Genomes and Genes
cystathionine beta synthase
Gene Symbol: cystathionine beta synthase
Alias: HIP4, cystathionine beta-synthase, beta-thionase, methylcysteine synthase, serine sulfhydrase
Products: cystathionine beta synthase
- Boyles A, Billups A, Deak K, Siegel D, Mehltretter L, Slifer S, et al. Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions. Environ Health Perspect. 2006;114:1547-52 pubmed
- Golimbet V, Korovaitseva G, Abramova L, Kaleda V. The 844ins68 polymorphism of the cystathionine beta-synthase gene is associated with schizophrenia. Psychiatry Res. 2009;170:168-71 pubmed publisher..In conclusion, our study revealed a possible relation of the CBS 844ins68 polymorphism to schizophrenia. ..
- Shan X, Kruger W. Correction of disease-causing CBS mutations in yeast. Nat Genet. 1998;19:91-3 pubmed..These findings suggest a new drug target to treat homocystinuria and homocysteine-related vascular disease...
- Wang L, Chen X, Tang B, Hua X, Klein Szanto A, Kruger W. Expression of mutant human cystathionine beta-synthase rescues neonatal lethality but not homocystinuria in a mouse model. Hum Mol Genet. 2005;14:2201-8 pubmed..These transgenic animals should be useful in the study of homocysteine related human disease...
- Chen X, Jhee K, Kruger W. Production of the neuromodulator H2S by cystathionine beta-synthase via the condensation of cysteine and homocysteine. J Biol Chem. 2004;279:52082-6 pubmed..In addition, these studies provide a biochemical explanation for the previously inexplicable homocysteine-lowering effects of N-acetylcysteine treatments in humans. ..
- Frank N, Kent J, Meier M, Kraus J. Purification and characterization of the wild type and truncated human cystathionine beta-synthase enzymes expressed in E. coli. Arch Biochem Biophys. 2008;470:64-72 pubmed..The activity of the enzyme was unaffected by the redox status of the heme iron. Finally, we show that CBS is stimulated by S-adenosyl- l-methionine but not its analogs. ..
- Grossmann R, Schwender S, Geisen U, Schambeck C, Merati G, Walter U. CBS 844ins68, MTHFR TT677 and EPCR 4031ins23 genotypes in patients with deep-vein thrombosis. Thromb Res. 2002;107:13-5 pubmed..A putative protective effect of CBS 844ins68 should be further investigated. ..
- Singh L, Kruger W. Functional rescue of mutant human cystathionine beta-synthase by manipulation of Hsp26 and Hsp70 levels in Saccharomyces cerevisiae. J Biol Chem. 2009;284:4238-45 pubmed publisher..Based on these results we propose a novel model in which the ratio of Hsp70 and Hsp26 determines whether misfolded proteins will either be refolded or degraded...
- Pare G, Chasman D, Parker A, Zee R, Malarstig A, Seedorf U, et al. Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma homocysteine in a healthy population: a genome-wide evaluation of 13 974 participants in the Women's Genome Health Study. Circ Cardiovasc Genet. 2009;2:142-50 pubmed publisher..These associations offer new insight into the biochemical pathways involved in homocysteine metabolism and provide opportunities to better delineate the role of homocysteine in health and disease. ..
- Kopecká J, Krijt J, Raková K, Kozich V. Restoring assembly and activity of cystathionine β-synthase mutants by ligands and chemical chaperones. J Inherit Metab Dis. 2011;34:39-48 pubmed publisher..This study identified chaperone-responsive mutants that represent 56 of 713 known patient-derived CBS alleles and may serve as a basis for exploring pharmacological approaches aimed at correcting misfolding in homocystinuria. ..
- Kozich V, Kraus J. Screening for mutations by expressing patient cDNA segments in E. coli: homocystinuria due to cystathionine beta-synthase deficiency. Hum Mutat. 1992;1:113-23 pubmed..This bacterial expression system proved to be a rapid screening method for localizing pathogenic mutations in CBS, allowing us to sequence the affected portions of mutant cDNA within 7-10 days of harvesting cultured fibroblasts...
