CORRECTION OF DISEASE-CAUSING CBS MUTATIONS IN YEAST

Mutations in cystathionine beta-synthase (CBS) are known to cause homo cystinuria, a recessive disorder characterized by excessive levels of total homocysteine (tHcy) in plasma(1). The primary cause of mortality is thromboembolism induced by the excessive tHcy levels. Mild increas es in tHcy levels are a significant risk factor in the development of vascular disease in the general population(2). This can result from he terozygosity at the CB5 locus or polymorphic variation in other enzyme s involved in homocysteine re-methylation. We report here that a mutat ion which deletes the carboxy-terminal 145 amino acids of CBS can func tionally suppress the phenotype of several CBS mutant alleles found in homocystinurics when expressed in yeast. This C-terminal domain of CB 5 acts to inhibit enzymatic activity and is in turn regulated by S-ade nosylmethionine (AdoMet), a positive effector of CBS. Our results indi cate that most mutations found in homocystinurics do not cause dysfunc tion of the catalytic domain, but rather interfere with the activation of the enzyme. These findings suggest a new drug target to treat homo cystinuria and homocysteine-related vascular disease.