Inborn disorders of the malate aspartate shuttle.

Over the last few years, various inborn disorders have been reported in the malate aspartate shuttle (MAS). The MAS consists of four metabolic enzymes and two transporters, one of them having two isoforms that are expressed in different tissues. Together they form a biochemical pathway that shuttles electrons from the cytosol into mitochondria, as the inner mitochondrial membrane is impermeable to the electron carrier NADH. By shuttling NADH across the mitochondrial membrane in the form of a reduced metabolite (malate), the MAS plays an important role in mitochondrial respiration. In addition, the MAS maintains the cytosolic NAD+ /NADH redox balance, by using redox reactions for the transfer of electrons. This explains why the MAS is also important in sustaining cytosolic redox-dependent metabolic pathways, such as glycolysis and serine biosynthesis. The current review provides insights into the clinical and biochemical characteristics of MAS deficiencies. To date, five out of seven potential MAS deficiencies have been reported. Most of them present with a clinical phenotype of infantile epileptic encephalopathy. Although not specific, biochemical characteristics include high lactate, high glycerol 3-phosphate, a disturbed redox balance, TCA abnormalities, high ammonia, and low serine, which may be helpful in reaching a diagnosis in patients with an infantile epileptic encephalopathy. Current implications for treatment include a ketogenic diet, as well as serine and vitamin B6 supplementation.

[Vitamin B6 dependency syndrome].

Many enzymes that require pyridoxal 5'-phosphate (PLP), a coenzyme from a vitamin B6, are involved in amino acid metabolism. B6 dependency syndromes are defined as a group of metabolic disorders which are prevented or alleviated by non-physiologically large doses of vitamin B6, and, hence, they are tacitly accounted for by some structural alteration in a responsible B6-dependent enzyme such as a decrease on the affinity for PLP as compared to the normal. In this article, the mode of binding the coenzyme is exemplified by the case of aspartate aminotransferase, a typical B6-dependent enzyme whose three-dimensional structure is known, and, several B6 dependency syndromes are briefly reviewed. Among these syndromes, the molecular basis of only gyrate atrophy has recently been defined by the identification of a mutation in the relevant enzyme, ornithine aminotransferase.