Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.3.5.1 (succinate dehydrogenase)
8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The assembly of the mitochondrial respiratory chain is mediated by a large number of helper proteins. To better understand the biogenesis of the yeast succinate dehydrogenase (SDH), we searched for assembly-defective mutants. SDH is encoded by the SDH1, SDH2, SDH3, and SDH4 genes. The holoenzyme is composed of two domains. The membrane extrinsic domain, consisting of Sdh1p and Sdh2p, contains a covalent FAD cofactor and three iron-sulfur clusters. The membrane intrinsic domain, consisting of Sdh3p and Sdh4p, is proposed to bind two molecules of ubiquinone and one heme. We isolated one mutant that is respiration-deficient with a specific loss of SDH oxidase activity. SDH is not assembled in this mutant. The complementing gene, TCM62 (also known as SCYBR044C), does not encode an SDH subunit and is not essential for cell viability. It encodes a mitochondrial membrane protein of 64,211 Da. The Tcm62p sequence is 17.3% identical to yeast hsp60, a molecular chaperone. The Tcm62p amino terminus is in the mitochondrial matrix, whereas the carboxyl terminus is accessible from the intermembrane space. Tcm62p forms a complex containing at least three SDH subunits. We propose that Tcm62p functions as a chaperone in the assembly of yeast SDH.
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PMID:The Saccharomyces cerevisiae TCM62 gene encodes a chaperone necessary for the assembly of the mitochondrial succinate dehydrogenase (complex II). 982 78

The Saccharomyces cerevisiae succinate-ubiquinone reductase or succinate dehydrogenase (SDH) is a tetramer of non-equivalent subunits encoded by the SDH1, SDH2, SDH3, and SDH4 genes. In most organisms, SDH contains one or two endogenous b-type hemes. However, it is widely believed that the yeast SDH does not contain heme. In this report, we demonstrate the presence of a stoichiometric amount of cytochrome b562 in the yeast SDH. The cytochrome is detected as a peak present in fumarate-oxidized, dithionite-reduced mitochondria. The peak is centered at 562 nm and is present at a heme:covalent FAD molar ratio of 0.92+/-0.11. The cytochrome is not detectable in mitochondria isolated from SDH3 and SDH4 deletion strains. These observations strongly support our conclusion that cytochrome b562 is a component of the yeast SDH.
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PMID:The Saccharomyces cerevisiae succinate-ubiquinone reductase contains a stoichiometric amount of cytochrome b562. 992 2

The yeast succinate dehydrogenase (SDH) is a tetramer of non-equivalent subunits, Sdh1p-Sdh4p, that couples the oxidation of succinate to the transfer of electrons to ubiquinone. One of the membrane anchor subunits, Sdh4p, has an unusual 30 amino acid extension at the C-terminus that is not present in SDH anchor subunits of other organisms. We identify Lys-132 in the Sdh4p C-terminal region as necessary for enzyme stability, ubiquinone reduction, and cytochrome b562 assembly in SDH. Five Lys-132 substituted SDH4 genes were constructed by site-directed mutagenesis and introduced into an SDH4 knockout strain. The mutants, K132E, K132G, K132Q, K132R, and K132V were characterized in vivo for respiratory growth and in vitro for ubiquinone reduction, enzyme stability, and cytochrome b562 assembly. Only the K132R substitution, which conserves the positive charge of Lys-132, produces a wild-type enzyme. The remaining four mutants do not affect the ability of SDH to oxidize succinate in the presence of the artificial electron acceptor, phenazine methosulfate, but impair quinone reductase activity, enzyme stability, and heme insertion. Our results suggest that the presence of a positive charge on residue 132 in the C-terminus of Sdh4p is critical for establishing a stable conformation in the SDH hydrophobic domain that is compatible with ubiquinone reduction and cytochrome b562 assembly. In addition, our data suggest that heme does not play an essential role in quinone reduction.
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PMID:The Saccharomyces cerevisiae succinate dehydrogenase anchor subunit, Sdh4p: mutations at the C-terminal lys-132 perturb the hydrophobic domain. 1021 63