- Hnizda A, Spiwok V, Jurga V, Kozich V, Kodicek M, Kraus J. Cross-talk between the catalytic core and the regulatory domain in cystathionine ?-synthase: study by differential covalent labeling and computational modeling. Biochemistry. 2010;49:10526-34 pubmed publisher..Subtle differences at CBS surface indicate that enzyme activity is not regulated by conformational conversions but more likely by different allosteric mechanisms. ..
- Majtan T, Liu L, Carpenter J, Kraus J. Rescue of cystathionine beta-synthase (CBS) mutants with chemical chaperones: purification and characterization of eight CBS mutant enzymes. J Biol Chem. 2010;285:15866-73 pubmed publisher..This finding could have direct implications for the development of a therapeutical approach to pyridoxine unresponsive homocystinuria. ..
- Kraus J, Le K, Swaroop M, Ohura T, Tahara T, Rosenberg L, et al. Human cystathionine beta-synthase cDNA: sequence, alternative splicing and expression in cultured cells. Hum Mol Genet. 1993;2:1633-8 pubmed..Lastly, we demonstrate that expression of the human enzyme in CHO cells yields enzymatically active protein of the expected size with a half-life of approximately 14 hrs. ..
- Kery V, Bukovska G, Kraus J. Transsulfuration depends on heme in addition to pyridoxal 5'-phosphate. Cystathionine beta-synthase is a heme protein. J Biol Chem. 1994;269:25283-8 pubmed..These findings suggest that heme is functionally incorporated into CBS only during protein folding. This report describes the first instance of an enzyme that depends upon both heme and PLP for its function. ..
- Zhang G, Dai C. Gene polymorphisms of homocysteine metabolism-related enzymes in Chinese patients with occlusive coronary artery or cerebral vascular diseases. Thromb Res. 2001;104:187-95 pubmed..However, CBS 844ins68 may be a protective factor against vascular thromboembolic disease. The prevalence of CBS 844ins68 and MS A2756G in Chinese population is obviously lower than in Western Caucasian population. ..
- Münke M, Kraus J, Ohura T, Francke U. The gene for cystathionine beta-synthase (CBS) maps to the subtelomeric region on human chromosome 21q and to proximal mouse chromosome 17. Am J Hum Genet. 1988;42:550-9 pubmed..Mice partially trisomic for MMU 16 or MMU 17 should allow gene-specific dissection of the trisomy 21 phenotype. ..
- Kluijtmans L, Boers G, Stevens E, Renier W, Kraus J, Trijbels F, et al. Defective cystathionine beta-synthase regulation by S-adenosylmethionine in a partially pyridoxine responsive homocystinuria patient. J Clin Invest. 1996;98:285-9 pubmed..Furthermore, it indicates the importance of S-adenosylmethionine regulation of the transsulfuration pathway in homocysteine homeostasis in humans...
- Hu F, Gu Z, Kozich V, Kraus J, Ramesh V, Shih V. Molecular basis of cystathionine beta-synthase deficiency in pyridoxine responsive and nonresponsive homocystinuria. Hum Mol Genet. 1993;2:1857-60 pubmed..This missense mutation was detected in one allele of a pyridoxine nonresponsive patient and in both alleles of a pyridoxine responsive patient. The latter suggests that I278T is probably associated with pyridoxine responsiveness...
- Kraus J. Komrower Lecture. Molecular basis of phenotype expression in homocystinuria. J Inherit Metab Dis. 1994;17:383-90 pubmed..Using this method we identified the first 14 mutations in homocystinuria. The most common mutation in patients of predominantly 'Celtic' origin is the G919A transition which substitutes serine for glycine 307. ..
- Kruger W, Cox D. A yeast system for expression of human cystathionine beta-synthase: structural and functional conservation of the human and yeast genes. Proc Natl Acad Sci U S A. 1994;91:6614-8 pubmed..These results demonstrate the evolutionary conservation of CBS and establish the utility of a yeast expression system for studying human CBS. ..
