cGST isoforms, like the other drug-metabolizing superfamilies we have already considered, are classified on the basis of sequence homology. However, cGST nomenclature is quite distinct because each of the six gene subfamilies is represented by a letter; i.e. A- (alpha-), M- (mu-), O- (omega), P- (pi), T- (theta), and Z- (zeta).123 Within these six subfamilies there exist a total of 16 functional mammalian cGST genes, i.e., GSTA1-GSTA5, GSTM1-GSTM5, GSTO1-GSTO2, GSTP1, GST1-GST2, and GSTZ1.123 Because cGSTs exist as dimers, a second number is added to the specific subfamily member to designate the dimer subunit composition, e.g., GSTA1-1 Finally, cGSTs usually exist as homodimers, but heterodimers are also known.
cGSTs are versatile catalysts that typically carry out nucleophilic addition and nucleophilic replacement reactions with GSH. However, these enzymes can also catalyze isomerization of double bonds without net consumption of GSH. 1-Chloro-2,4-dinitrobenzene (CDNB) is considered a 'universal' substrate for the cGSTs, although some T-isoforms have no activity. Class- and isoform-dependent substrate selectivity is broad and overlapping, as with the other detoxification enzymes. A few generalizations are: M-class GSTs have high activity toward planar aromatic hydrocarbon epoxides. T-class have high affinity for aryl sulfates and catalyze desulfation. A-class GSTs have relatively high activity toward organic peroxides. GSTA4-4 is selective for lipid hydroxy-enals (4-hydroxy-nonenal, HNE). GSTP1-1 may have a 'unique' function related to cancer cell response in that it inhibits c-Jun kinase, thereby regulating signal transduction pathways involved in apoptotic/proliferative responses.124
Given their functional versatility and anticipated role in a variety of biological processes, GST inhibitors could have the potential to impact a variety of therapeutic categories.125 Historically, GST inhibitors have been S-linked conjugates of GSH with additional hydrophobic groups. In essence, these inhibitors are products of the reaction, and the fact that they are useful in vitro inhibitors reflects the product inhibition kinetics often observed for these enzymes. Such inhibitors tend not to be isoform-selective, which is not surprising because all isoforms have a GSH-binding site (G-site). Some progress has been made towards the development of isoform-selective inhibitors of GSTP1-1, wherein substitution of the GSH backbone is accommodated by this isoform, but not by others.126
X-ray structures are available for human A-, P-, M-, T-, and S-class cGSTs.124 The overall subunit structure is very similar across these classes and contains two distinct domains. The N-terminal domain possesses the G-site that binds nucleophilic GS-, which is stabilized, for example in GSTA, by hydrogen bonding to a conserved Arg residue. The much larger C-terminal domain contributes to the xenobiotic binding site (H-site) that lies between the domains. In some cases, the hydrophobic H-site includes an appropriate residue that can aid in the catalysis of specific substrates. For example, in GSTM an H-site Tyr provides a general base for the 'leaving' oxygen of epoxide substrates.
Was this article helpful?
Our internal organs, the colon, liver and intestines, help our bodies eliminate toxic and harmful matter from our bloodstreams and tissues. Often, our systems become overloaded with waste. The very air we breathe, and all of its pollutants, build up in our bodies. Today’s over processed foods and environmental pollutants can easily overwhelm our delicate systems and cause toxic matter to build up in our bodies.