Figure 1

Metabolic interrelationships of γ -aminobutyric acid (GABA) synthesis and metabolism in mammals, and metabolic abnormalities identified in murine and human aldehyde dehydrogenase 5A1 (ALDH5A1) deficiency (not all steps are shown). The site of the block in ALDH5A1 deficiency is indicated by the shaded box. The reader's attention is called to potential disturbances in the tricarboxylic acid (TCA) cycle induced by ALDH5A1 deficiency. Note that α-ketoglutarate (α-KG; also known as 2-ketoglutarate) is the nitrogen acceptor for conversion of GABA to succinic semialdehyde (SSA) (thus regenerating glutamate in the GABA shunt), and is the acceptor for hydrogen moieties in the reaction consuming γ-hydroxybutyrate (GHB), with production of D-2-hydroxyglutaric acid (D-2-HG) catalysed by D-2-hydroxyglutarate transhydrogenase (HOT). Especially in neural tissue, the TCA cycle may be depleted in α-KG, which may be further attenuated by loss of succinate from blocked GABA degradation, and the potential consumption of either pyruvate or acetyl coenzyme A in the formation of 4,5-dihydroxyhexanoic acid (DHHA) from SSA. Circled numbers represent the following enzymes: 1, glutaminase; 2, glutamic acid decarboxylase; 3, homocarnosinase (probably the same as carnosinase); 4, arginine:glycine amidinotransferase (putative); 5, GABA transaminase; 6, unproven reaction, but likely to involve pyruvate dehydrogenase; 7, succinate semialdehyde dehydrogenase (ALDH5A1); 8, aldo-keto reductase 7A2 (AKR7A2); 9, HOT. Note that HOT is a reversible, NAD⁺-independent transhydrogenase converting GHB and α-KG to SSA and D-2-HG.