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

Malaspina P, Picklo MJ, Jakobs C, Snead OC, Gibson KM - Hum. Genomics (2009)

Bottom Line: 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).Accordingly, subtle decreases in SSADH activity may have the capacity to lead to regional accumulation of neurotoxic intermediates (GHB, 4-HNE).

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, Tor Vergata University, Rome, Italy.

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.

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Corresponding chemical structures of intermediates and metabolites depicted in Figure 1, and throughout the text.
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Figure 2: Corresponding chemical structures of intermediates and metabolites depicted in Figure 1, and throughout the text.

Mentions: In mammalian brain, γ-aminobutyric acid (GABA) is quantitatively the most important inhibitory neuro-transmitter, and more than 30 per cent of neurones in the central nervous system (CNS) employ it to mediate inhibitory signalling [1,2]. As for other neuro-transmitters, the process of release, reuptake and further metabolism is tightly controlled, tuned to ensure that excitatory/inhibitory transmission maintains equilibrium. For GABA, these processes are mediated by three enzymes: glutamic acid decarboxy-lase (GAD), which forms GABA from glutamate, and the degradative enzymes GABA transaminase (GABA-T) and aldehyde dehydrogenase 5A1 (ALDH5A1; succinate semialdehyde dehydrogenase [SSADH]) (Figures 1 and 2). Human disorders of GAD and GABA-T are rare to non-existent;[3] conversely, numerous patients with ALDH5A1 deficiency have been identified since the description of the index patient [4-6]. Patient detection was facilitated by the description of γ-hydroxybutyrate (GHB), the key biomarker for the disorder, in the urine of patients using combined gas chromatography mass spectrometry (GCMS). Accordingly, human ALDH5A1 deficiency is a rare neurometabolic disorder in which two neuromodulatory species, namely GABA and GHB, accumulate in patients' physiological fluids [6].


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

Malaspina P, Picklo MJ, Jakobs C, Snead OC, Gibson KM - Hum. Genomics (2009)

Corresponding chemical structures of intermediates and metabolites depicted in Figure 1, and throughout the text.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2657722&req=5

Figure 2: Corresponding chemical structures of intermediates and metabolites depicted in Figure 1, and throughout the text.
Mentions: In mammalian brain, γ-aminobutyric acid (GABA) is quantitatively the most important inhibitory neuro-transmitter, and more than 30 per cent of neurones in the central nervous system (CNS) employ it to mediate inhibitory signalling [1,2]. As for other neuro-transmitters, the process of release, reuptake and further metabolism is tightly controlled, tuned to ensure that excitatory/inhibitory transmission maintains equilibrium. For GABA, these processes are mediated by three enzymes: glutamic acid decarboxy-lase (GAD), which forms GABA from glutamate, and the degradative enzymes GABA transaminase (GABA-T) and aldehyde dehydrogenase 5A1 (ALDH5A1; succinate semialdehyde dehydrogenase [SSADH]) (Figures 1 and 2). Human disorders of GAD and GABA-T are rare to non-existent;[3] conversely, numerous patients with ALDH5A1 deficiency have been identified since the description of the index patient [4-6]. Patient detection was facilitated by the description of γ-hydroxybutyrate (GHB), the key biomarker for the disorder, in the urine of patients using combined gas chromatography mass spectrometry (GCMS). Accordingly, human ALDH5A1 deficiency is a rare neurometabolic disorder in which two neuromodulatory species, namely GABA and GHB, accumulate in patients' physiological fluids [6].

Bottom Line: 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).Accordingly, subtle decreases in SSADH activity may have the capacity to lead to regional accumulation of neurotoxic intermediates (GHB, 4-HNE).

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, Tor Vergata University, Rome, Italy.

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.

Show MeSH
Related in: MedlinePlus