CGL

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Introductions

In some bacteria and mammals, including humans, this enzyme takes part in generating hydrogen sulfide. Hydrogen sulfide is one of a few gases that was recently discovered to have a role in cell signaling in the body.

Structure

Cystathione-γ-lyase is a member of the Cys/Met metabolism PLP-dependent enzyme family. Other members include cystathione-γ synthase, cystathione-β lyase, and methionine γ lyase. It is also a member of the broader aspartate aminotransferase family. Like many other PLP-dependent enzymes, cystathione-γ-lyase is a tetramer with D2 symmetry.

Regulation

H₂S decreases transcription of cystathionase at concentrations between 10 and 80 μM. However, transcription is increased by concentrations near 120 μM, and inhibited completely at concentrations in excess of 160 μM.

Inhibitor Screening Methods

Screening technique is a common method to identify new pharmacological agents. In this method, a number of functional properties (e.g. ligand binding or enzymatic activity) are measured in the presence of one or more potential inhibitors in the library. A major advantage of screening methods is that the binding of inhibitors or other ligands is not limited to the primary ligand binding site/active site, which usually occurs in the context of rational design and structure-based drug discovery activities (which usually cause competitive inhibition)

Virtual Screening

Virtual screening is used to identify compounds from a large library of compounds that bind to a specific target, usually an enzyme or receptor) bound to a compound. There are two main methods in common use today: ligand-based methods and structure-based methods. Each approach can generate quantitative correlations between molecular structures and chemical properties or biological activities by using machine learning, computational pattern recognition or statistical modeling algorithms. the LB strategy explores similarities between known molecules responsible for biological activities, while SB looks at chemical interactions between molecules and known biological targets. Virtual screening allows the selection of effective CGL inhibitors.

Clinial Relevance

Cysteine is the rate-limiting substrate in the intraocular glutathione synthesis pathway. Glutathione is an antioxidant that protects lens proteins in the eye from reactive oxygen species; denatured lens proteins can lead to cataracts. Cystathionase is also a target of reactive oxygen species. Therefore, as cystathionase is oxidized, its activity decreases, leading to a decrease in cysteine, which in turn leads to a decrease in glutathione in the eye, leading to a decrease in antioxidant availability, leading to a further decrease in cystathionase activity. Defects in cystathionase activity have also been shown to contribute to glutathione depletion in patients with cancer and AIDS. Mutations and defects in cystathionase are associated with cystathionuria. the T67I and Q240E mutations impair the affinity of the enzyme for pyridoxal phosphate, a cofactor essential for enzymatic function. Low levels of H₂S have also been associated with hypertension in mice.

High-throughput Screening

High-throughput screening assays are designed to identify small molecules that interfere with protein function, activity, or conformation, which can be an effective tool for chemical biology studies involving targets of physiological processes or disease models.