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)

Onchocerciasis or river blindness, caused by the filarial worm Onchocerca volvulus, is the world's second leading infectious cause of blindness. In order to chronically infect the host, O. volvulus has evolved molecular strategies that influence and direct immune responses away from the modes most damaging to it. The O. volvulus GST1 (OvGST1) is a unique glutathione S-transferase (GST) in that it is a glycoprotein and possesses a signal peptide that is cleaved off in the process of maturation. The mature protein starts with a 25-amino-acid extension not present in other GSTs. In all life stages of the filarial worm, it is located directly at the parasite-host interface. Here, the OvGST1 functions as a highly specific glutathione-dependent prostaglandin D synthase (PGDS). The enzyme therefore has the potential to participate in the modulation of immune responses by contributing to the production of parasite-derived prostanoids and restraining the host's effector responses, making it a tempting target for chemotherapy and vaccine development. Here, we report the crystal structure of the OvGST1 bound to its cofactor glutathione at 2.0 A resolution. The structure reveals an overall structural homology to the haematopoietic PGDS from vertebrates but, surprisingly, also a large conformational change in the prostaglandin binding pocket. The observed differences reveal a different vicinity of the prostaglandin H(2) binding pocket that demands another prostaglandin H(2) binding mode to that proposed for the vertebrate PGDS. Finally, a putative substrate binding mode for prostaglandin H(2) is postulated based on the observed structural insights.
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PMID:Structure of the extracellular glutathione S-transferase OvGST1 from the human pathogenic parasite Onchocerca volvulus. 1825 57

Glaucoma is the leading cause of irreversible blindness worldwide. This review aims to provide a greater understanding of the complex genetic influences that may lead to mitochondrial dysfunction and increase susceptibility to retinal ganglion cell (RGC) loss in primary open angle glaucoma (POAG), and thus elucidate potentially important pathophysiological pathways amenable to therapeutic intervention. Emerging evidence from genome wide association and other genetic studies suggests that changes in the mitochondrial DNA (mtDNA) and in nuclear DNA genes that encode mitochondrial proteins may influence mitochondrial structure and function and, therefore, contribute to the pathogenesis of POAG. We propose that a variety of genes (OPA1, MFN1, MFN2, CYP1B1, PARL, SOD2, SRBD1, GST, NOS3, TNFa and TP53) may each confer a background susceptibility to POAG in different populations having one common link: mitochondrial dysfunction. The relationship between polymorphisms in these genes and increasing risk for POAG is presented and the limitations of the available current knowledge are discussed.
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PMID:Mitochondrial dysfunction in glaucoma: understanding genetic influences. 2213 60

Although many monogenic diseases are understood based upon structural changes of gene products, less progress has been made concerning polygenic disease mechanisms. This article presents a new interdisciplinary approach to understand complex diseases, especially their genetic polymorphisms. I focus upon primary open angle glaucoma (POAG). Although elevated intraocular pressure (IOP) and oxidative stress are glaucoma hallmarks, the linkages between these factors and cell death are obscure. Reactive oxygen species (ROS) promote the formation of oxidatively truncated phosphoglycerides (OTP), free fatty acids, lysophosphoglycerides, oxysterols, and other chemical species that promote membrane disruption and decrease membrane surface tension. Several POAG-linked gene polymorphisms identify proteins that manage damaged lipids and/or influence membrane surface tension. POAG-related genes expected to participate in these processes include: ELOVL5, ABCA1, APOE4, GST, CYP46A1, MYOC, and CAV. POAG-related gene products are expected to influence membrane surface tension, strength, and repair. I propose that heightened IOP overcomes retinal ganglion cell (RGC) membrane compressive strength, weakened by damaged lipid accumulation, to form pores. The ensuing structural failure promotes apoptosis and blindness. The linkage between glaucoma genotype and phenotype is mediated by physical events. Force balancing between the IOP and compressive strength regulates pore nucleation; force balancing between pore line tension and membrane surface tension regulates pore growth. Similar events may contribute to traumatic brain injury, Alzheimer's disease, and macular degeneration.
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PMID:Frontiers of Complex Disease Mechanisms: Membrane Surface Tension May Link Genotype to Phenotype in Glaucoma. 2968 2