Cloning and expression of succinic semialdehyde reductase from human brain

Abstract

The neuromodulator γ-hydroxybutyrate is synthesized in vivo from γ-aminobutyrate by transamination to succinic semialdehyde and subsequent reduction of the aldehyde group. In human brain, succinic semialdehyde reductase is thought to be responsible for the conversion of succinic semialdehyde to γ-hydroxybutyrate. In the present work, we cloned the cDNA coding for succinic semialdehyde reductase and expressed it in Escherichia coli. A data bank search indicated that the enzyme is identical with aflatoxin B₁-aldehyde reductase, an enzyme implicated in the detoxification of xenobiotic carbonyl compounds. Structurally, succinic semialdehyde reductase thus belongs to the aldo–keto reductase superfamily. The recombinant protein was indistinguishable from native human brain succinic semialdehyde reductase by SDS/PAGE. In addition to succinic semialdehyde, it readily catalyzed the reduction 9,10-phenanthrene quinone, phenylglyoxal and 4-nitrobenzaldehyde, typical substrates of aflatoxin B₁ aldehyde reductase. The results suggest multiple functions of succinic semialdehyde reductase/aflatoxin B₁ aldehyde reductase in the biosynthesis of γ-hydroxybutyrate and the detoxification of xenobiotic carbonyl compounds, respectively.