The X-ray crystal structure of Escherichia coli succinic semialdehyde dehydrogenase; structural insights into NADP+/enzyme interactions

Christopher Langendorf, Trevor Key, Gustavo Fenalti, Wan-Ting Kan, Ashley Maurice Buckle, Tom T Caradoc-Davies, Kellie Louise Tuck, Ruby Hong Ping Law, James Whisstock

Research output: Contribution to journalArticleResearchpeer-review

29 Citations (Scopus)


BACKGROUND: In mammals succinic semialdehyde dehydrogenase (SSADH) plays an essential role in the metabolism of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) to succinic acid (SA). Deficiency of SSADH in humans results in elevated levels of GABA and gamma-Hydroxybutyric acid (GHB), which leads to psychomotor retardation, muscular hypotonia, non-progressive ataxia and seizures. In Escherichia coli, two genetically distinct forms of SSADHs had been described that are essential for preventing accumulation of toxic levels of succinic semialdehyde (SSA) in cells. METHODOLOGY/PRINCIPAL FINDINGS: Here we structurally characterise SSADH encoded by the E coli gabD gene by X-ray crystallographic studies and compare these data with the structure of human SSADH. In the E. coli SSADH structure, electron density for the complete NADP+ cofactor in the binding sites is clearly evident; these data in particular revealing how the nicotinamide ring of the cofactor is positioned in each active site. CONCLUSIONS/SIGNIFICANCE: Our structural data suggest that a deletion of three amino acids in E. coli SSADH permits this enzyme to use NADP+, whereas in contrast the human enzyme utilises NAD+. Furthermore, the structure of E. coli SSADH gives additional insight into human mutations that result in disease.
Original languageEnglish
Pages (from-to)1 - 12
Number of pages12
JournalPLoS ONE
Issue number2
Publication statusPublished - 2010

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