L-3-Hydroxyacyl-CoA dehydrogenases

Step 3 of Figure 29.3 Alcohol Oxidation The /3-hydroxyacyl CoA from step 2 is oxidized to a /3-ketoacyl CoA in a reaction catalyzed by one of a family of L-3-hydroxyacyl-CoA dehydrogenases, which differ in substrate specificity according to the chain length of the acyl group. As in the oxidation of sn-glycerol 3-phosphate to dihydroxyacetone phosphate mentioned at the end of Section 29.2, this alcohol oxidation requires NAD+ as a coenzyme and yields reduced NADH/H+ as by-product. Deprotonation of the hydroxyl group is carried out by a histidine residue at the active site. 

The hydration of enoyl CoA is a prelude to the second oxidation reaction, which converts the hydroxyl group at C-3 into a keto group and generates NADH. This oxidation is catalyzed by l-3-hydroxyacyl CoA dehydrogenase, which is specific for the 1 isomer of the hydroxyacyl substrate. 

An interesting recent finding in transgenic mice overexpressing L-3-hydroxyacyl-CoA dehydrogenase II supports this model of MPTP toxicity. Overexpression of this enzyme, which is a mitochondrial oxire-ductase system involved in neuronal survival, protects the animals from the consequences of MPTP intoxication [17]. 

Yan SD, Przedborski S. L-3-hydroxyacyl-CoA dehydrogenase 11 protects in a model of Parkinsoris disease. Ann Neurol 2004, 56, 51-60. 

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. 

The third reaction in the P-oxidation cycle is the reversible dehydrogenation of L-3-hydroxyacyl-CoA to 3-ketoacyl-CoA catalyzed by L-3-hydroxyacyl-CoA dehydrogenase as shown in the following equation. 

L-3-Hydroxyacyl CoA dehydrogenase, Short-Chain 4-16 Activity decreases with increasing chain length... 

Figure 4. Alignment of the amino acid sequence between His and Glu of the coli multifunctional protein (MP) with those of homologous regions of pig mitochondrial long-chain-specific bifunctional enzyme (LT), plant glyoxysomal tetrafunctional protein (PT), rat peroxisomal trifunctional enzyme (TE), and pig liver L-3-hydroxyacyl-CoA dehydrogenase (LD). The conserved histidine and glutamate residues are indicated by asterisks. The large subunit of human mitochondrial trifunctional P-oxidation complex has the same amino acid sequence as that of LT in this region. Qlu of MP corresponds to Glu of the large subunits of these mammalian p-oxidation complexes and to Glu of their precursors.

The majority of the CoA-moiety of L-3-hydroxyacyl-CoA is in contact with the bulk medium while the fatty acid tail is inserted into the cleft and buried by the enzyme. This orientation of the substrate is consistent with the fact that the length of the acyl chain has a significant effect on the turnover number of pig heart L-3-hydroxyacyl-CoA dehydrogenase. Since detailed structural information about the liganded active site is not available, it is not known why the dehydrogenase displays the top catalytic efficiency with substrates of medium acyl chain length. A more intensive study of the substrate chain length specificity, a characteristic which contributes enormously to the complexity of fatty acid P-oxidation systems, shall be made in the future. 

Hartmann, D., Philipp, R., Schmadel, K., Birktoft, J.J., Banaszak, L.J. Trommer, W.E. (1991) Biochenistry 30, 2782-2790. Spatial arrangement of coenzyme and substrates bound to L-3-hydroxyacyl-CoA dehydrogenase as studied by spin-labeled analogues of NAD and CoA. 

Torroja, L., Ortuno-Sahagun, D., Ferrus, A., Hammerle, B. Barbas, J.A. (1998)7. Cell Biol 141, 1009-1017. scully, an essential gene of Drosophila, is homologous to mammalian mitochondrial type II L-3-hydroxyacyl-CoA dehydrogenase/amyloid -P-peptide-binding protein. 

Harris, D. Das, A. (1991) Biochem. J. 280, 561-573. Control of mitochondrial ATP synthesis in heart. He, X., Yang, S. Schulz, H. (19 9) Anal. Biochem. 180, 105-109. Assay of L-3-hydroxyacyl-CoA dehydrogenase with substrates of different chain lengths. 

Schifferdecker, J. Schulz, H. (1974) Life Sci. 14, 1487-1492. The inhibition of L-3-hydroxyacyl-CoA dehydrogenase by acetoacetyl-CoA and the possible effect of this inhibitor on fatty acid oxidation. Waterson, R. Hill, R. (1972) J. Biol. Chem. 247, 5258-5265. Enoyl coenzyme A hydratase (crotonase). Catalytic properties of crotonase and its possible regulatory role in fatty acid oxidation. 

Medium-/short-chain L-3-hydroxyacyl-CoA dehydrogenase defidency (M/SCHAD)"... 

The dehydrogenation of L- and D-3-hydroxyacyl-CoAs is catalyzed by L- and D-3-hydroxyacyl-CoA dehydrogenases, respectively. These enzymes display strict substrate stereochemical specificity, but they both produce 3-ketoacyl-CoAs. The L-3-hydroxyacyl-CoA dehydrogenase binds its coenzyme NAD and its substrate to a cleft between its... 

N- and C-terminal domains. " The crystal structure of pig heart L-3-hydroxyacyl-CoA dehydrogenase was published a decade ago, but the catalytic mechanism of this type of dehydrogenase was not known until we identified a conserved histidine as the catalytic residue. L-3-Hydroxyacyl-CoA dehydrogenases are associated with the C-terminal region of multifunctional proteins except for those in the mitochondrial matrix (see Table 1). In contrast, D-3-hydroxyacyl-CoA dehydrogenases are associated with the N-terminal region of peroxisomal multifunctional proteins. ... 

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