Cystathionine Beta Synthase - Enzymatic Activity

Transsulfuration, catalyzed by CBS, converts homocysteine to cystathionine, which cystathione gamma lyase converts to cysteine.

CBS occupies a pivotal position in mammalian sulfur metabolism at the homocysteine junction where the decision to conserve methionine or to convert it to cysteine via the transsulfuration pathway, is made. Moreover, the transsulfuration pathway is the only pathway capable of removing sulfur-containing amino acids under conditions of excess.

In analogy with other β-replacement enzymes, the reaction catalyzed by CBS is predicted to involve a series of adoMet-bound intermediates. Addition of serine results in a transchiffization reaction, which forms of an external aldimine. The aldimine undergoes proton abstraction at the α-carbon followed by elimination to generate an amino-acrylate intermediate. Nucleophilic attack by the thiolate of homocysteine on the aminoacrylate and reprotonation at Cα generate the external aldimine of cystathionine. A final transaldimination reaction releases the final product, cystathionine. The final product, L-cystathionine can also form an aminoacrylate intermediate, indicating that the entire reaction of CBS is reversible.

The measured V₀ of an enzyme-catalyzed reaction, in general, reflects the steady state (where is constant), even though V₀ is limited to the early part of a reaction, and analysis of these initial rates is referred to as steady-state kinetics. Steady-state kinetic analysis of yeast CBS yields parallel lines. These results agree with the proposed ping-pong mechanism in which serine binding and release of water are followed by homocysteine binding and release of cystathionine. In contrast, the steady-state enzyme kinetics of rat CBS yields intersecting lines, indicating that the β-substitutent of serine is not released from the enzyme prior to binding of homocysteine.

One of the alternate reactions involving CBS is the condensation of cysteine with homocysteine to form cystathionine and hydrogen sulfide (H₂S). H₂S in the brain is produced from L-cysteine by CBS. This alternative metabolic pathway is also dependent on adoMet.

CBS enzyme activity is not found in all tissues and cells. It is absent from heart, lung, testes, adrenal, and spleen in rats. In humans, it has been shown to be absent in heart muscle and primary cultures of human aortic endothelial cells. The lack of CBS in these tissues implies that these tissues are unable to synthesize cysteine and that cysteine must be supplied from extracellular sources. It also suggests that these tissues might have increased sensitivity to homocysteine toxicity because they cannot catabolize excess homocysteine via transsulfuration.

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