Succinic semialdehyde reductase

Identifiers
EC number	1.1.1.24
CAS number	9028-16-2
Alt. names
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway

Introduction

Succinic semialdehyde reductase (SSAR) is an enzyme that plays a crucial role in the metabolism of gamma-aminobutyric acid (GABA), a key neurotransmitter in the central nervous system. This enzyme catalyzes the reduction of succinic semialdehyde to gamma-hydroxybutyrate (GHB), a process that is important in both normal physiological functions and certain pathological conditions.

Structure

Succinic semialdehyde reductase is a member of the oxidoreductase family, specifically acting on the CH-OH group of donors with NAD+ or NADP+ as acceptors. The enzyme is typically a monomeric protein, although its exact structure can vary between species. The active site of SSAR contains key residues that facilitate the binding of NADPH and the substrate, succinic semialdehyde.

Function

The primary function of succinic semialdehyde reductase is to catalyze the conversion of succinic semialdehyde to gamma-hydroxybutyrate. This reaction is part of the GABA shunt, a metabolic pathway that bypasses two steps of the tricarboxylic acid cycle. The reaction can be summarized as follows:

Succinic semialdehyde + NADPH + H⁺ → Gamma-hydroxybutyrate + NADP⁺

This reaction is important for maintaining the balance of GABA and GHB in the brain, both of which have significant roles in neurotransmission and neuromodulation.

Clinical Significance

Succinic semialdehyde reductase is involved in the pathophysiology of certain neurological disorders. An imbalance in the activity of this enzyme can lead to altered levels of GHB, which is associated with conditions such as succinic semialdehyde dehydrogenase deficiency (SSADH deficiency). This rare genetic disorder results in the accumulation of GABA and GHB, leading to a range of symptoms including developmental delay, hypotonia, and ataxia.

Regulation

The activity of succinic semialdehyde reductase is regulated by the availability of its substrates and cofactors, primarily succinic semialdehyde and NADPH. Additionally, the enzyme's activity can be modulated by changes in the cellular redox state and by various allosteric effectors.

Research and Therapeutic Implications

Research into succinic semialdehyde reductase has implications for understanding and treating disorders related to GABA metabolism. Inhibitors or modulators of SSAR activity are being investigated as potential therapeutic agents for conditions such as epilepsy and narcolepsy, where GHB levels may be dysregulated.

Conclusion

Succinic semialdehyde reductase is a vital enzyme in the GABA metabolic pathway, with significant implications for both normal brain function and neurological disorders. Understanding its structure, function, and regulation is crucial for developing therapeutic strategies for related conditions.

See Also

• Gamma-aminobutyric acid
• Gamma-hydroxybutyrate
• Succinic semialdehyde dehydrogenase
• GABA shunt

External Links

• [Link to enzyme database]
• [Link to protein structure database]