Succinate semialdehyde reductase (SSR)

Succinate semialdehyde reductase (SSR), primarily encoded by the AKR7A2 gene in humans, is a key enzyme in the gamma-aminobutyric acid (GABA) shunt pathway that catalyzes the NADPH-dependent reduction of succinate semialdehyde to gamma-hydroxybutyrate (GHB) (UniProt, GeneCards). While the primary catabolic route for succinate semialdehyde is oxidation to succinate by succinate semialdehyde dehydrogenase (SSADH), SSR provides an alternative pathway that becomes particularly significant in SSADH deficiency, leading to the pathological accumulation of GHB (Wikipedia, MDPI). SSR is widely expressed in the brain, particularly in glial cells such as astrocytes and microglia, where it plays a role in regulating inhibitory neurotransmission and detoxifying reactive aldehydes like aflatoxin B1 and lipid peroxidation products (NIH, UniProt). The enzyme is a recognized target of the mood stabilizer and anticonvulsant valproic acid, which inhibits SSR activity to modulate GABA and GHB levels (NIH, Sav.sk). Research has shown that SSR expression is significantly elevated in the brains of patients with Alzheimer's disease and Dementia with Lewy Bodies, particularly within reactive astrocytes and microglia (NIH). Additionally, SSR is the primary enzyme responsible for the metabolism of anthracyclines in the heart, where its activity can contribute to drug-induced cardiotoxicity (Maayanlab.cloud).

Other names

Aldo-keto reductase family 7 member A2Aflatoxin B1 aldehyde reductase member 2AFAR2SSA reductaseAKR7A24-hydroxybutyrate dehydrogenaseSuccinic semialdehyde reductase

Inhibition of the enzyme's catalytic activity, leading to the modulation of gamma-aminobutyric acid (GABA) and gamma-hydroxybutyrate (GHB) levels in the central nervous system.