A lyase catalyzes the breaking of chemical bonds by means other than hydrolysis and oxidation.
b-lyase belongs to the lyase family and is classified
as shown below:
- EC 4 – Lyases (subdivided into 7 sub-classes)
- EC.4.4 – Carbon-Sulphur lyases
- E.C.18.104.22.168 – cysteine-S-conjugate b-lyase
In phase II drug metabolism, the conjugation of electrophilic compounds with glutathione forms an innate protective mechanism in the body. However, the further metabolism of glutathione S-conjugates to cysteine conjugates can conversely lead to the formation of reactive components which can covalently bind to tissue macromolecules and lead to organ toxicity.
Cysteine conjugates of aromatic drugs are metabolised principally to the corresponding mercapturic acids, however, it is now understood that they may also undergo b-elimination or transamination. Until 1978, no other metabolic fate of cysteine conjugates was known, however, investigation of rat liver showed enzymatic cleavage of the S-C bond in cysteine conjugates. Several mammalian enzymes which carry out cleavage of S-cysteines have now been identified, and their role in the production of reactive sulphur containing compounds in toxicology is a rapidly evolving field of investigation.
Cysteine conjugate b-lyases are now believed to be responsible for the generation of reactive thiols from glutathione conjugates of halogenated hydrocarbons, in the kidney. As a result of b-lyases role in bioactivation, as apposed to detoxifying role, the enzyme has become the focus of many studies. Further, the thiol group is easily methylated to form the methylthiolated product, providing further interest in drug metabolism. These enzymes will be discussed further, taking into consideration their role in toxicity, and any therapeutics that can be developed as a result.
The further metabolism of glutathione conjugates is illustrated below.