Author(s): Jhee KH, Kruger WD
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Abstract Cystathionine beta-synthase (CBS) is the first enzyme in the transsulfuration pathway, catalyzing the conversion of serine and homocysteine to cystathionine and water. The enzyme contains three functional domains. The middle domain contains the catalytic core, which is responsible for the pyridoxal phosphate-catalyzed reaction. The C-terminal domain contains a negative regulatory region that is responsible for allosteric activation of the enzyme by S-adenosylmethionine. The N-terminal domain contains heme, and this domain regulates the enzyme in response to redox conditions. Besides its canonical reaction, CBS can catalyze alternative reactions that produce hydrogen sulfide, a novel neuromodulator in the brain. Mutations in human CBS result in homocystinuria, an autosomal recessive disorder characterized by defects in a variety of different organ systems. The most common CBS allele is 833T>C (I278T), which is associated with pyridoxine-responsive homocystinuria. A complementation system in S. cerevisiae has been developed for analysis of human CBS mutations. Using this system, it has been discovered that deletion of the C-terminal domain of CBS can suppress the functional defects of many patient-derived mutations. This finding suggests it may be possible to develop drugs that interact with the C-terminal domain of CBS to treat elevated homocysteine in humans.
This article was published in Antioxid Redox Signal
and referenced in Biochemistry & Physiology: Open Access