**5.2 Fatty acid** β**-oxidation**

As in the case of glycolysis, the end product of fatty acid β-oxidation is acetyl-CoA (Fig. 1) which feeds into the TCA cycle to produce energy in the form of NADH and FADH2. The enzymes involved in fatty acid β-oxidation all act on acyl-CoA, i.e. fatty acids linked to CoA as thioesters. They belong to an oxido-reductase superfamily with broad substrate specificity. The enzymes are subdivided into several groups, according to the substrate chain length. Each of the constituent steps of the pathway comprises three consecutive enzymatic reactions catalyzed by a trifunctional enzymatic complex: 2-enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase and 3-ketoacyl-CoA thiolase. The reactions yield acetyl-CoA plus a chain-shortened acyl-CoA (at each step, the fatty acid chain loses two carbons) (Eaton et al., 2000).

In the present review, we focus attention on the penultimate step of the process, i.e. acyl-CoA dehydrogenation. It involves four classes of enzymes: short-chain acyl-CoA dehydrogenase (SCAD, active with C4 and C6), medium-chain acyl-CoA dehydrogenase (MCAD, active with C4 to C12), long-chain acyl-CoA dehydrogenase (LCAD, active with C8 to C20) and very-long-chain acyl-CoA dehydrogenase (VLCAD, active with C12 to C24). SCAD, MCAD and LCAD are homotetramers located in the mitochondrial matrix. VLCAD, however, is a homodimer and is located in the inner mitochondrial membrane. VLCAD is a constituent of the trifunctional protein described above.

Short chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) also known as L-3-hydroxyacyl-CoA dehydrogenase/amyloid-peptide binding alcohol dehydrogenase (HADH II/ABAD) is predominantly a mitochondrial enzyme (Furuta et al., 1997; Kobayashi et al., 1996) that belongs to the short-chain dehydrogenase/reductase superfamily (Jornvall et al., 1995). It acts on a wide spectrum of substrates, including steroids, cholic acids, and fatty acids, with a preference for short chain methyl-branched acyl-CoAs. Abnormally low or high levels of SCHAD in certain brain regions may contribute to the pathogenesis of some neural disorders. The human SCHAD gene and its protein product are therefore potential targets for intervention in conditions such as PD, AD and an X-linked mental retardation, which may arise from the impaired degradation of branched fatty acid chains and of isoleucine (Yang et al., 2005; Zschocke et al., 2000).

The levels of SCHAD/HADH II are significantly reduced in the ventral midbrain of both PD patients and of a PD mouse model generated by MPTP injection (Przedborski et al., 2004). Conversely, transgenic mice with increased expression of human HADH II/ABAD are significantly more resistant to MPTP; overexpression of the enzyme mitigates MPTPinduced impairment of oxidative phosphorylation and ATP production (Tieu et al., 2004). This observation suggests that a new way to prevent PD may be to increase expression of SCHAD/HADH II in the midbrain.
