Cystathionine Beta Synthase - Regulation

Regulation

Allosteric activation of CBS adoMet determines the metabolic fate of L-homocysteine. Mammalian CBS is activated 2.5-5-fold by adoMet with a dissociation constant of 15 µM. adoMet is an allosteric activator that increases the Vmax of the CBS reaction but does not affect the Kms for the substrates. In other words, adoMet stimulates CBS activity by increasing the turnover rate rather than the binding of substrates to the enzyme. This protein may use the morpheein model of allosteric regulation.

Human CBS performs a crucial step in the biosynthetic pathway of cysteine by providing a regulatory control point for adoMet . L-homocysteine, after being methylated to methionine, can be converted to adoMet, which donates methyl groups to a variety of substrates, e.g., neurotransmitters, proteins, and nucleic acids. adoMet functions as an allosteric activator of CBS and exerts control on its biosynthesis: low concentrations of adoMet result in low CBS activity, thereby funneling homocysteine in the transmethylation pathway toward adoMet formation. Methionine is transmethylated to homocysteine via S-adenosyl-methionine (SAM). In contrast, high adoMet concentrations allow the clearance of homocysteine into the transsulfuration pathway, leading to cysteine biosynthesis.

In mammals, CBS is a highly regulated enzyme, which contains a heme cofactor that functions as a redox sensor, that can modulate its activity in response to changes in the redox potential. If the resting form of CBS in the cell has ferrous heme, the potential exists for activating the enzyme under oxidizing conditions by conversion to the ferric state. The Fe (II) form of the enzyme is inhibited upon binding CO or nitric oxide, whereas enzyme activity is doubled when the Fe (II) is oxidized to Fe (III). The redox state of the heme is pH dependent, with oxidation of Fe (II)-CBS to Fe (III)-CBS being favored at low pH conditions.

Since mammalian CBS contains a heme cofactor, whereas yeast and protozoan enzyme from Trypanosoma cruzi do not have heme cofactors, researchers have speculated that heme is not required for CBS activity.

CBS is regulated at the transcriptional level by NF-Y, SP-1, and SP-3. In addition it is upregulated transcriptionally by glucocorticoids and glucogen, and downregulated by insulin. Methionine upregulates CBS at the post-transcriptional level.