The enzymes of the glyoxylate cycle and gluconeogenesis are tightly regulated by transcriptional, posttranscriptional, and posttranslational mechanisms in Saccharomyces cerevisiae. We have previously identified four genes, ACN8, ACN9, ACN17, and ACN18, whose mutant phenotype includes two- to fourfold elevated levels of enzymes of the glyoxylate cycle, gluconeogenesis, and acetyl-CoA metabolism. The affected enzymes are elevated on nonfermentable carbon sources but are still fully repressed by glucose. Catabolite inactivation of the cytosolic malate dehydrogenase is not affected in the mutants. Instead, the phenotype appeared to be manifested primarily at the level of transcription. The ACN8, ACN17, and ACN18 genes were isolated by functional complementation of the respective mutant's inability to utilize acetate as a carbon and energy source, and these genes were shown to encode subunits of metabolic enzymes. ACN8 was identical to FBP1, which encodes the gluconeogenic enzyme, fructose 1,6-bisphosphatase, while ACN17 and ACN18 were identical to the SDH2 and SDH4 genes, respectively, that encode subunits of the respiratory chain and tricarboxylic acid cycle enzyme, succinate dehydrogenase. Mutants defective in other glyoxylate cycle and gluconeogenic enzymes also display the elevated enzyme phenotype, indicating that the enzyme superinduction is a general property of gluconeogenic dysfunction. Glucose 6-phosphate levels were diminished in the mutants, suggesting that endogenous glucose synthesis can regulate the expression of gluconeogenic enzymes.
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PMID:Yeast mutants of glucose metabolism with defects in the coordinate regulation of carbon assimilation. 1032 23

We have mapped large (cybL) and small (cybS) subunits of cytochrome b in the succinate-ubiquinone oxidoreductase (complex II) of human mitochondria to chromosome 1q21 and 11q23, respectively (H. Hirawake et al., Cytogenet. Cell Genet. 79 (1997) 132-138). In the present study, the human SDHD gene encoding cybS was cloned and characterized. The gene comprises four exons and three introns extending over 19 kb. Sequence analysis of the 5' promoter region showed several motifs for the binding of transcription factors including nuclear respiratory factors NRF-1 and NRF-2 at positions -137 and -104, respectively. In addition to this gene, six pseudogenes of cybS were isolated and mapped on the chromosome.
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PMID:Characterization of the human SDHD gene encoding the small subunit of cytochrome b (cybS) in mitochondrial succinate-ubiquinone oxidoreductase. 1048 92

Most pheochromocytomas are sporadic but about 10% are though to be hereditary. Although the etiology of most inherited pheochromocytoma is well known, little is known about the etiology of the more common sporadic tumor. Recently, germ-line mutations of SDHD, a mitochondria complex II gene, were found in patients with hereditary paraganglioma. We sought to determine whether SDHD plays a role in the development of sporadic pheochromocytomas and performed a mutation and deletion analysis of SDHD. Among 18 samples, we identified 4 heterozygous sequence variants (3 germ-line, 1 somatic). One germ-line SDHD mutation IVS1+2T>G (absent among 78 control alleles) is predicted to cause aberrant splicing. On reinvestigation, this patient was found to have a tumor of the carotid body, which was likely a paraganglioma. Another patient with malignant, extra-adrenal pheochromocytoma was found to have germ-line c.34G> A (G12S). However, this sequence variant was also found in 1 of 78 control alleles. The third, germ-line nonsense mutation R38X was found in a patient with extra-adrenal pheochromocytoma. The only somatic heterozygous mutation, c.242C>T (P81L), has been found in the germ line of two families with hereditary paraganglioma and is conserved among four eukaryotic multicellular organisms. Hence, this mutation is most likely of functional significance too. Overall, loss of heterozygosity in at least one of the two markers flanking SDHD was found in 13 tumors (72%). All of the tumors that already harbored intragenic SDHD mutations, whether germ-line or somatic, also had loss of heterozygosity. Our results indicate that SDHD plays a role in the pathogenesis of pheochromocytoma. Given the minimum estimated germline SDHD mutation frequency of 11% (maximum estimate up to 17%) in this set of apparently sporadic pheochromocytoma cases and if these data can be replicated in other populations, our observations might suggest that all such patients be considered for SDHD mutation analysis.
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PMID:Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma. 1115 72

