Disease relevance of GSTM2

• The human muscle and liver glutathione transferase clones GTHMUS and GTH411 have been expressed in Escherichia coli [1].

High impact information on GSTM2

• The close physical proximity of the GSTM1 and GSTM2 loci, which share 99% nucleotide sequence identity over 460 nucleotides of 3'-untranslated mRNA, suggests that the GSTM1-null allele may result from unequal crossing-over [2].
• A class-mu glutathione transferase cDNA clone, GTHMUS, was isolated from human myoblasts and its sequence was determined [1].
• This sequence conservation suggests that gene conversion has occurred between the human GST1 and GST4 glutathione transferase gene loci [1].
• GSTM2, a striated muscle-specific isozyme, occurred minimally in the epithelium of the terminal airways, and GSTM3, an enzyme of broad extrahepatic occurrence, was observable in the ciliated airway epithelium and smooth muscle of the lung [3].
• Negative cooperativity is also found in GSTM2-2 and GSTP1-1, but it does not affect the catalytic competence of the second subunit [4].

Biological context of GSTM2

• For the mu family, 90% of the lines had GSTM2, 68% had GSTM3, but only 28% were positive for the M1 phenotype [5].
• The N-terminal amino acid sequence of GST6 was found to be identical with that of GST4 previously purified from human muscle [6].
• This complex binds with extraordinary affinity to the active site of all these dimeric enzymes; GSTA1-1 shows the strongest interaction (KD congruent with 10-10 m), whereas GSTM2-2 and GSTP1-1 display similar and slightly lower affinities (KD congruent with 10-9 m) [4].
• Other isoenzymes with fast anodal mobilities were also identified in several tissues; these are believed to be GST3 isoenzymes that have undergone posttranslational modification rather than products of the putative GST4 locus [7].
• We also identified regions of conserved synteny, each containing the Gstm2 gene, on mouse chromosome 3 and human chromosome 1 [8].

Anatomical context of GSTM2

• In colon fibroblasts, butyrate (4 mM, 72 h) also induced GSTM2 protein (1.7-fold) and GST activity (1.4-fold) [9].
• An hGSTM2-2-like protein was isolated from rabbit skeletal muscle and sheep heart, at concentrations of approximately 17-93muM [10].
• When added to the cytoplasmic side of RyRs, hGSTM2-2 and GST isolated from skeletal or cardiac muscle, modified channel activity in an RyR isoform-specific manner [10].

Associations of GSTM2 with chemical compounds

• However, butyrate, an important luminal component produced from fermentation of dietary fibers, is an efficient inducer of GSTs and especially of GSTM2 [9].
• GSTM2-2 and 3-3 may play crucial roles in temperature regulation, nociception, and sleep-wake regulation by producing PGE2 in the brain [11].
• Michaelis-Menten constants and turnover numbers for PGH2 were 141 microM and 10.8 min(-1) for GSTM2-2 and 1.5 mM and 130 min(-1) for GSTM3-3, respectively [11].
• Cloning, expression, and characterization of a class-mu glutathione transferase from human muscle, the product of the GST4 locus [1].
• CDNA-derived amino acid sequence analysis revealed that mfaGSTM1 and mfaGSTM2 share 97% and 96% homology with the human mu-class GSTs hGSTM4 and hGSTM2, respectively [12].

Regulatory relationships of GSTM2

• GSTM2 transcript was expressed in all patients in contradistinction to GSTM5, which was not detected in any sample [13].

Other interactions of GSTM2

• This resistance was attributed to the induction of certain glutathione S-transferases (hGSTP1-1, hGSTM2-2, and hGSTA1-1) and also for the tripeptide glutathione (GSH) synthesizing enzymes [14].
• In vitro hybridisation and SDS-discontinuous polyacrylamide gel electrophoresis were used to show that the GST4 isoenzyme is a homodimer composed of monomers that have a slightly larger molecular weight than the near-neutral isoenzyme [15].
• In contrast, hGSTM2-2 and GSTs isolated from muscle (1-30muM) in the cytoplasmic solution, caused a voltage-independent inhibition of cardiac RyR2 channels [10].

Analytical, diagnostic and therapeutic context of GSTM2

• The three-dimensional structure of ligand-free hGSTM2-2 determined by x-ray crystallography suggests that Arg(107) maintains an electrostatic interaction with the Asp(161) side chain (3 A apart), but is distant from the GSH-binding site [16].
• Human muscle specific glutathione S-transferase (RX: glutathione R-transferase, EC 2.5.1.18) (GST-4) and liver GST-1 have been purified and subjected to N-terminal sequence analysis [17].

References