- Singh L, Chen X, Kozich V, Kruger W. Chemical chaperone rescue of mutant human cystathionine beta-synthase. Mol Genet Metab. 2007;91:335-42 pubmed
- Kraus J, Oliveriusova J, Sokolova J, Kraus E, Vlcek C, de Franchis R, et al. The human cystathionine beta-synthase (CBS) gene: complete sequence, alternative splicing, and polymorphisms. Genomics. 1998;52:312-24 pubmed..Additionally, we report on a number of DNA sequence repeats that are polymorphic in North American and European Caucasians. ..
- Meier M, Janosik M, Kery V, Kraus J, Burkhard P. Structure of human cystathionine beta-synthase: a unique pyridoxal 5'-phosphate-dependent heme protein. EMBO J. 2001;20:3910-6 pubmed..This heme binding motif together with a spatially adjacent oxidoreductase active site motif could explain the regulation of its enzyme activity by redox changes. ..
- Linnebank M, Homberger A, Junker R, Nowak Goettl U, Harms E, Koch H. High prevalence of the I278T mutation of the human cystathionine beta-synthase detected by a novel screening application. Thromb Haemost. 2001;85:986-8 pubmed..800. Our data indicate that homocystinuria due to cystathionine beta-synthase deficiency is a frequently unrecognized disorder resulting in a high risk of thromboembolic events...
- Janosik M, Meier M, Kery V, Oliveriusova J, Burkhard P, Kraus J. Crystallization and preliminary X-ray diffraction analysis of the active core of human recombinant cystathionine beta-synthase: an enzyme involved in vascular disease. Acta Crystallogr D Biol Crystallogr. 2001;57:289-91 pubmed..The truncated CBS yielded crystals diffracting to 2.6 A which belong to space group P3(1) or P3(2). This is the first comprehensive structural investigation of a PLP and heme-containing enzyme. ..
- Taoka S, Lepore B, Kabil O, Ojha S, Ringe D, Banerjee R. Human cystathionine beta-synthase is a heme sensor protein. Evidence that the redox sensor is heme and not the vicinal cysteines in the CXXC motif seen in the crystal structure of the truncated enzyme. Biochemistry. 2002;41:10454-61 pubmed
- Sokolova J, Janosikova B, Terwilliger J, Freiberger T, Kraus J, Kozich V. Cystathionine beta-synthase deficiency in Central Europe: discrepancy between biochemical and molecular genetic screening for homocystinuric alleles. Hum Mutat. 2001;18:548-9 pubmed..In conclusion, homocystinuria in Central Europe may be sufficiently common to consider sensitive newborn screening programs for this disease...
- Aléssio A, Siqueira L, Bydlowski S, Hoehr N, Annichino Bizzacchi J. Polymorphisms in the CBS gene and homocysteine, folate and vitamin B12 levels: association with polymorphisms in the MTHFR and MTRR genes in Brazilian children. Am J Med Genet A. 2008;146A:2598-602 pubmed publisher..034). Since B(12) and folate were not different between these groups, a genetic interaction between diverse polymorphisms probably influences Hcy. Our results emphasize the role of genetic interactions in Hcy levels. ..
- Butler C, Knox A, Bowersox J, Forbes S, Patterson D. The production of transgenic mice expressing human cystathionine beta-synthase to study Down syndrome. Behav Genet. 2006;36:429-38 pubmed..They can also be used to develop therapies that target abnormalities in 1C-TS metabolism to improve cognition in persons with DS. ..
- Sebastio G, Sperandeo M, Panico M, de Franchis R, Kraus J, Andria G. The molecular basis of homocystinuria due to cystathionine beta-synthase deficiency in Italian families, and report of four novel mutations. Am J Hum Genet. 1995;56:1324-33 pubmed..Mutations A114V and I278T are carried by three and by seven independent alleles, respectively. The other four mutations--including G307S and A1224-2C, common among northern European patients--have not been detected...
