Disease relevance of CBS

• Mutations in CBS are the most common cause of severe hereditary hyperhomocysteinemia [1].
• Gene-gene interaction between the cystathionine beta-synthase 31 base pair variable number of tandem repeats and the methylenetetrahydrofolate reductase 677C > T polymorphism on homocysteine levels and risk for neural tube defects [2].
• The methionine-synthase-reductase A66G, the methionine-synthase A2756G and the cystathionine-beta-synthase 844ins68 polymorphisms were not associated with increased risk of Down syndrome [3].
• CBS deficiency is associated with homocystinuria, which is known to affect various physiological systems, including the central nervous system [4].
• A major complication in CBS deficiency is deep venous thrombosis or pulmonary embolism [5].

Psychiatry related information on CBS

• It has been suggested that Huntington's disease involves the action of excitotoxic amino acids and this interaction with CBS may suggest a mechanism for such excitotoxic damage [4].
• Cystathionine beta-synthase (CBS) is encoded on chromosome 21 and deficiency in its activity causes homocystinuria, the most common inborn error of sulfur amino acid metabolism and characterized by mental retardation and vascular disease [6].
• Only two diseases characterized by alterations of hydrogen sulfide metabolism have been described: decreased hydrogen sulfide synthesis in the brains of Alzheimer's disease patients and increased hydrogen sulfide synthesis due to the overexpression of CBS in Down syndrome patients [7].
• Spatial and temporal expression of the cystathionine beta-synthase gene during early human development [8].

High impact information on CBS

• Homocystinuria due to cystathionine beta-synthase deficiency was confirmed by quantitative amino acid analyses [9].
• BACKGROUND: Mental retardation and other disabilities (including ectopia lentis, osteoporosis, and thromboembolism) in patients who have homocystinuria as a result of a deficiency of cystathionine beta-synthase can be prevented by the screening of newborns with measurement of blood methionine, followed by the early treatment of affected infants [9].
• The presence of cystathionine beta-synthase deficiency was confirmed in 18 of 23 patients with vascular disease who had hyperhomocysteinemia [10].
• Hyperhomocysteinemia is an independent risk factor for vascular disease, including coronary disease, and in most instances is probably due to cystathionine beta-synthase deficiency [10].
• A new study establishes that Bateman domains bind adenosyl compounds and regulate IMP dehydrogenase, CBS, chloride channels, and AMP-activated protein kinase [11].

Chemical compound and disease context of CBS

• Among the IBD patients the only independent factor significantly associated with hyperhomocysteinemia was folate deficiency (p = 0.0002), regardless of the MTHFR or the CBS genotype [12].
• Early studies on patients with vascular disease described elevated Hcy concentrations after methionine loading and decreased CBS activity, resembling heterozygotes for CBS deficiency [13].
• The mutation was introduced in an E. coli expression system and CBS activities were measured after addition of different S-adenosylmethionine concentrations (0-200 microM) [14].
• We determined the molecular basis of cystathionine beta-synthase (CBS) deficiency in a partially pyridoxine-responsive homocystinuria patient [14].
• Furthermore, diminished CBS levels are associated with reduced cell viability in hepatoma cells challenged with tert-butyl hydroperoxide [15].

Biological context of CBS

• The molecular basis of the organ-specific pathologies associated with CBS deficiency is unknown as is the significance of the reported interaction between CBS and Huntingtin protein [1].
• We screened genomic DNA of 88 NBD patients, 100 mothers, 88 fathers, and 505 controls for this CBS 31 bp VNTR [2].
• We have examined four apparently non-functional polymorphisms in the CBS gene and have determined their frequency, degree of linkage disequilibrium and association with plasma homocysteine levels [16].
• Because of both the high prevalence of the 833T-->C mutation among homozygotes for CBS deficiency and its absence in 60 cardiovascular patients, we may conclude that heterozygosity for CBS deficiency does not appear to be involved in premature cardiovascular disease [17].
• The results of this study with clinically relevant cell line models suggest potential mechanisms for disparate patterns of CBS gene expression in DS and non-DS myeloblasts and may, in part, explain the greater sensitivity to chemotherapy shown by patients with DS AML [18].

