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

22 Citations (Scopus)

Abstract

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
Volume5
Issue number2
DOIs
Publication statusPublished - 2010

Cite this

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title = "The X-ray crystal structure of Escherichia coli succinic semialdehyde dehydrogenase; structural insights into NADP+/enzyme interactions",
abstract = "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.",
author = "Christopher Langendorf and Trevor Key and Gustavo Fenalti and Wan-Ting Kan and Buckle, {Ashley Maurice} and Caradoc-Davies, {Tom T} and Tuck, {Kellie Louise} and Law, {Ruby Hong Ping} and James Whisstock",
year = "2010",
doi = "10.1371/journal.pone.0009280",
language = "English",
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pages = "1 -- 12",
journal = "PLoS ONE",
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The X-ray crystal structure of Escherichia coli succinic semialdehyde dehydrogenase; structural insights into NADP+/enzyme interactions. / Langendorf, Christopher; Key, Trevor; Fenalti, Gustavo; Kan, Wan-Ting; Buckle, Ashley Maurice; Caradoc-Davies, Tom T; Tuck, Kellie Louise; Law, Ruby Hong Ping; Whisstock, James.

In: PLoS ONE, Vol. 5, No. 2, 2010, p. 1 - 12.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - The X-ray crystal structure of Escherichia coli succinic semialdehyde dehydrogenase; structural insights into NADP+/enzyme interactions

AU - Langendorf, Christopher

AU - Key, Trevor

AU - Fenalti, Gustavo

AU - Kan, Wan-Ting

AU - Buckle, Ashley Maurice

AU - Caradoc-Davies, Tom T

AU - Tuck, Kellie Louise

AU - Law, Ruby Hong Ping

AU - Whisstock, James

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

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