Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Crystallins, the principal components of the lens, have been regarded simply as soluble, structural proteins. It now appears that the major taxon-specific crystallins of vertebrates and invertebrates are either enzymes or closely related to enzymes. In terms of sequence similarity, size, and other physical characteristics delta-crystallin is closely related to argininosuccinate lyase, tau-crystallin to enolase, and SIII-crystallin to glutathione S-transferase; moreover, it has recently been demonstrated that epsilon-crystallin is an active lactate dehydrogenase. Enzymes may have been recruited several times as lens proteins, perhaps because of the developmental history of the tissue or simply because of evolutionary pragmatism (the selection of existing stable structures for a new structural role).
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PMID:Recruitment of enzymes as lens structural proteins. 358 69

The major water-soluble proteins--or crystallins--of the eye lens are either identical to or derived from proteins with non-refractive functions in numerous tissues. In general, the recruitment of crystallins has come from metabolic enzymes (usually with detoxification functions) or stress proteins. Some crystallins have been recruited without duplication of the original gene (i.e., lactate dehydrogenase B and alpha-enolase), while others have incurred one (i.e., argininosuccinate lyase and a small heat shock protein) or several (i.e., glutathione S-transferase) gene duplications. Enzyme (or stress protein)-crystallins often maintain their non-refractive function in the lens and/or other tissues as well as their refractive role, a process we call gene sharing. alpha-Crystallin/small heat shock protein/molecular chaperone is of special interest since it is the major crystallin of humans. There are two alpha-crystallin genes (alpha A and alpha B), with alpha B retaining the full functions of a small heat shock protein. Here we describe recent evidence indicating that alpha A and alpha B have kinase activity, which would make them members of the enzyme-crystallins. We also describe various regulatory elements of the mouse alpha-crystallin genes responsible for their expression in the lens and, for alpha B, in skeletal muscle. Delineating the control elements for gene expression of these multifunctional protective proteins provides the foundations for their eventual use in gene therapy. Finally, comparison of the mouse and chicken alpha A-crystallin genes reveals similarities and differences in their functional cis-acting elements, indicative of evolution at the level of gene regulation.
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PMID:Recruitment of enzymes and stress proteins as lens crystallins. 803 55

Injury to motor neurons associated with mutant Cu,Zn-superoxide dismutase (SOD1)-related familial amyotrophic lateral sclerosis (FALS) results from a toxic gain-of-function of the enzyme. The mechanisms by which alterations to SOD1 elicit neuronal death remain uncertain despite intensive research effort. Analysis of the cellular proteins that are differentially expressed in the presence of mutant SOD1 represents a novel approach to investigate further this toxic gain-of-function. By using the motor neuron-like cell line NSC34 stably transfected with wild-type, G93A, or G37R mutant human SOD1, we investigated the effects of mutant human SOD1 on protein expression using proteomic approaches. Seven up-regulated proteins were identified as argininosuccinate synthase, argininosuccinate lyase, neuronal nitric-oxide synthase, RNA-binding motif protein 3, peroxiredoxin I, proteasome subunit beta 5 (X), and glutathione S-transferase (GST) Alpha 2. Seven down-regulated proteins were identified as GST Mu 1, GST Mu 2, GST Mu 5, a hypothetical GST Mu, GST Pi B, leukotriene B(4) 12-hydroxydehydrogenase, and proteasome subunit beta5i (LMP7). GST assays demonstrated a significant reduction in the total GST activity of cells expressing mutant human SOD1. Proteasome assays demonstrated significant reductions in chymotrypsin-like, trypsin-like, and post-glutamylhydrolase proteasome activities. Laser capture microdissection of spinal cord motor neurons from human FALS cases, in conjunction with reverse transcriptase-PCR, demonstrated decreased levels of mRNA encoding GST Mu 1, leukotriene B(4) 12-hydroxydehydrogenase, and LMP7. These combined approaches provide further evidence for involvement of alterations in antioxidant defenses, proteasome function, and nitric oxide metabolism in the pathophysiology of FALS.
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PMID:Analysis of the cytosolic proteome in a cell culture model of familial amyotrophic lateral sclerosis reveals alterations to the proteasome, antioxidant defenses, and nitric oxide synthetic pathways. 1247 80

The crystallins account for 80-90% of the water-soluble proteins of the transparent lens. These diverse proteins are responsible for the optical properties of the lens and have been recruited from metabolic enzymes and stress proteins. They often differ among species (i.e. are taxon-specific) and may be expressed outside of the lens where they have non-refractive roles (a situation we call gene sharing). Crystallin recruitment has occurred by changes in gene regulation resulting in high lens expression. Duck lactate dehydrogenase/epsilon-crystallin and alpha-enolase/tau-crystallin are each encoded in single-copy genes, consistent with these enzymes acquiring a crystallin role, without loss of their nonlens metabolic function, by a change in gene regulation in the absence of gene duplication. The small heat shock protein/alpha-crystallins and avian argininosuccinate lyase/delta-crystallins were also recruited by a change in gene regulation leading to high lens expression, except this was followed by a gene duplication with further lens specialization of the alphaA and the delta1 (in chickens) crystallin genes. Cephalopod (squid and octopus) S-crystallins were recruited from glutathione S-transferase apparently after duplication of the original gene encoding the enzyme, although this remains uncertain. We speculate that one of the new genes (glutathione S-transferase/S11-crystallin) specialized for lens expression by a change in gene regulation and subsequently duplicated many times to form the lens-specialized, multiple S-crystallins that lack enzymatic activity. That similar transcription factors (e.g. Pax-6, retinoic acid receptors, maf, Sox, AP-1, CREB) regulate different crystallin genes suggest that common features of lens-specific expression have played a pivotal role for recruiting the diverse, multifunctional proteins as crystallins.
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PMID:Crystallin genes: specialization by changes in gene regulation may precede gene duplication. 1283 92

Tissue accumulation and high urinary excretion of argininosuccinate (ASA) is the biochemical hallmark of argininosuccinate lyase deficiency (ASLD), a urea cycle disorder mainly characterized by neurologic abnormalities, whose pathogenesis is still unknown. Thus, in the present work, we evaluated the in vitro and in vivo effects of ASA on a large spectrum of oxidative stress parameters in brain of adolescent rats in order to test whether disruption of redox homeostasis could be involved in neurodegeneration of this disorder. ASA provoked in vitro lipid and protein oxidation, decreased reduced glutathione (GSH) concentrations, and increased reactive oxygen species generation in cerebral cortex and striatum. Furthermore, these effects were totally prevented or attenuated by the antioxidants melatonin and GSH. Similar results were obtained by intrastriatal administration of ASA, in addition to increased reactive nitrogen species generation and decreased activities of superoxide dismutase, glutathione peroxidase, and glutathione S-transferase. It was also observed that melatonin and N-acetylcysteine prevented most of ASA-induced in vivo pro-oxidant effects in striatum. Taken together, these data indicate that disturbance of redox homeostasis induced at least in part by high brain ASA concentrations per se may potentially represent an important pathomechanism of neurodegeneration in patients with ASLD and that therapeutic trials with appropriate antioxidants may be an adjuvant treatment for these patients.
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PMID:Free Radical Scavengers Prevent Argininosuccinic Acid-Induced Oxidative Stress in the Brain of Developing Rats: a New Adjuvant Therapy for Argininosuccinate Lyase Deficiency? 3170 33