Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency

Abstract

Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5A1 [ALDH5A1]; locus 6p22) occupies a central position in central nervous system (CNS) neurotransmitter metabolism as one of two enzymes necessary for gamma-aminobutyric acid (GABA) recycling from the synaptic cleft. Its importance is highlighted by the neurometabolic disease associated with its inherited deficiency in humans, as well as the severe epileptic phenotype observed in Aldh5a1(-/-) knockout mice. Expanding evidence now suggests, however, that even subtle decreases in human SSADH activity, associated with rare and common single nucleotide polymorphisms, may produce subclinical pathological effects. SSADH, in conjunction with aldo-keto reductase 7A2 (AKR7A2), represent two neural enzymes responsible for further catabolism of succinic semialdehyde, producing either succinate (SSADH) or gamma-hydroxybutyrate (GHB; AKR7A2). A GABA analogue, GHB is a short-chain fatty alcohol with unusual properties in the CNS and a long pharmacological history. Moreover, SSADH occupies a further role in the CNS as the enzyme responsible for further metabolism of the lipid peroxidation aldehyde 4-hydroxy-2-nonenal (4-HNE), an intermediate known to induce oxidant stress. Accordingly, subtle decreases in SSADH activity may have the capacity to lead to regional accumulation of neurotoxic intermediates (GHB, 4-HNE). Polymorphisms in SSADH gene structure may also associate with quantitative traits, including intelligence quotient and life expectancy. Further population-based studies of human SSADH activity promise to reveal additional properties of its function and additional roles in CNS tissue.

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.

Figure 2

Corresponding chemical structures of intermediates and metabolites depicted in Figure 1, and throughout the text.

Figure 3

Proposed scheme highlighting concepts and principles reported in this review. The central box focuses on variation in the ALDH5A1 gene, whether complete loss of activity or partial alteration linked to single nucleotide polymorphism (SNP), splicing variation or other features. The outward arrows reveal the potential results of these nucleic acid alterations, including metabolic findings (altered levels of γ-aminobutyric acid [GABA], γ-hydroxybutyrate [GHB], succinate semialdehyde [SSA] and 4-hydroxy-2-nonenal [4-HNE]), processes (receptor stimulation and/or downregulation, including GABA_A receptor [GABA_AR], GABA_B receptor [GABA_B R] and GHB receptor [GHBR]) and other processes (eg oxidative stress, altered bioenergetics and the accumulation of other metabolic toxins whose role in pathophysiology remains to be clarified). Additional abbreviations: HOT, D-2-hydroxyglutarate transhydrogenase; AKR7A2, aldo-keto reductase 7A2; QTL, quantitative trait loci.