- Kozich V, Sokolova J, Klatovská V, Krijt J, Janosik M, Jelínek K, et al. Cystathionine beta-synthase mutations: effect of mutation topology on folding and activity. Hum Mutat. 2010;31:809-19 pubmed publisher..In summary, our results show that topology of mutations predicts in part the behavior of mutant CBS, and that misfolding may be an important and frequent pathogenic mechanism in CBS deficiency. ..
- Dawson P, Cox A, Emmerson B, Dudman N, Kraus J, Gordon R. Characterisation of five missense mutations in the cystathionine beta-synthase gene from three patients with B6-nonresponsive homocystinuria. Eur J Hum Genet. 1997;5:15-21 pubmed..All of the mutant proteins exhibited decreased catalytic activity in vitro, which confirmed the association between the individual mutation and CBS dysfunction in each patient...
- Kim C, Gallagher P, Guttormsen A, Refsum H, Ueland P, Ose L, et al. Functional modeling of vitamin responsiveness in yeast: a common pyridoxine-responsive cystathionine beta-synthase mutation in homocystinuria. Hum Mol Genet. 1997;6:2213-21 pubmed..These studies show that the G797A mutation is an important cause of pyridoxine-responsive CBS deficiency and demonstrate the utility of yeast functional assays in the analysis of human mutations...
- Hnizda A, Majtan T, Liu L, Pey A, Carpenter J, Kodicek M, et al. Conformational properties of nine purified cystathionine β-synthase mutants. Biochemistry. 2012;51:4755-63 pubmed publisher..This study demonstrates that the proteolytic techniques are useful tools for the assessment of the biochemical penalty of missense mutations in CBS. ..
- Evande R, Blom H, Boers G, Banerjee R. Alleviation of intrasteric inhibition by the pathogenic activation domain mutation, D444N, in human cystathionine beta-synthase. Biochemistry. 2002;41:11832-7 pubmed..e., wild-type enzyme as isolated), "activated" (wild-type enzyme + AdoMet or the D444N mutant as isolated), and superactivated (D444N mutant + AdoMet or wild-type enzyme lacking the C-terminal regulatory domain). ..
- Giusti B, Saracini C, Bolli P, Magi A, Martinelli I, Peyvandi F, et al. Early-onset ischaemic stroke: analysis of 58 polymorphisms in 17 genes involved in methionine metabolism. Thromb Haemost. 2010;104:231-42 pubmed publisher..This study identifies significant genetic associations between premature ischaemic stroke and haplotypes in BHMT, CBS, FOLH1, MTR, PON2, TCN2 and TYMS genes involved in methionine metabolism. ..
- Marble M, Geraghty M, de Franchis R, Kraus J, Valle D. Characterization of a cystathionine beta-synthase allele with three mutations in cis in a patient with B6 nonresponsive homocystinuria. Hum Mol Genet. 1994;3:1883-6 pubmed..The apparently simultaneous appearance of more than one mutation in a single exon suggests they may have arisen by a gene conversion event or by nonhomologous recombination...
- Janosik M, Oliveriusova J, Janosikova B, Sokolova J, Kraus E, Kraus J, et al. Impaired heme binding and aggregation of mutant cystathionine beta-synthase subunits in homocystinuria. Am J Hum Genet. 2001;68:1506-13 pubmed..These data suggest that abnormal folding, impaired heme binding, and aggregation of mutant CBS polypeptides may be common pathogenic mechanisms in CBS deficiency...
- Gordon R, Cox A, Dawson P, Emmerson B, Kraus J, Dudman N. Mutational analysis of the cystathionine beta-synthase gene: a splicing mutation, two missense mutations and an insertion in patients with homocystinuria. Mutations in brief no. 120. Online. Hum Mutat. 1998;11:332 pubmed..Expression of recombinant CBS protein, containing the C165Y mutation, had no detectable catalytic activity. Each mutation was confirmed in genomic DNA...
