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

All six mammalian peroxiredoxins are expressed in the lung. Peroxiredoxin (Prx) VI is the isoform expressed at the highest level and its lung expression exceeds that for other organs. The predominant location of Prx VI is the cytosol and acidic organelles of Clara cells of the conducting airways and type II epithelial cells and macrophages in the alveoli. Prx I and VI show developmental induction of transcription at birth. PrxVI shares structural homology with other peroxiredoxins exhibiting a thioredoxin fold and a conserved catalytic Cys residue in the N-terminus of the protein. This enzyme is highly inducible by oxidative stress in both the neonatal and adult lung consistent with a role in antioxidant defense. Prx VI has several properties that distinguish its peroxidase activity from other peroxiredoxins: it can reduce phospholipid hydroperoxides in addition to other organic hydroperoxides and H2O2; the electron donor that serves to reduce the oxidized peroxidatic cysteine is not thioredoxin but GSH; instead of homodimerization, heterodimerization with pi-glutathione S-transferase is required for regeneration of the active enzyme. Prx VI also expresses a phospholipase A2 activity that is Ca2+-independent, maximal at acidic pH, and dependent on a serine-based catalytic triad and nucleophilic elbow at the surface of the protein. Models of altered Prx VI expression at the cellular, organ and whole animal levels have demonstrated that Prx VI functions as an important anti-oxidant enzyme with levels of protection that exceed those ascribed to GSH peroxidase (GPx1). The phospholipase A2 activity plays an important role in lung surfactant homeostasis and is responsible for the bulk of the degradation of internalized phosphatidylcholine and its resynthesis by the reacylation pathway. Expression of peroxiredoxins is elevated in several lung diseases including lung cancer, mesothelioma and sarcoidosis, although the mechanism for these alterations is not known. The unique properties of Prx VI enable it to play an important role in lung cell function.
 ...
PMID:Peroxiredoxins in the lung with emphasis on peroxiredoxin VI. 1808 1

Tumour necrosis factor (TNF) blockade has become an important immunomodulatory therapy, particularly in patients refractory to conventional immunosuppression, but responses can be unpredictable. Understanding the complex biology of TNF processing may be key to predicting such responses and reduce unwanted side effects. TNF bioavailability is regulated partly by TNF-alpha converting enzyme (TACE) cleavage; however, it can also be cleaved by proteinase-3 (PR-3). We have demonstrated this mechanism previously in healthy human alveolar macrophages (AM), leading us to hypothesize that PR-3-mediated TNF processing may be an important mechanism in inflammatory lung disease. Furthermore, this may be more apparent in diseases with a neutrophil component typical of usual interstitial pneumonia (UIP), compared with sarcoidosis, where lymphocytes predominate. We isolated AM from patients with UIP and sarcoidosis and healthy subjects. We found increased TACE expression on AM in sarcoidosis. In contrast, TACE was not increased in UIP; we found increased cleavage of glutathione S-transferase-proTNF) substrate, relative to both sarcoidosis and healthy controls. Furthermore, cleavage was subject to inhibition by serine protease inhibitor, rather than a TACE inhibitor BB-3103. Cleavage was proportional to the number of neutrophils isolated from bronchoalveolar lavage, whereas there was an inverse relationship between neutrophils and BB-3103 inhibition. There was also increased PR-3 on the AM surface in UIP relative to healthy controls. These data provide evidence for PR-3-mediated cleavage in UIP, which may have implications for future therapeutic targeting of TACE.
 ...
PMID:Tumour necrosis factor-alpha processing in interstitial lung disease: a potential role for exogenous proteinase-3. 1929 64

Sarcoidosis is a chronic inflammatory disease, characterized by granulomatous inflammation, prominently involving the respiratory system. The etiology of this disease has not yet been elucidated and the contribution of genetic is not yet completely understood. We searched for novel candidate genes, utilizing a system biology approach, based on data from published transcriptional, proteomic and linkage studies of sarcoidosis. The search revealed several new potential candidate genes involved in the pathogenesis of inflammatory lung diseases: 25-(OH)-vitamin D(3)-1alpha-hydroxylase (CYP27B1), endothelin-1 (EDN1) and glutathione S-transferase Pi (GSTP1). Variants of selected polymorphisms: -1260/ C>A in CYP27B1, Lys198Asn in EDN1, and Ile105Val in GSTP1, were examined to determine if they confer susceptibility to sarcoidosis, based on an analysis of 180 Slovenian patients in comparison with 283 healthy controls. Polymerase chain reactions using allele-specific oligonucleotides were performed. This disease was not significantly associated with genotypes CC at -1260/ C>A polymorphism in CYP27B1 (P = 0.68, odds ratio (OR) = 1.10, 95% confidence interval (CI) = 0.75-1.61), GG genotype at Lys198Asn polymorphism in EDN1 (P = 1.00, OR = 0.97, 95%CI = 0.65-1.44) and AA genotypes at Ile105Val polymorphism in GSTP1 (P = 0.53, OR = 0.87, 95%CI = 0.60-1.27). There was no association of polymorphisms in any of the genes with sarcoidosis.
 ...
PMID:Lack of association of immune-response-gene polymorphisms with susceptibility to sarcoidosis in Slovenian patients. 2008 71