Chromosomal region 11q22-q23 is a frequent target for deletion during the development of many solid tumour types, including breast, ovary, cervix, stomach, bladder carcinomas and melanoma. One of the most commonly deleted subregions contains the SDHD gene, which encodes the small subunit of cytochrome b (cybS) in mitochondrial complex II (succinate-ubiquinone oxidoreductase). Germline mutations in SDHD cause hereditary paraganglioma type 1 (PGL1), and suggest a tumour suppressor role for cybS. We present a high-resolution physical map spanning SDHD, covered by 19 YACs and 20 BACs. An approximate 1.1-Mb gene-rich region around SDHD is spanned by a complete BAC contig. Twenty-six new STSs are developed from the BAC clone ends. In addition to the discovery and characterisation of 15 new simple tandem repeat polymorphisms, we provide integrated positional information for 33 ESTs and known genes, including KIAA1391, POU2AF1 (OBF1), PPP2R1B, CRYAB, HSPB2, DLAT, IL-18, PTPS, KIAA0781 and KAIA4591, which is mapped by NotI site cloning. We describe full-length transcript sequence for PPP2R1B, encoding the protein phosphatase 2A regulatory subunit A beta isoform. We also discover a processed pseudogene for USA-CYP, a cyclophilin associated with U4/U6 snRPNs, and a novel gene, DDP2, encoding a mitochondrial protein similar to the X-linked deafness-dystonia protein, which is juxtaposed 5'-to-5' to SDHD. This map will help assess this gene-rich region in PGL and in other common tumours.
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PMID:A high-resolution integrated map spanning the SDHD gene at 11q23: a 1.1-Mb BAC contig, a partial transcript map and 15 new repeat polymorphisms in a tumour-suppressor region. 1131 45

Familial paragangliomas (PGL) are slow-growing, highly vascular, generally benign neoplasms, usually of the head and neck, that arise from neural crest cells. This rare autosomal dominant disorder is highly penetrant and influenced by genomic imprinting through paternal transmission. Timely detection of these tumors may afford the affected individual the opportunity to avoid the potential serious morbidity associated with surgical removal and the mortality that may accompany local and distant metastases. Linkage to two distinct chromosomal loci, 11q13.1 and 11q23, has been previously reported. Recently, germline mutations in SDHD, a mitochondrial complex II gene on chromosome 11q23, have been demonstrated. We evaluated members of seven families with PGL, five previously studied and shown to have linkage to chromosome 11q23. The entire coding region of the SDHD gene was sequenced and yielded four novel mutations and one mutation shared in three of our unrelated families. Novel mutations found included a truncating mutation in exon 2, as well as a missense mutation, a deletion, and an insertion in exon 4. Three of our families had a common mutation in exon 3 (P81L) that has been reported and thought to be a founder mutation. A restriction enzyme assay was developed for initial screening of this mutation. Molecular analysis is now available and recommended for presymptomatic diagnosis in those at-risk individuals and for confirmatory diagnosis in those having PGL.
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PMID:Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma. 1134 22

Hereditary paragangliomas or glomus tumors are usually benign slow-growing tumors in the head and neck region. The inheritance pattern of hereditary paraganglioma is autosomal dominant with imprinting. Recently, we have identified the SDHD gene encoding subunit D of the mitochondrial respiratory chain complex II as one of the genes involved in hereditary paragangliomas. Here, we demonstrate that two founder mutations, Asp92Tyr and Leu139Pro, are responsible for paragangliomas in 24 and 6 of the 32 independently ascertained Dutch paraganglioma families, respectively. These two mutations were also detected among 20 of 55 isolated patients. Ten of the isolated patients had multiple paragangliomas, and in eight of these SDHD germline mutations were found, indicating that multicentricity is a strong predictive factor for the hereditary nature of the disorder in isolated patients. In addition, we demonstrate that the maternally derived wild-type SDHD allele is lost in tumors from mutation-carrying patients, indicating that SDHD functions as a tumor suppressor gene.
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PMID:Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene. 1139 98

The pheochromocytomas are an important cause of secondary hypertension. Although pheochromocytoma susceptibility may be associated with germline mutations in the tumor-suppressor genes VHL and NF1 and in the proto-oncogene RET, the genetic basis for most cases of nonsyndromic familial pheochromocytoma is unknown. Recently, pheochromocytoma susceptibility has been associated with germline SDHD mutations. Germline SDHD mutations were originally described in hereditary paraganglioma, a dominantly inherited disorder characterized by vascular tumors in the head and the neck, most frequently at the carotid bifurcation. The gene products of two components of succinate dehydrogenase, SDHC and SDHD, anchor the gene products of two other components, SDHA and SDHB, which form the catalytic core, to the inner-mitochondrial membrane. Although mutations in SDHC and in SDHD may cause hereditary paraganglioma, germline SDHA mutations are associated with juvenile encephalopathy, and the phenotypic consequences of SDHB mutations have not been defined. To investigate the genetic causes of pheochromocytoma, we analyzed SDHB and SDHC, in familial and in sporadic cases. Inactivating SDHB mutations were detected in two of the five kindreds with familial pheochromocytoma, two of the three kindreds with pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic pheochromocytoma. These findings extend the link between mitochondrial dysfunction and tumorigenesis and suggest that germline SDHB mutations are an important cause of pheochromocytoma susceptibility.
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PMID:Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. 1140 20


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