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

Brief description

In mammals succinic semialdehyde dehydrogenase (SSADH) plays an essential role in the metabolism of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) to succinic acid (SA). Deficiency of SSADH in humans results in elevated levels of GABA and γ-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 which are essential for preventing accumulation of toxic levels of succinic semialdehyde (SSA) in cells. Here we structurally characterise SSADH encoded by the E coli gabD gene and compare these data with the structure of human SSADH. Interestingly, in contrast to the human enzyme 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 co-facto is positioned in each active site. Furthermore, 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+. Finally, the structure of E. coli SSADH gives additional insight into human mutations that result in disease. To cite this data use the following DOI: 10.4225/52/557FAF18B53C8