Anatomical context of CBS

• Sumoylated CBS is present in the nucleus where it is associated with the nuclear scaffold [1].
• Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid [19].
• In conclusions, hyperhomocysteinemia is common in patients with atheromatous renal artery stenosis; a subclinical folate deficiency seems to be involved, regardless of MTHFR thermolabile or CBS insertion genotypes [20].
• The effect of glucose and insulin on the activity of methylene tetrahydrofolate reductase and cystathionine-beta-synthase: studies in hepatocytes [21].
• Genetic variation of the methylenetetrahydrofolate reductase and cystathionine beta-synthase genes in Korean patients with coronary artery disease and a new polymorphism in intron 7 [22].

Associations of CBS with chemical compounds

• The endogenous H(2)S donor L-cysteine also induced secretion that was diminished significantly by capsaicin desensitization, the CBS inhibitor amino-oxyacetic acid, and the CSE inhibitor propargylglycine [23].
• Cystathionine beta-synthase (CBS) catalyzes the first irreversible step in the transsulfuration pathway and commits the toxic metabolite, homocysteine, to the synthesis of cysteine [1].
• These data demonstrate that variation in the CBS gene as detected with these four polymorphisms, had no statistically significant effect on plasma homocysteine levels in these healthy young men [16].
• Recently, our group showed that a 31 bp VNTR in the CBS gene was associated with decreased CBS activity and increased tHcy levels after methionine loading in a CVD population [2].
• Homocysteine can be irreversibly converted to cystathionine by the vitamin B6-dependent enzyme CBS [2].
• CBS is predicted to be virtually the sole source of lanthionine, and CSE, but not CBS, efficiently cleaves lanthionine [24].

Physical interactions of CBS

• Huntingtin interacts with cystathionine beta-synthase [4].

Enzymatic interactions of CBS

• It suffers two major metabolic fates: transmethylation catalyzed by methionine synthase or betaine homocysteine methyl transferase and transsulfuration catalyzed by cystathionine beta-synthase leading to cystathionine [25].

Regulatory relationships of CBS

• The gastrin/CCK receptor antagonist dibutyryl cGMP inhibited the proliferation of two human colon carcinoma cell lines HCT 116 (EC50 = 1.3 mM) and CBS (EC50 = 2.5 mM) in a dose-dependent manner [26].
• We have shown that oxidative stress of H2O2 could increase the flux of this transsulfuration pathway by committing more homocysteine to cysteine and glutathione production as H2O2 (0.1 mM) inhibited the remethylation enzyme of methionine synthase while concurrently activating the CBS enzyme [27].

Other interactions of CBS

• Subsequent quantitative analysis of CBS and PDXK revealed levels comparable between DS and controls [28].
• RESULTS: Two variants, the CBS 844ins68 polymorphism and NOS3 894T homozygosity, were associated with a change in IQ scores (p = 0.01 and 0.007, respectively) [29].
• We demonstrate that CBS is modified by the small ubiquitin-like modifier-1 protein (SUMO-I) under both in vitro and in vivo conditions [1].
• Heterozygosity for T833C mutation in the CBS gene was observed in 9.99% (2/22) of our patients with HCA [30].
• Cystathionine beta synthase as a risk factor for Alzheimer disease [31].

Analytical, diagnostic and therapeutic context of CBS

• Heterozygosity for the 833T-->C mutation in the CBS gene was observed in one individual of the control group but was absent in patients with premature cardiovascular disease [17].
• METHODS: Subjects were genotyped for MTHFR using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and PCR-restriction fragment length polymorphism (PCR-RFLP) techniques, and for CBS using PCR [32].
• We suggest a simple epidemiologic approach to explore gene-gene interactions, and use it to reevaluate data from a recent case-control study on the possible association of neural tube defects (NTDs) with specific mutations of two genes, 5,10-methylene-tetrahydrofolate reductase (MTHFR) and cystathionine-beta synthase (CBS) [33].
• Plasma homocysteine, MTHFR C677T, CBS 844ins68bp, and MTHFD1 G1958A polymorphisms in spontaneous cervical artery dissections [34].
• The association of MTHFR and CBS variants with the doubling time and responsiveness to several chemodrugs was analyzed in 26 human cancer xenografts [35].

References