Cystathionine β synthase —Creative Enzymes

Background Cystathionine-β-synthase, also known as CBS enzyme, is an enzyme (EC ) that in humans is encoded by the CBS gene. CBS uses the cofactor pyridoxal-phosphate (PLP) and can be allosterically regulated by effectors such as the ubiquitous cofactor S-adenosyl-L-methionine (adoMet). This enzyme belongs to the family of lyases, to be specific, the hydro-lyases, which cleave carbon-oxygen bonds. CBS is a multidomain enzyme composed of an N-terminal enzymatic domain and two CBS domains. The CBS gene is the most common locus for mutations associated with homocystinuria.CBS enzyme

Structure CBS is localized to the cytoplasm and is a homotetramer composed by 63 kDa subunits. CBS is a haemoglobin protein belonging to the β family of pyridoxal phosphate (PLP)- dependent enzymes. Each subunit binds to the two cofactors: haemoglobin and PLP. Human CBS includes a haemoglobin-binding region, a highly conserved catalytic domain, and a regulatory domain. Haemoglobin binds to the first 70 amino acid residues at the N-terminus, where Cys52 and His65 are heme iron-binding residues. The highly conserved catalytic domain is located at amino acid residues 40 to 413 and can form a 45 kDa active center. The Lys119 residue in this region is a PLP-binding residue, and PLP is a requisite for the CBS catalyzed reaction.

Catalytic Mechanism Hcy is a sulfur-containing amino acid, which is formed by the demethylation of methionine, and its metabolism has two pathways of transsulfuration and methylation. CBS is a key enzyme in the transsulfuration pathway. Under the participation of PLP as a coenzyme, CBS catalyzes the β-substitution reaction, which mediates the condensation of Hcy and serine to generate cystathionine. Cystathionine is further converted to cysteine α-ketobutyric acid by the action of cystathionine-γ-lyase (CSE). In the human body, about 53% of Hcy is irreversibly converted into cysteine by CBS and CSE. The methylation pathway is that Hcy re- synthesizes methionine with the aid of folic acid and VitB 12. The above two pathways mainly rely on AdoMet concentration to coordinate roughly balance, and the decrease of CBS activity may lead to HHcy caused by the failure of the transsulfuration pathway.

Influencing Factors First, allosteric activators. AdoMet is an allosteric activator of CBS that increases its activity by 2 to 5 fold. The activation mechanism may be related to the spatial conformational change of self-inhibitory regions in the C-terminal regulatory domain where AdoMet induces. Second, the cofactors. Haemoglobin is a redox sensor, and its redox state can result in changes of CBS activity. Therefore, cofactors that can cause changes in the redox state of hemoglobin can affect CBS activity. Third, gene mutations of CBS. Mutations in the CBS gene can cause changes in the stability of the enzyme, the binding of the enzyme to the cofactor and the substrate, and the disruption of the regulation of the allosteric agents, thereby affecting the enzyme activity. So far, 132 CBS gene mutations have been found, mostly in exon 3 and exon 8. Most of them are missense mutations, followed by deletion mutations, insertion mutations, and splicing mutations.

Mutations in the CBS gene cause the decrease of CBS activity and the formation of HHcy, and HHcy participates in the formation of AS. At present, most clinical and epidemiological studies have shown that the level of tHcy is related to the extent of atherosclerosis in carotid artery, coronary artery, and peripheral artery. It can participate in the formation of AS from the following aspects. Related Diseases

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