation increases, and dicarboxylic acids are excreted in the urine. The diminished capacity to oxidize fatty acids in liver mitochondria results in decreased levels of acetyl CoA, the substrate for ketone body synthesis. 

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