Disease relevance of SARDH

• We now report a mutation in the nuclear-encoded flavoprotein (Fp) subunit gene of the succinate dehydrogenase (SDH) in two siblings with complex II deficiency presenting as Leigh syndrome [1].
• These findings clearly suggest that SDH plays an important role in cellular communication between streptococci and pharyngeal cells that may be important in host cell gene transcription, and hence in the pathogenesis of streptococcal infection [2].
• A number of mutations in human SDH genes are responsible for the development of paragangliomas, cancers of the head and neck region [3].
• We suggest that certain mutations in SDH can make it a significant source of superoxide production in mitochondria, which may contribute directly to disease progression [3].
• CONTEXT: The identification of mutations in genes encoding peptides of succinate dehydrogenase (SDH) in pheochromocytoma/paraganglioma syndromes has necessitated clear elucidation of genotype-phenotype associations [4].

Psychiatry related information on SARDH

• Here, PDHc and SDH activity were stimulated with each of the two stereoisomers of alpha lipoic acid in post-mortem parietal brain cortex of patients with DAT, DVT, and one case of Pick's disease and compared to stimulation effects in a control group, matched for age, sex, post-mortem delay, and storage time of brain tissue [5].
• Seven days of partial water deprivation did not alter the LDH activity of lizards of all three age groups but caused an increase in SDH activity of old lizards only [6].

High impact information on SARDH

• Therefore, these data indicated that streptococci/SDH-mediated phosphorylation plays a critical role in bacterial entry into the host cell [2].
• SDH, a major surface protein of group A streptococci, has both glyceraldehyde-3-phosphate dehydrogenase and ADP-ribosylating enzyme activities that may relate to early stages of streptococcal infection [2].
• Intact streptococci and purified SDH induce a similar protein phosphorylation pattern with the de novo tyrosine phosphorylation of a 17-kD protein found in the membrane/particulate fraction of the pharyngeal cells [2].
• Both phosphotyrosine and phosphoserine-specific monoclonal antibodies reacted with the 17-kD protein by Western blot, suggesting that the binding of SDH to these pharyngeal cells elicits a novel signaling pathway that ultimately leads to activation of histone H3-specific kinases [2].
• This streptococcal surface GAPDH (SDH) exhibits a dose-dependent dehydrogenase activity on glyceraldehyde-3-phosphate in the presence of beta-nicotinamide adenine dinucleotide both in its pure form and on the streptococcal surface [7].

Chemical compound and disease context of SARDH

• Although promoter region methylation was also detected in two neuroblastoma cell lines, this was not associated with silencing of SDHB expression, and treatment with a demethylating agent (5-azacytidine) did not increase SDH activity [8].
• 3-Nitropropionic acid (3-NPA) produces hypothermia and inhibits histochemical labeling of succinate dehydrogenase (SDH) in rat brain [9].
• OBJECTIVES: To validate the novel lymphocyte toxicity assay (LTA) based on the mitochondrial succinate dehydrogenase (SDH) activity vs. the LTA by using trypan blue exclusion and to determine the utility of the assay to confirm drug hypersensitivity syndrome (DHS) to sulphonamides (SMX) and aromatic anticonvulsants [10].
• The lack of positive correlation between plasma glucose and SDH levels suggests that SDH, like hemoglobin A1C, reflect the degree of previous metabolic control of diabetes mellitus [11].
• The NAD-binding domains of TH are homologous to bacterial alanine dehydrogenases (ADH) and eukaryotic saccharopine dehydrogenases (SDH) as well as N5(carboxyethyl)-L-ornithine synthase of Lactococcus lactis and dipicolinate synthase of Bacillus subtilis [12].

Biological context of SARDH

• The availability of the SDH gene sequence will enable characterization of the genotypes of sarcosinemia patients with different phenotypes [13].
• Two smaller cDNA clones, isolated from adult liver and infant brain libraries, were assembled from the same sarcosine dehydrogenase gene by the use of alternate polyadenylation and splice sites [13].
• A full-length cDNA for human sarcosine dehydrogenase was isolated from an adult liver cDNA library [13].
• The human sarcosine dehydrogenase gene is at least 75.3 kb long and located on chromosome 9q34 [13].
• Molecular cloning and tissue distribution of rat sarcosine dehydrogenase [14].

