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Cystathionine Beta-Synthase (CBS), Genetic Testing

Cystathionine beta-synthase (CBS) catalyzes the condensation of homocysteine with serine to form cystathionine, which is the initial and rate-limiting step in the transsulfuration pathway. Cystathionine is subsequently cleaved by the enzyme cystathionine gamma-lyase (CTH) to form cysteine, a precursor of glutathione. Besides this canonical pathway, CBS also participates in the desulfuration reactions that contribute to endogenous hydrogen sulfide (H2S) production. Thus, CBS acting mainly through control of homocysteine and H2S metabolism exerts diverse biological functions including mitochondrial bioenergetics, redox homeostasis, DNA methylation, and protein modification. Deregulation of CBS and the associated alterations in homocysteine and/or H2S levels leads to a wide range of pathological disturbances in the cardiovascular, immune, and central nervous systems and contributes to disease development. It is now becoming clear that CBS activity also plays an important but complex role in cancer biology.

The human CBS gene, located on chromosome 21 (21q22.3), encodes a protein of 551 amino acids. The catalytic domain of the enzyme encompasses a binding site for another cofactor, pyridoxal-phosphate (PLP). CBS is predominantly expressed in the brain, liver, kidney, and pancreas. It is mainly a cytosolic enzyme, but localization in the nucleus and mitochondria had been detected in specific cell types.

CBS plays a critical role in homocysteine elimination. Patients with CBS deficiency exhibit elevated homocysteine plasma levels.

Homocysteine is a sulfur-containing nonproteinogenic amino acid linked to the metabolism of methionine and cysteine. Methionine is converted to homocysteine via S-adenosyl methionine (SAM) and S-adenosyl homocysteine (SAH), releasing a methyl group that is used in numerous methylation reactions. Homocysteine can reform methionine by the remethylation pathway. Homocysteine is also irreversibly metabolized by CBS to cystathionine that subsequently converts to cysteine via CTH in the transsulfuration pathway. Homocysteine metabolism mainly occurs in the liver and conversion to cystathionine by CBS is a major elimination route of homocysteine.

Hyperhomocysteinemia (HHcy) is recognized as an independent risk factor for atherosclerotic vascular disease. Hyperhomocysteinemia may result from mutations in genes encoding enzymes of homocysteine biosynthesis and metabolism or deficiencies of vitamin cofactors including vitamin B12 and B6. The molecular mechanisms underlying hyperhomocysteinemia-induced atherosclerosis are complex and multifactorial. Elevated homocysteine concentration reduces nitric oxide (NO) bioavailability and causes oxidative stress. 

The CBS gene has a large number of mutations and polymorphisms. The 844ins68 polymorphism at position 844 in the CBS gene disrupts the structure of the protein, causing a reduction in the functional activity of the CBS enzyme. Decreased enzyme activity causes an increase in blood homocysteine and in urine (homocystinuria).

844ins68 polymorphism has also been linked to other diseases, including neural tube defects and cancer.

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