A detailed structural description of Escherichia coli succinyl-CoA synthetase 1 1Edited by D. Rees

Fraser, M.E.; James, Michael N.G.; Bridger, William A.; Wolodko, William T.

doi:10.1006/jmbi.1998.2324

Cited by 90 publications

(105 citation statements)

References 53 publications

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“…The movement of the phosphohistidine loop with phosphorylated catalytic histidine has been suggested to shuttle the phosphate between the active sites of both subunits. 14,15 The missing fragment in the case of skipping of exon 6 and part of exon 7, encompassing residues 221-267, contains Glu256, a critical residue for ADP phosphorylation. 21 Location of Asp333, a part of 'power' helix b and the interface between subunits, within the modeled human mitochondrial SCS-A (b).…”

Section: Discussionmentioning

confidence: 99%

“…Homology modeling for a and b subunits of human SCS-A was performed in SWISS-Model Server (http://swissmodel.expasy.org/) using a and b subunits of E. coli SCS-Aas templates 14 (PDB id 1CQI). Building the SCS-A dimer, the structural analysis of the attained model and visualization of the results were performed using Discovery Studio v.2.5.5 (Accelrys).…”

Section: Molecular Karyotypingmentioning

confidence: 99%

“…Dimerization is unlikely to be affected because hydrophobic residues form the main contact surface 14 and Asp333Gly will not perturb these interactions. As glycine is a known 'helix breaker' 16 the main effect of the Asp333Gly change is predicted to affect the configuration of the 'power' helix affecting the coordination of the phosphate ion, resulting in a much slower phosphorylation rate.…”

Section: Quantification Of Mtdnamentioning

confidence: 99%

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Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion

et al. 2014

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Mutations in SUCLA2, encoding the -subunit of succinyl-CoA synthetase of Krebs cycle, are one cause of mitochondrial DNA depletion syndrome. Patients have been reported to have severe progressive childhood-onset encephalomyopathy, and methylmalonic aciduria, often leading to death in childhood. We studied two families, with children manifesting with slowly progressive mitochondrial encephalomyopathy, hearing impairment and transient methylmalonic aciduria, without mtDNA depletion. The other family also showed dominant inheritance of bilateral retinoblastoma, which coexisted with mitochondrial encephalomyopathy in one patient. We found a variant in SUCLA2 leading to Asp333Gly change, homozygous in one patient and compound heterozygous in one. The latter patient also carried a deletion of 13q14 of the other allele, discovered with molecular karyotyping. The deletion spanned both SUCLA2 and RB1 gene regions, leading to manifestation of both mitochondrial disease and retinoblastoma. We made a homology model for human succinyl-CoA synthetase and used it for structure-function analysis of all reported pathogenic mutations in SUCLA2. On the basis of our model, all previously described mutations were predicted to result in decreased amounts of incorrectly assembled protein or disruption of ADP phosphorylation, explaining the severe early lethal manifestations. However, the Asp333Gly change was predicted to reduce the activity of the otherwise functional enzyme. On the basis of our findings, SUCLA2 mutations should be analyzed in patients with slowly progressive encephalomyopathy, even in the absence of methylmalonic aciduria or mitochondrial DNA depletion. In addition, an encephalomyopathy in a patient with retinoblastoma suggests mutations affecting SUCLA2.

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Section: Discussionmentioning

confidence: 99%

Section: Molecular Karyotypingmentioning

confidence: 99%

Section: Quantification Of Mtdnamentioning

confidence: 99%

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Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion

et al. 2014

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“…It has been pointed out that other members in this superfamily also commonly harbor these five domains, although the order and distribution of the domains between the two subunits display variation (18). Although all previously characterized classical SCSs share the same subunit and domain structure (domain order: ␣-subunit, 1-2; and ␤-subunit, 3-4-5) (23,24,27,28), the SCS identified here from T. kodakaraensis exhibits a distinct structure: domain 5 is fused to the ␣-subunit (␣-subunit, domains 1-2-5; and ␤-subunit, domains 3-4) (Fig. 2).…”

Section: Identification Of An Scs In Cell-free Extracts Of Tmentioning

confidence: 99%

“…They have been proposed to be members of the nucleoside diphosphate (NDP)-forming acyl-CoA synthetase superfamily (18). ADP/GDP-forming succinyl-CoA synthetase (SCS) also belongs to this superfamily and catalyzes the reversible conver-sion of succinyl-CoA to succinate and CoA concomitant with substrate level phosphorylation of ADP/GDP (23,24). Generally, SCS functions in the tricarboxylic acid cycle of aerobic organisms, and it has been suggested that the mammalian ATPdependent enzyme serves a catabolic role, whereas the GTPdependent enzyme is involved in succinyl-CoA synthesis (24).…”

