Mutations in cystathionine beta-synthase (CBS) are known to cause homocystinuria, a recessive disorder characterized by excessive levels of total homocysteine (tHcy) in plasma. The primary cause of mortality is thromboembolism induced by the excessive tHcy levels. Mild increases in tHcy levels are a significant risk factor in the development of vascular disease in the general population. This can result from heterozygosity at the CBS locus or polymorphic variation in other enzymes involved in homocysteine re-methylation. 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. 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. Our results indicate that most mutations found in homocystinurics do not cause dysfunction of the catalytic domain, but rather interfere with the activation of the enzyme. These findings suggest a new drug target to treat homocystinuria and homocysteine-related vascular disease.
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Evidence ID | Analyze ID | Gene/Complex | Systematic Name/Complex Accession | Qualifier | Gene Ontology Term ID | Gene Ontology Term | Aspect | Annotation Extension | Evidence | Method | Source | Assigned On | Reference |
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Evidence ID | Analyze ID | Gene | Gene Systematic Name | Phenotype | Experiment Type | Experiment Type Category | Mutant Information | Strain Background | Chemical | Details | Reference |
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Evidence ID | Analyze ID | Gene | Gene Systematic Name | Disease Ontology Term | Disease Ontology Term ID | Qualifier | Evidence | Method | Source | Assigned On | Reference |
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Evidence ID | Analyze ID | Regulator | Regulator Systematic Name | Target | Target Systematic Name | Direction | Regulation of | Happens During | Regulator Type | Direction | Regulation Of | Happens During | Method | Evidence | Strain Background | Reference |
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Site | Modification | Modifier | Source | Reference |
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Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Allele | Assay | Annotation | Action | Phenotype | SGA score | P-value | Source | Reference | Note |
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Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Assay | Annotation | Action | Modification | Source | Reference | Note |
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Complement ID | Locus ID | Gene | Species | Gene ID | Strain background | Direction | Details | Source | Reference |
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Evidence ID | Analyze ID | Dataset | Description | Keywords | Number of Conditions | Reference |
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