- Ott N, Geddert H, Sarbia M. Polymorphisms in methionine synthase (A2756G) and cystathionine beta-synthase (844ins68) and susceptibility to carcinomas of the upper gastrointestinal tract. J Cancer Res Clin Oncol. 2008;134:405-10 pubmed..6%). The gene allele constellation I/I was not present. The current study suggests that there is no association between MTR A2756G polymorphism and the CBS (844ins68) insertion polymorphism and cancer of the upper gastrointestinal tract. ..
- Maclean K, Gaustadnes M, Oliveriusova J, Janosik M, Kraus E, Kozich V, et al. High homocysteine and thrombosis without connective tissue disorders are associated with a novel class of cystathionine beta-synthase (CBS) mutations. Hum Mutat. 2002;19:641-55 pubmed
- Song X, Zheng X, Zhu W, Huang L, Li Y. Relationship between polymorphism of cystathionine beta synthase gene and congenital heart disease in Chinese nuclear families. Biomed Environ Sci. 2006;19:452-6 pubmedTo study the relationship between polymorphism of cystathionine beta synthase (CBS) gene and development of congenital heart disease (CHD)...
- Kozich V, de Franchis R, Kraus J. Molecular defect in a patient with pyridoxine-responsive homocystinuria. Hum Mol Genet. 1993;2:815-6 pubmed
- Le Marchand L, Donlon T, Hankin J, Kolonel L, Wilkens L, Seifried A. B-vitamin intake, metabolic genes, and colorectal cancer risk (United States). Cancer Causes Control. 2002;13:239-48 pubmed..Our data also suggest that the relationships between CRC and the MTHFR A1298C and CBS 844ins68 polymorphisms warrant further study. ..
- Kruger W, Cox D. A yeast assay for functional detection of mutations in the human cystathionine beta-synthase gene. Hum Mol Genet. 1995;4:1155-61 pubmed..Our results also demonstrate that the yeast CBS assay can detect a large percentage of individuals heterozygous for mutations in CBS. This system should be useful in determining the relationship between CBS mutations and human disease...
- de Franchis R, Kraus E, Kozich V, Sebastio G, Kraus J. Four novel mutations in the cystathionine beta-synthase gene: effect of a second linked mutation on the severity of the homocystinuric phenotype. Hum Mutat. 1999;13:453-7 pubmed..In this context, a search for additional mutations in cis may sometimes be necessary to establish a good genotype-phenotype relationship...
- Kraus J, Janosik M, Kozich V, Mandell R, Shih V, Sperandeo M, et al. Cystathionine beta-synthase mutations in homocystinuria. Hum Mutat. 1999;13:362-75 pubmed..Mutations due to deaminations of methylcytosines represent 53% of all point substitutions in the coding region of the CBS gene...
- Li Y, Cheng J, Zhu W, Dao J, Yan L, Li M, et al. [Study of serum Hcy and polymorphisms of Hcy metabolic enzymes in 192 families affected by congenital heart disease]. Beijing Da Xue Xue Bao Yi Xue Ban. 2005;37:75-80 pubmed..68 bp insertion at exon 8 of CBS gene base 844 could be a risk factor for CHD, and the insertion in parents (especially in mothers) could increase CHD risk in offspring. ..
- Griffioen P, de Jonge R, van Zelst B, Montserrate Brouns R, Lindemans J. Detection and allele-frequencies of the 833T>C, 844ins68 and a novel mutation in the cystathionine beta-synthase gene. Clin Chim Acta. 2005;354:191-4 pubmedThe most common 833T>C/844ins68 in cis double mutation in the cystathionine beta synthase (CBS) gene probably is non-pathogenic because the 68-bp insertion eliminates the 833T>C mutation due to alternative splicing...