Anatomical context of SARDH

• The islet cells in the patient showed a high activity when examined for SDH [15].
• Next, we examined whether the streptococcal Plr/SDH/GAPDH inhibits the biological effects of C5a on human neutrophils [16].
• COS cells transfected with BPR2 constructs carrying only SCR 1-3 or 1-4 gave similar rosetting behavior [17].
• Together, these results indicate that the multifunctional protein Plr/SDH/GAPDH has additional functions that help S. pyogenes escape detection by the host immune system [16].
• The S bodies themselves exhibited most intense 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) activity but did not exhibit glucose-6-phosphate dehydrogenase (G6PD), NADP-dependent isocitrate dehydrogenase (NADP-ICDH), or succinate dehydrogenase (SDH) activity, confirming histochemically the origin of S bodies in the smooth endoplasmic reticulum [18].

Associations of SARDH with chemical compounds

• In addition, there is a small increase in the intensity of the HDO resonance over the period of the study, which is interpreted to reflect the ultimate oxidation of the labeled sarcosine methyl group via mitochondrial sarcosine dehydrogenase [19].
• Sarcosine dehydrogenase (SarDH) is a mitochondrial flavoenzyme involved in the oxidative degradation of choline to glycine [14].
• Enzymatic properties of dimethylglycine dehydrogenase and sarcosine dehydrogenase from rat liver [20].
• Covalent binding of FAD to SarDH was demonstrated by the observation of strong fluorescence at 530 nm under excitation at 450 nm of the enzyme immunoprecipitated under denaturing conditions from liver extracts [14].
• Also, methoxyacetic acid is a competitive inhibitor of sarcosine dehydrogenase with a Ki of 0.26 mM [20].

Other interactions of SARDH

• When electron transferring flavoprotein and porcine dimethylglycine dehydrogenase or sarcosine dehydrogenase were incubated together in the absence of substrate, a relative molecular mass corresponding to the flavoprotein.electron transferring flavoprotein complex was observed, providing the first direct observation of these mammalian complexes [21].
• Of these proteins, sarcosine dehydrogenase, liver carboxylesterase, peptidyl-prolyl isomerase A, and lamin B1 are considered novel HCC marker candidates [22].

Analytical, diagnostic and therapeutic context of SARDH

• The localization of SarDH immunoreactivity in the mitochondrial matrix was confirmed by Western-blot analysis of purified mitochondrial fractions [14].
• Finally, the tissue distribution of SarDH was investigated by Northern-blot analysis of total RNA and Western-blot analysis of total protein from several rat tissues [14].
• Site-directed mutagenesis in GAS resulting in SDH with altered C-terminal ends, and the removal of uPAR from pharyngeal cells by phosphatidylinositol-phopsholipase C treatment decreased GAS ability to adhere to pharyngeal cells [23].
• We evaluated tubular ultrastructural changes using electron microscopy and estimated spectrophotometrically activity or concentrations of succinate dehydrogenase (SDH), cytochromes a and c, which are components of mitochondrial respiratory chain, on postnatal days 2 and 9 (PD2 and PD9) [24].
• The catalytic zinc atoms in class III (chi) alcohol dehydrogenase (ADH) and sorbitol dehydrogenase (SDH) from human liver have been specifically removed and replaced by cobalt(II) with a new ultrafiltration technique [25].

