Disease relevance of CYS4

• Mutations in cystathionine beta-synthase (CBS) are known to cause homocystinuria, a recessive disorder characterized by excessive levels of total homocysteine (tHcy) in plasma [1].
• We report methods that yielded high expression of the yeast gene in Escherichia coli and of purified yeast cystathionine beta-synthase [2].

Psychiatry related information on CYS4

• Moreover, in the case of the other strain, higher levels of enzymes required for sulfur metabolism (Cys4p, Hom6p, and Met22p) are observed, which could be related to the production of particular organoleptic compounds or to detoxification processes [3].

High impact information on CYS4

• This can result from heterozygosity at the CBS locus or polymorphic variation in other enzymes involved in homocysteine re-methylation [1].
• This C-terminal domain of CBS acts to inhibit enzymatic activity and is in turn regulated by S-adenosylmethionine (AdoMet), a positive effector of CBS [1].
• We report here that a mutation which deletes the carboxy-terminal 145 amino acids of CBS can functionally suppress the phenotype of several CBS mutant alleles found in homocystinurics when expressed in yeast [1].
• We have isolated the samB gene (suppressor of anucleate metulae) of Aspergillus nidulans which encodes a 66 kDa protein carrying an atypical Cys4 and an additional Cys2/His/Cys Zn finger motif at the carboxy-terminus [4].
• By screening based on these phenotypes and the inability of vma mutants to accumulate the lysosomotropic dye quinacrine in their vacuoles, five new vma complementation groups (vma41 to vma45) were identified [5].

Chemical compound and disease context of CYS4

• The most common CBS allele is 833T>C (I278T), which is associated with pyridoxine-responsive homocystinuria [6].

Biological context of CYS4

• The CYS4 gene was deleted in a strain in which the catalytic site cysteine residue implicated in oxidative inhibition of the yeast V-ATPase has been mutagenized (Liu, Q., Leng, X.-H., Newman, P., Vasilyeva, E., Kane, P. M., and Forgac, M. (1997) J. Biol. Chem. 272, 11750-11756) [7].
• The N-terminal amino acid sequence of the enzyme perfectly coincided with that deduced from the nucleotide sequence of CYS4, except for the absence of initiation The purified beta-CTSase catalysed cysteine synthesis from serine (or O-acetylserine) and H2S [8].
• A DNA fragment containing the CYS4 gene of Saccharomyces cerevisiae was isolated from a genomic library [9].
• According to the 2 microns DNA chromosome-loss procedure, the cys2 and cys4 mutations, which are linked together and co-operatively confer cysteine dependence, were assigned to chromosome VII [9].
• This catalytic site point mutation suppresses the effects of the cys4 mutation [7].

Anatomical context of CYS4

• In addition, we have used the yeast CBS assay to identify eight mutant CBS alleles in cell lines from patients with CBS deficiency [10].
• The data indicate that the acidification defect of cys4 mutants arises from inactivation of the vacuolar ATPase in the less reducing cytosol resulting from loss of Cys4p activity and provide the first evidence for the modulation of V-ATPase activity by the redox state of the environment in vivo [7].

Associations of CYS4 with chemical compounds

• The introduction of genes from Sac. cerevisiae constituting the cystathionine pathway (CYS4 and CYS3) into Sch. pombe Deltamet26 cells restored growth in the absence of adenine [11].
• The repressive effect of methionine was not observed, however, in a cys2 cys4 strain which is deficient of serine O-acetyltransferase and cystathionine beta-synthase, indicating that methionine itself is not the effector [12].
• Yeast cystathionine beta-synthase is a pyridoxal phosphate enzyme but, unlike the human enzyme, is not a heme protein [2].
• Schizosaccharomyces pombe, in contrast to Saccharomyces cerevisiae and Aspergillus nidulans, lacks cystathionine beta-synthase and cystathionine gamma-lyase, two enzymes in the pathway from methionine to cysteine [13].
• The elevated synthesis of glutathione could be associated with the increased levels of cysteine which in its turn was found to be controlled by the oxygen-dependent activation of cystathionine beta-synthase [14].

Other interactions of CYS4

• Using a Saccharomyces cerevisiae strain having the activities of serine O-acetyl-transferase (SATase), O-acetylserine/O-acetylhomoserine sulphydrylase (OAS/OAH SHLase), cystathionine beta-synthase (beta-CTSase) and cystathionine gamma-lyase (gamma-CTLase), we individually disrupted CYS3(coding for gamma-CTLase) and CYS4 (coding for beta-CTSase) [15].
• By further mapping involving tetrad analysis, the cys2-cys4 pair was localized between SUP77 (SUP166) and ade3 on the right arm of chromosome VII [9].
• Molecular characterization of a cystathionine beta-synthase gene, CBS1, in Magnaporthe grisea [16].
• We compare our results with cystathionine beta-synthase with those of related investigations of tryptophan synthase and O-acetylserine sulfhydrylase [17].

Analytical, diagnostic and therapeutic context of CYS4

• The absorption and circular dichroism spectra of the homogeneous enzyme were characteristic of a pyridoxal phosphate enzyme and showed the absence of heme, which is found in human and rat cystathionine beta-synthase [2].
• CBS activity assays and Western blotting indicated that growth-specific regulation of CBS is evolutionarily conserved in a range of human cell lines [18].
• Analysis by electrospray ionization mass spectrometry showed that further trypsin treatment cleaves CBS in its COOH-terminal region at Arg 413 to yield 45-kDa subunits [19].
• Sensitive determination of cystathionine and assays for cystathionine beta- and gamma-lyase, as well as cystathionine beta-synthase, using high-performance liquid chromatography [20].

References