Dataset Information

Phenotypic variability in deficiency of the ? subunit of succinate-CoA ligase.

ABSTRACT: Succinyl-CoA synthetase or succinate-CoA ligase deficiency can result from biallelic mutations in SUCLG1 gene that encodes for the alpha subunit of the succinyl-CoA synthetase. Mutations in this gene were initially associated with fatal infantile lactic acidosis. We describe an individual with a novel biallelic pathogenic mutation in SUCLG1 with a less severe phenotype dominated by behavioral problems. The mutation was identified to be c.512A>G corresponding to a p.Asn171Ser change in the protein. The liquid chromatography tandem mass spectrometry-based enzyme activity assay on cultured fibroblasts revealed a markedly reduced activity of succinyl-CoA synthetase enzyme when both ATP and GTP were substrates, affecting both ADP-forming and GDP-forming functions of the enzyme.

SUBMITTER: Demirbas D

PROVIDER: S-EPMC6498818 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Phenotypic variability in deficiency of the α subunit of succinate-CoA ligase.

Demirbas Didem D Harris David J DJ Arn Pamela H PH Huang Xiaoping X Waisbren Susan E SE Anselm Irina I Lerner-Ellis Jordan P JP Wong Lee-Jun LJ Levy Harvey L HL Berry Gerard T GT

JIMD reports 20190314 1

Succinyl-CoA synthetase or succinate-CoA ligase deficiency can result from biallelic mutations in <i>SUCLG1</i> gene that encodes for the alpha subunit of the succinyl-CoA synthetase. Mutations in this gene were initially associated with fatal infantile lactic acidosis. We describe an individual with a novel biallelic pathogenic mutation in <i>SUCLG1</i> with a less severe phenotype dominated by behavioral problems. The mutation was identified to be c.512A>G corresponding to a p.Asn171Ser change ...[more]

PMID: 31240156

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Project description:Three succinate coenzyme A (succinate-CoA) ligases (SucCD) from Escherichia coli, Advenella mimigardefordensis DPN7(T), and Alcanivorax borkumensis SK2 were characterized regarding their substrate specificity concerning succinate analogues. Previous studies had suggested that SucCD enzymes might be promiscuous toward succinate analogues, such as itaconate and 3-sulfinopropionate (3SP). The latter is an intermediate of the degradation pathway of 3,3'-dithiodipropionate (DTDP), a precursor for the biotechnical production of polythioesters (PTEs) in bacteria. The sucCD genes were expressed in E. coli BL21(DE3)/pLysS. The SucCD enzymes of E. coli and A. mimigardefordensis DPN7(T) were purified in the native state using stepwise purification protocols, while SucCD from A. borkumensis SK2 was equipped with a C-terminal hexahistidine tag at the SucD subunit. Besides the preference for the physiological substrates succinate, itaconate, ATP, and CoA, high enzyme activity was additionally determined for both enantiomeric forms of malate, amounting to 10 to 21% of the activity with succinate. Km values ranged from 2.5 to 3.6 mM for l-malate and from 3.6 to 4.2 mM for d-malate for the SucCD enzymes investigated in this study. As l-malate-CoA ligase is present in the serine cycle for assimilation of C1 compounds in methylotrophs, structural comparison of these two enzymes as members of the same subsubclass suggested a strong resemblance of SucCD to l-malate-CoA ligase and gave rise to the speculation that malate-CoA ligases and succinate-CoA ligases have the same evolutionary origin. Although enzyme activities were very low for the additional substrates investigated, liquid chromatography/electrospray ionization-mass spectrometry analyses proved the ability of SucCD enzymes to form CoA-thioesters of adipate, glutarate, and fumarate. Since all SucCD enzymes were able to activate 3SP to 3SP-CoA, we consequently demonstrated that the activation of 3SP is not a unique characteristic of the SucCD from A. mimigardefordensis DPN7(T). The essential role of sucCD in the activation of 3SP in vivo was proved by genetic complementation.

Dataset Information

Phenotypic variability in deficiency of the ? subunit of succinate-CoA ligase.

Publications

Phenotypic variability in deficiency of the α subunit of succinate-CoA ligase.

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