Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A sequence encoding a novel glutathione transferase, GST A4-4, has been identified in a human fetal brain cDNA library. The protein has been produced in Escherichia coli after optimization of the codon usage for high-level heterologous expression. The dimeric protein has a subunit molecular mass of 25704 Da based on the deduced amino acid composition. Human GST A4-4 is a member of the Alpha class but shows only 53% amino acid sequence identity with the major liver enzyme GST A1-1. High catalytic efficiency with 4-hydroxyalkenals and other cytotoxic and mutagenic products of radical reactions and lipid peroxidation is a significant feature of GST A4-4. The kcat/Km values for 4-hydroxynonenal and 4-hydroxydecenal are > 3 x 10(6) M-1. s-1, several orders of magnitude higher than the values for conventional GST substrates. 4-Hydroxynonenal and other reactive electrophiles produced by oxidative metabolism have been linked to aging, atherosclerosis, cataract formation, Parkinson's disease and Alzheimer's disease, as well as other degenerative human conditions, suggesting that human GST A4-4 fulfills an important protective role and that variations in its expression may have significant pathophysiological consequences.
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PMID:Human glutathione transferase A4-4: an alpha class enzyme with high catalytic efficiency in the conjugation of 4-hydroxynonenal and other genotoxic products of lipid peroxidation. 946 7

The oxidation of lipids and cell membranes generates cytotoxic compounds implicated in the etiology of aging, cancer, atherosclerosis, neurodegenerative diseases, and other illnesses. Glutathione transferase (GST) A4-4 is a key component in the defense against the products of this oxidative stress because, unlike other Alpha class GSTs, GST A4-4 shows high catalytic activity with lipid peroxidation products such as 4-hydroxynon-2-enal (HNE). The crystal structure of human apo GST A4-4 unexpectedly possesses an ordered C-terminal alpha-helix, despite the absence of any ligand. The structure of human GST A4-4 in complex with the inhibitor S-(2-iodobenzyl) glutathione reveals key features of the electrophilic substrate-binding pocket which confer specificity toward HNE. Three structural modules form the binding site for electrophilic substrates and thereby govern substrate selectivity: the beta1-alpha1 loop, the end of the alpha4 helix, and the C-terminal alpha9 helix. A few residue changes in GST A4-4 result in alpha9 taking over a predominant role in ligand specificity from the N-terminal loop region important for GST A1-1. Thus, the C-terminal helix alpha9 in GST A4-4 provides pre-existing ligand complementarity rather than acting as a flexible cap as observed in other GST structures. Hydrophobic residues in the alpha9 helix, differing from those in the closely related GST A1-1, delineate a hydrophobic specificity canyon for the binding of lipid peroxidation products. The role of residue Tyr212 as a key catalytic residue, suggested by the crystal structure of the inhibitor complex, is confirmed by mutagenesis results. Tyr212 is positioned to interact with the aldehyde group of the substrate and polarize it for reaction. Tyr212 also coopts part of the binding cleft ordinarily formed by the N-terminal substrate recognition region in the homologous enzyme GST A1-1 to reveal an evolutionary swapping of function between different recognition elements. A structural model of catalysis is presented based on these results.
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PMID:Human glutathione transferase A4-4 crystal structures and mutagenesis reveal the basis of high catalytic efficiency with toxic lipid peroxidation products. 1032 52

The role of alpha-class mammalian glutathione S-transferases (GSTs) in the protection of many cell types, including vascular smooth muscle cells, against oxidant damage has been demonstrated, but the role of GSTs in the endothelial cell is not well studied. In order to examine the role of GSTs in the endothelial cell, a stable transfection of mouse pancreatic islet endothelial cells (MS1) with cDNA of mGSTA4-4, mouse isozyme of GSTs with activity in vascular wall, was established. Transfected cells demonstrated significantly higher GSTs enzyme activity and expressed significantly increased resistance to the cytotoxicity of allylamine, acrolein, 4-hydroxy-2-nonenal (4-HNE), and H(2)O(2) (P < 0.05). A significantly higher rate of proliferation and lower baseline level of intracellular malondialdehyde (MDA) and 4-HNE were present when compared to wild-type or vector-transfected MS1 endothelial cells (P < 0.05). Transfection protected MS1 endothelial cells from 4-HNE and H(2)O(2) induced apoptosis by inhibiting phosphorylation of c-Jun N-terminal kinases (p-JNK) and consequent activation of p53 and Bax. In early human fibrous atherosclerotic plaques, immunohistochemical studies demonstrated marked induction of hGSTA4-4 in endothelial cells overlying plaque, and in proliferating plaque vascular smooth muscle cells. Our results indicate that endothelial cell mGSTA4-4 can play a key role in protecting blood vessels against oxidative stress and, thus, is likely to be a critical defense mechanism against oxidants that act as atherogens.
Atherosclerosis 2004 Apr
PMID:Glutathione-S-transferase A4-4 modulates oxidative stress in endothelium: possible role in human atherosclerosis. 1506 94