A new model of cystic fibrosis pathology: Lack of transport of glutathione and its thiocyanate conjugates

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Medical Hypotheses (Impact Factor: 1.07). 02/2007; 68(1):101-12. DOI: 10.1016/j.mehy.2006.06.020
Source: PubMed


Many of the symptoms of cystic fibrosis are not explained by the current disease mechanisms. Therefore, the authors conducted an extensive literature review and present a new model of cystic fibrosis pathology, which is the culmination of this research. Understanding that the cystic fibrosis transmembrane conductance regulator (CFTR) is responsible for glutathione (GSH) transport, the authors hypothesize that mutations of the CFTR, which create abnormal GSH transport, will lead to aberrations of GSH levels in both the intracellular as well as the extracellular milieu. These alterations in normal cellular GSH levels affect the redox state of the cell, thereby affecting the intracellular stress protein, metallothionein. The authors describe how this disruption of the redox state caused by excess cellular GSH, will naturally prevent the delivery of zinc as a cofactor for various enzymatic processes, and how these disruptions in normal redox may cause alterations in both humoral and cell-mediated immunity. Moreover, the symptom of thick sticky mucus in these patients might be explained through the understanding that oversulfation of mucus is a direct result of elevated cellular GSH and cysteine. The issues of hyperinflammation, altered pH and the imbalance of fatty acids that are typical in cystic fibrosis are addressed-all of which may also be linked to disruptions in GSH homeostasis. Additionally, this new model of cystic fibrosis pathology, clarifies the relationship between the CFTR and the multi-drug resistance proteins, and the lack of cell-mediated immunity by predicting that the substrate of these proteins is a glutathione adduct of thiocyanate. Finally, a new therapeutic strategy by using isothiocyanates to rectify the GSH imbalance and restore the immune system is suggested for the treatment of cystic fibrosis patients.

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    • "On the other hand, biological processes can be comprehended as a dynamically fluctuating system, whereby the biological role of the unknown membrane protein can be defined more precisely [3] [4]. Accordingly, destabilisation of the three-dimensional structure of a membrane protein caused by mutations or ligand interactions are triggers for numerous diseases, for example, diabetes insipidus, cystic fibrosis, hereditary deafness and retinitis pigmentosa [5] [6] [7]. Although 20%–30% of all open reading frames of a typical genome are encoding membrane proteins [5] [8] [9] and 60% of all drug targets are membrane proteins [2], membrane proteomics is still an experimentally challenging field due to poor protein solubility, wide intracellular concentration range, and thus, inaccessibility to many proteomics methodologies [10]. "
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    ABSTRACT: Motivation. Membrane proteins play essential roles in cellular processes of organisms. Photosynthesis, transport of ions and small molecules, signal transduction, and light harvesting are examples of processes which are realised by membrane proteins and contribute to a cell's specificity and functionality. The analysis of membrane proteins has shown to be an important part in the understanding of complex biological processes. Genome-wide investigations of membrane proteins have revealed a large number of short, distinct sequence motifs. Results. The in silico analysis of 32 membrane protein families with domains of unknown functions discussed in this study led to a novel approach which describes the separation of motifs by residue-specific distributions. Based on these distributions, the topology structure of the majority of motifs in hypothesised membrane proteins with unknown topology can be predicted. Conclusion. We hypothesise that short sequence motifs can be separated into structure-forming motifs on the one hand, as such motifs show high prediction accuracy in all investigated protein families. This points to their general importance in íµí»¼-helical membrane protein structure formation and interaction mediation. On the other hand, motifs which show high prediction accuracies only in certain families can be classified as functionally important and relevant for family-specific functional characteristics.
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    • "Cystic fibrosis is often observed together with cholestatic liver disease (Moyer and Balistreri, 2009). Cystic fibrosis is a genetic disorder with a mutation of the cystic fibrosis membrane conductance regulator (CFTR), which is also an ABC transport protein (ABCC7) (Childers et al., 2007 ). Additionally, the cystic fibrosis–disturbed pathways involve the ER-Golgi trafficking, emphasizing that ER stress and affected ER-Golgi trafficking are core elements of cyclosporin A–induced cholestasis. "
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    • "A portion of accumulated CdMT is continuously released into the urine by unresolved mechanisms, and can be used as a biomarker of Cd nephrotoxicity (k) are also not clear. Furthermore, the cystic fibrosis transmembrane conductance regulator CFTR and the multidrug resistance protein MRP-1, which are present in the lung epithelium (Torky et al. 2005; Regnier et al. 2008), are known to export glutathione (GSH) (reviewed in: Cole and Deeley 2006; Childers et al. 2007), but their possible contribution in Cdinduced toxicity as the exporters of Cd-GSH conjugate into the blood, has not been studied. "
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