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Renal Disease; Fluid and Electrolyte Disorders
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
This is an X-linked genetic deficiency of the enzyme alpha galactosidase A (Gal A) resulting in intracellular accumulation of glycosphingolipid. Proteinuria occurs in adult life and progresses to end-stage renal disease. Systemic features include angiokeratomas (dark red papules) of the skin, coronary artery disease resulting from endothelial thickening and autonomic dysfunction.
Hereditary and Metabolic Diseases of the Central Nervous System in Adults
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
α-Galactosidase activity: Males have decreased activity. Both plasma and leukocytes should be tested.Affected females have variable activity (undetectable up to normal range).
Galactosialidosis
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Multienzyme complexes may work synergistically and provide more efficient responses to changes in the load and composition of substrates. The glycoprotein storage diseases, β-galactosidase deficiency, neuraminidase deficiency, and PPCA, the defect in galactosialidosis, are representative of such a multiprotein complex [23]. In contrast, GM1 gangliosidosis is a glycosphingolipids storage disease. Both are components of the lysosomal network of organelles involved in sorting, digestion, recycling, and secretion of cellular components. The functional mutations in each component of the glycoprotein complex result in impressive lysosomal storage disorders. The multiprotein complex includes the protective cathepsin A protein in which mutations lead to galactosialidosis. The protective protein protects both enzymes from proteolytic degradation. Mutations have been reported in the PPCA gene [24]. Features of GM1 gangliosidosis and sialidosis result from defective activity of both β-galactosidase and neuraminidase as a result of fundamental deficiency in the lysosomal PPCA, which is itself a serine carboxypeptidase.
Thermodynamic and kinetic approaches for drug discovery to target protein misfolding and aggregation
Published in Expert Opinion on Drug Discovery, 2023
Based on the example of tafamidis, other compounds with a similar mechanism of action, known as pharmacological chaperones [16,55], have been developed. Six drugs for three other amyloidoses have been recently approved by the FDA: (i) migalastat, which targets destabilized mutant α-galactosidase A in Fabry disease [56], (ii) voxelotor, which targets a mutant form of hemoglobin in sickle cell disease by stabilizing the tetrameric oxygenated form of the protein [57], and (iii) ivacaftor (also known as VX-770) [58], elexacaftor (VX-445) [59] and tezacaftor (VX-661) [60], which act synergistically to target mutant forms of the anion channel cystic fibrosis transmembrane conductance regulator (CFTR) in cystic fibrosis by promoting channel gating (ivacaftor) and by stabilizing the native state (elexacaftor and tezacaftor) [16,59]. Other compounds with a similar mechanism of action are under development. A small molecule in the sterol class has been shown to act as pharmacological chaperone by inhibiting amyloid fibril formation of mutant α-crystallins, and to reverse cataract in mouse models of these mutants [61,62]. Another sterol (lanosterol) was shown to ameliorate cataract in dogs [63], and is currently commercialized as a veterinary drug (Lanomax, https://www.lanomax.com/). Pharmacological chaperones are also being investigated with great promise to target oncogenic mutants of the tumor suppressor protein p53 [64].
Coordinated interaction between Lon protease and catalase-peroxidase regulates virulence and oxidative stress management during Salmonellosis
Published in Gut Microbes, 2022
Perumalraja Kirthika, Vijayakumar Jawalagatti, Amal Senevirathne, John Hwa Lee
Potential interactions between Lon protease and KatG were evaluated using the bacterial two-hybrid (B2H) assay.56,57 The E. coli BTH101 (cyaA) strain was co-transformed with derivatives of the pUT18 and pKT25 plasmids. The E. coli host and plasmids for the B2H assay were a kind gift from Professor Eun-Jin Lee, School of Life Sciences and Biotechnology, Korea University. Transformants were grown in LB medium supplemented with 100 μg/ml ampicillin and 50 μg/ml kanamycin, at 37°C overnight. Then, 2 μl from broth cultures were withdrawn and spotted on solid MacConkey-maltose agar containing 100 μM IPTG, 100 μg/ml ampicillin, and 50 μg/ml kanamycin. Plates were incubated at 30°C for 40 h. In addition, the results were validated by quantitative β-galactosidase assay, as described in a previous study.58 Bacteria co-transformed with empty or zip vectors served as negative and positive controls, respectively.
Kidney and lipids: novel potential therapeutic targets for dyslipidemia in kidney disease?
Published in Expert Opinion on Therapeutic Targets, 2022
Konrad Zuzda, Wiktoria Grycuk, Jacek Małyszko, Jolanta Małyszko
Although the exact pathogenesis of Fabry nephropathy has not been established, studies have highlighted the role of excessive glycosphingolipid storage in kidney damage [101]. Fabry disease is caused by a deficiency of the lysosomal enzyme α-galactosidase A, leading to the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), in lysosomes [101,102]. Abnormal glycosphingolipid deposition in podocytes results in progressive glomerulosclerosis and interstitial fibrosis, eventually leading to irreversible renal failure [102]. In cultured human podocytes, Gb3 acts as a biologically active molecule through the release of podocyte injury mediators such as TGF-β1 and CD74 [103]. A study of 55 biopsies obtained from patients with Fabry disease revealed that Gb3 accumulation was associated with an increase in foot process width, which is an indicator of podocyte injury and podocyte loss. Moreover, a study documented a correlation between the volume of Gb3 deposits and proteinuria, indicating that Gb3-related podocyte injury may underlie the initiation and progression of Fabry nephropathy [103].