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2. Regulation of the phosphorylation of human pharyngeal cell proteins by group A streptococcal surface dehydrogenase: signal transduction between streptococci and pharyngeal cells. Pancholi, V., Fischetti, V.A. J. Exp. Med. (1997)
3. The ubiquinone-binding site of the Saccharomyces cerevisiae succinate-ubiquinone oxidoreductase is a source of superoxide. Guo, J., Lemire, B.D. J. Biol. Chem. (2003)
4. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. Benn, D.E., Gimenez-Roqueplo, A.P., Reilly, J.R., Bertherat, J., Burgess, J., Byth, K., Croxson, M., Dahia, P.L., Elston, M., Gimm, O., Henley, D., Herman, P., Murday, V., Niccoli-Sire, P., Pasieka, J.L., Rohmer, V., Tucker, K., Jeunemaitre, X., Marsh, D.J., Plouin, P.F., Robinson, B.G. J. Clin. Endocrinol. Metab. (2006)
5. (r)-, but not (s)-alpha lipoic acid stimulates deficient brain pyruvate dehydrogenase complex in vascular dementia, but not in Alzheimer dementia. Frölich, L., Götz, M.E., Weinmüller, M., Youdim, M.B., Barth, N., Dirr, A., Gsell, W., Jellinger, K., Beckmann, H., Riederer, P. Journal of neural transmission (Vienna, Austria : 1996) (2004)
6. Effect of partial water deprivation and restricted feeding on age-related changes in two enzymes of energy metabolism in the brain of male garden lizards. Das, S., Patnaik, B.K. Archives of gerontology and geriatrics. (1993)
7. A major surface protein on group A streptococci is a glyceraldehyde-3-phosphate-dehydrogenase with multiple binding activity. Pancholi, V., Fischetti, V.A. J. Exp. Med. (1992)
8. Investigation of the role of SDHB inactivation in sporadic phaeochromocytoma and neuroblastoma. Astuti, D., Morris, M., Krona, C., Abel, F., Gentle, D., Martinsson, T., Kogner, P., Neumann, H.P., Voutilainen, R., Eng, C., Rustin, P., Latif, F., Maher, E.R. Br. J. Cancer (2004)
9. 3-Nitropropionic acid (3-NPA) produces hypothermia and inhibits histochemical labeling of succinate dehydrogenase (SDH) in rat brain. Nony, P.A., Scallet, A.C., Rountree, R.L., Ye, X., Binienda, Z. Metabolic brain disease. (1999)
10. A novel lymphocyte toxicity assay to assess drug hypersensitivity syndromes. Neuman, M.G., Malkiewicz, I.M., Shear, N.H. Clin. Biochem. (2000)
11. Plasma sorbitol dehydrogenase in diabetic subjects with or without vascular complications. Sgambato, S., Ceriello, A., Passariello, N., Giuliano, D. Biochemistry and experimental biology. (1979)
12. Phylogenetic analyses of proton-translocating transhydrogenases. Studley, W.K., Yamaguchi, M., Hatefi, Y., Saier, M.H. Microb. Comp. Genomics (1999)
13. Cloning and mapping of the cDNA for human sarcosine dehydrogenase, a flavoenzyme defective in patients with sarcosinemia. Eschenbrenner, M., Jorns, M.S. Genomics (1999)
14. Molecular cloning and tissue distribution of rat sarcosine dehydrogenase. Bergeron, F., Otto, A., Blache, P., Day, R., Denoroy, L., Brandsch, R., Bataille, D. Eur. J. Biochem. (1998)
15. In situ characterization of islets in diabetes with a mitochondrial DNA mutation at nucleotide position 3243. Kobayashi, T., Nakanishi, K., Nakase, H., Kajio, H., Okubo, M., Murase, T., Kosaka, K. Diabetes (1997)
16. Multifunctional glyceraldehyde-3-phosphate dehydrogenase of Streptococcus pyogenes is essential for evasion from neutrophils. Terao, Y., Yamaguchi, M., Hamada, S., Kawabata, S. J. Biol. Chem. (2006)
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18. Spironolactone bodies in aldosteronomas and in the attached adrenals. Enzyme histochemical study of 19 cases of primary aldosteronism and a case of aldosteronism due to bilateral diffuse hyperplasia of the zona glomerulosa. Aiba, M., Suzuki, H., Kageyama, K., Murai, M., Tazaki, H., Abe, O., Saruta, T. Am. J. Pathol. (1981)
19. Metabolism of excess methionine in the liver of intact rat: an in vivo 2H NMR study. London, R.E., Gabel, S.A., Funk, A. Biochemistry (1987)
20. Enzymatic properties of dimethylglycine dehydrogenase and sarcosine dehydrogenase from rat liver. Porter, D.H., Cook, R.J., Wagner, C. Arch. Biochem. Biophys. (1985)
21. Mammalian electron transferring flavoprotein.flavoprotein dehydrogenase complexes observed by microelectrospray ionization-mass spectrometry and surface plasmon resonance. Hoard-Fruchey, H.M., Goetzman, E., Benson, L., Naylor, S., Vockley, J. J. Biol. Chem. (2004)
22. Proteome analysis of hepatocellular carcinoma. Lim, S.O., Park, S.J., Kim, W., Park, S.G., Kim, H.J., Kim, Y.I., Sohn, T.S., Noh, J.H., Jung, G. Biochem. Biophys. Res. Commun. (2002)
23. Group A streptococcal surface GAPDH, SDH, recognizes uPAR/CD87 as its receptor on the human pharyngeal cell and mediates bacterial adherence to host cells. Jin, H., Song, Y.P., Boel, G., Kochar, J., Pancholi, V. J. Mol. Biol. (2005)
24. Tubular mitochondrial alterations in neonatal rats subjected to RAS inhibition. Lasaitiene, D., Chen, Y., Mildaziene, V., Nauciene, Z., Sundelin, B., Johansson, B.R., Yano, M., Friberg, P. Am. J. Physiol. Renal Physiol. (2006)
25. Cobalt(II)-substituted class III alcohol and sorbitol dehydrogenases from human liver. Maret, W. Biochemistry (1989)