| Mitochondrial beta-oxidation of fatty acids is an essential energy source in oxidative tissues, including the heart, and is required for intermediary metabolism and ketone body production by the liver. Each cycle through the beta-oxidation spiral consists of four biochemical reactions that remove two carbons from the fatty acyl chain, producing acetyl-CoA and a shortened fatty acyl-CoA. The third reaction, the NAD+-dependent oxidation of 3-hydroxyacyl-CoA to 3-ketoacyl-CoA, is catalyzed by two enzymes, long chain (LCHAD) and medium and short chain (M/SCHAD) 3-hydroxyacyl-CoA dehydrogenase.; Mutations in the M/SCHAD gene have been identified in six patients. One patient is a compound heterozygote for two mutations in the NAD+-binding domain; the others are heterozygous for one mutation in M/SCHAD. The accumulation of medium chain fatty acid metabolites in these patients demonstrates that M/SCHAD is required for the metabolism of both medium and short chain fatty acids; this has prompted revision of the name of the enzyme from SCHAD to M/SCHAD. The identification of heterozygotes with elevated medium chain metabolites suggests that in situations of metabolic stress, haploinsufficiency may occur in heterozygotes.; The M/SCHAD mutations identified in patients have been characterized biochemically. In addition, other critical residues have been mutated to investigate the role of conserved residues. Histidine-158 has been shown experimentally to be the active site residue. Glutamate-170 has been mutated to glutamine; this mutation corresponds to the common LCHAD mutation, E474Q. The M/SCHAD E170Q mutation reduces the apparent vmax of M/SCHAD but does not alter substrate or cofactor binding.; Finally, a mouse model for M/SCHAD deficiency has been created by targeted ablation of the gene. The M/SCHAD knockout mice are viable and healthy, but they are sensitive to metabolic stress. The mice die within 10 hours of fasting and cold exposure, with lipid accumulation in both liver and kidney. This response to metabolic stress is similar to the situation observed in patients with disorders of beta-oxidation, who may be healthy under normal situations, but become ill after metabolic stress such as fasting or illness. The response of the mice to metabolic stress suggests that this model will be useful for studying M/SCHAD deficiency. |