- Singh L, Gupta S, Honig N, Kraus J, Kruger W. Activation of mutant enzyme function in vivo by proteasome inhibitors and treatments that induce Hsp70. PLoS Genet. 2010;6:e1000807 pubmed publisher..These findings suggest that proteasome inhibitors and other Hsp70 inducing agents may be useful in the treatment of a variety of genetic diseases caused by missense mutations. ..
- Ichinohe A, Kanaumi T, Takashima S, Enokido Y, Nagai Y, Kimura H. Cystathionine beta-synthase is enriched in the brains of Down's patients. Biochem Biophys Res Commun. 2005;338:1547-50 pubmed..The over-expression of CBS may cause the developmental abnormality in cognition in DS children and that may lead to AD in DS adults. ..
- Carballal S, Cuevasanta E, Marmisolle I, Kabil O, Gherasim C, Ballou D, et al. Kinetics of reversible reductive carbonylation of heme in human cystathionine ?-synthase. Biochemistry. 2013;52:4553-62 pubmed publisher..Reversible reduction of CBS by a physiologically relevant oxidoreductase is consistent with a regulatory role for the heme and could constitute a mechanism for cross talk among the CO, H2S, and superoxide signaling pathways. ..
- Janosik M, Sokolova J, Janosíková B, Krijt J, Klatovská V, Kozich V. Birth prevalence of homocystinuria in Central Europe: frequency and pathogenicity of mutation c.1105C>T (p.R369C) in the cystathionine beta-synthase gene. J Pediatr. 2009;154:431-7 pubmed publisher..To estimate the frequency of the cystathionine beta-synthase deficiency caused by c.1105C>T mutation in Central Europe compared to Norway, and to examine the pathogenicity of the corresponding p.R369C mutant enzyme...
- Sen S, Banerjee R. A pathogenic linked mutation in the catalytic core of human cystathionine beta-synthase disrupts allosteric regulation and allows kinetic characterization of a full-length dimer. Biochemistry. 2007;46:4110-6 pubmed..Furthermore, analysis of individual single mutations has permitted, for the first time, partial kinetic characterization of a full-length dimeric form of human cystathionine beta-synthase. ..
- Kraus J, Packman S, Fowler B, Rosenberg L. Purification and properties of cystathionine beta-synthase from human liver. Evidence for identical subunits. J Biol Chem. 1978;253:6523-8 pubmed..It is possesses serine sulfhydrase as well as cystathionine synthase activity. It has a broad pH optimum from 8.4 to 9...
- Ereño Orbea J, Majtan T, Oyenarte I, Kraus J, Martinez Cruz L. Structural insight into the molecular mechanism of allosteric activation of human cystathionine β-synthase by S-adenosylmethionine. Proc Natl Acad Sci U S A. 2014;111:E3845-52 pubmed publisher..The structure described herein paves the way for the rational design of compounds modulating hCBS activity and thus transsulfuration, redox status, and H2S biogenesis. ..
- Kim J, Hong S, Park J, Park S, Kim S, Cho E, et al. Expression of cystathionine beta-synthase is downregulated in hepatocellular carcinoma and associated with poor prognosis. Oncol Rep. 2009;21:1449-54 pubmed..0042) after considering tumor stage and tumor size. Thus, the expression level of CBS mRNA could be useful to predict clinical outcome of HCC, especially for patients with low AFP levels. ..
- Frank N, Kery V, Maclean K, Kraus J. Solvent-accessible cysteines in human cystathionine beta-synthase: crucial role of cysteine 431 in S-adenosyl-L-methionine binding. Biochemistry. 2006;45:11021-9 pubmed
- Oliveriusova J, Kery V, Maclean K, Kraus J. Deletion mutagenesis of human cystathionine beta-synthase. Impact on activity, oligomeric status, and S-adenosylmethionine regulation. J Biol Chem. 2002;277:48386-94 pubmed
- Botto L, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol. 2000;151:862-77 pubmed..Studies of the C677T allele in relation to oral clefts, Down syndrome, and fetal anticonvulsant syndrome either have yielded conflicting results or have not been yet replicated. ..