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confidence: 99%

A Novel ADP-forming Succinyl-CoA Synthetase in Thermococcus kodakaraensis Structurally Related to the Archaeal Nucleoside Diphosphate-forming Acetyl-CoA Synthetases

Shikata

Fukui

Atomi

et al. 2007

Journal of Biological Chemistry

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We have identified and characterized a structurally novel succinyl-CoA synthetase (SCS) from the hyperthermophilic Archaea Thermococcus kodakaraensis. The presence of an SCS completes the metabolic pathway from glutamate to succinate in Thermococcales, which had not been clarified because of the absence of classical SCS homologs on their genomes. The SCS from T. kodakaraensis (SCS Tk ) is a heteromeric enzyme (␣ 2 ␤ 2 ) encoded by TK1880 (␣-subunit) and TK0943 (␤-subunit). Although both SCS Tk and classical SCSs harbor the five domains present in enzymes of the acyl-CoA synthetase (nucleoside diphosphate-forming) superfamily, the domain order and distribution among subunits in SCS Tk (␣-subunit, domains 1-2-5; ␤-subunit, domains 3-4) are distinct from those of classical SCSs (␣-subunit, domains 1-2; ␤-subunit, domains 3-4-5) and instead resemble the acetyl-CoA synthetases from Pyrococcus furiosus (ACSs I Pf and II Pf ). Comparison of the four Thermococcales genomes revealed that each strain harbors five ␣-and two ␤-subunit homologs. Sequence similarity suggests that the ␤-subunit of SCS Tk is also a component of the presumed ACS II from T. kodakaraensis (ACS II Tk ). We coexpressed the ␣/␤-genes of SCS Tk (TK1880/TK0943) and of ACS II Tk (TK0139/ TK0943). ACS II Tk recognizes a broad range of hydrophobic/ aromatic acid compounds, as is the case with ACS II Pf , whereas SCS Tk displays a distinct and relatively strict substrate specificity for several acids, including succinate. This indicates that the ␣-subunits are responsible for the distinct substrate specificities of SCS Tk and ACS II Tk .Thermococcus and Pyrococcus species are hyperthermophilic Archaea that preferentially utilize peptides/amino acids for cell growth (1). It is presumed that amino acids are first deaminated to 2-oxo acids by aminotransferases, with 2-oxoglutarate as a key amino acceptor (2). The generated glutamate is converted back to 2-oxoglutarate by oxidative deamination catalyzed by glutamate dehydrogenase (3). The 2-oxo acids are then converted to CoA thioester compounds by oxidative decarboxylation. Ferredoxin-dependent oxidoreductases catalyze these reactions, and a number of enzymes with distinct substrate specificities have been identified in Pyrococcus furiosus (4 -7). Closely related genes are also found on the genomes of Thermococcus kodakaraensis (8), Pyrococcus abyssi (9), and Pyrococcus horikoshii (10). The final step is the hydrolysis of the thioester bond, releasing a carboxylic acid and CoA accompanied by substrate level phosphorylation, an important energy conservation reaction in these hyperthermophiles. The ADP-forming acetyl-CoA synthetases I and II from P. furiosus (ACSs I Pf 2 and II Pf ) have been identified to be involved in this step (11-14) and exhibit activity not only for acetyl-CoA but also for branched-chain acyl-CoAs (ACSs I Pf and II Pf ) and aryl-CoAs (ACS II Pf ) (13). The substrate specificities of the two enzymes are consistent with the preferential consumption of Leu, Ile, and Phe by P. furiosus during...

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Investigating the mechanism of ADP‐forming acetyl‐CoA synthetase from the protozoan parasite Entamoeba histolytica

2017

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ADP-forming acetyl-CoA synthetase (ACD) catalyzes the interconversion of acetyl-CoA and acetate. The related succinyl-CoA synthetase follows a three-step mechanism involving a single phosphoenzyme, but a novel four-step mechanism with two phosphoenzyme intermediates was proposed for Pyrococcus ACD. Characterization of enzyme variants of Entamoeba ACD in which the two proposed phosphorylated His residues were individually altered revealed that only His252 is essential for enzymatic activity. Analysis of variants altered at two residues proposed to interact with the phosphohistidine loop that swings between distinct parts of the active site are consistent with a mechanism involving a single phosphoenzyme intermediate. Our results suggest ACDs with different subunit structures may employ slightly different mechanisms to bridge the span between active sites I and II.

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A detailed structural description of Escherichia coli succinyl-CoA synthetase 1 1Edited by D. Rees

Cited by 90 publications

References 53 publications

Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion

Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion

A Novel ADP-forming Succinyl-CoA Synthetase in Thermococcus kodakaraensis Structurally Related to the Archaeal Nucleoside Diphosphate-forming Acetyl-CoA Synthetases

Investigating the mechanism of ADP‐forming acetyl‐CoA synthetase from the protozoan parasite Entamoeba histolytica

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