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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.
Using Medication Wisely
Published in Melissa G. Hunt, Aaron T. Beck, Reclaim Your Life From IBS, 2022
Melissa G. Hunt, Aaron T. Beck
There is emerging evidence that some folks with diarrhea-predominant (or mixed type) IBS may suffer from a lack of various enzymes (beyond lactase) that break down casein (the protein in milk), gluten, and various FODMAP carbohydrates.2,3 Different from pancreatic exocrine insufficiency, these digestive enzymes work at the “brush border” of the small intestine. Some people find that taking over-the-counter enzyme supplements (like SIBB-zymes) can be quite helpful in resolving diarrhea. Like pro-biotics, you are better off trying a brand with multiple different enzymes. Unfortunately, because such supplements are not regulated by the FDA, there are no compelling clinical trials proving their efficacy. There was one recent trial testing the specific enzyme α-galactosidase on GI symptoms in patient with IBS that didn’t find it did much good.4 But compounds that contain multiple enzymes might be more likely to be helpful. There is little downside to trying one of these products, beyond the expense. They are well-tolerated and don’t have any adverse effects. You’ll know within 24 hours if it’s helpful. If it reduces your GI symptoms, terrific.
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).
Investigation of ocular involvement in patients with Fabry disease
Published in Annals of Medicine, 2023
Yuan Wu, Wenbo Zhang, Xuyang Yao, Wenjing Song, Yawen Zhao, Yun Yuan, Wei Zhang
Forty-five FD patients (33 hemizygote/males and 12 heterozygote/females) attended the Department of Ophthalmology, Peking University and were included in this study between January 2014 and December 2021. All patients had their diagnosis confirmed by DNA testing that revealed the presence of an α-galactosidase A mutation. The mutation types included substitutions, deletions and duplications. Among them, 33 patients had substitution mutations, accounting for 73.3%, 10 patients had deletion mutations, accounting for 22.2% and 2 patients had duplication mutations, accounting for 4.4%. Informed consent was obtained from all participants, and the study protocol was approved by the Institutional Review Board of Peking University First Hospital; the study was performed in accordance with the tenets of the Declaration of Helsinki.
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
The Lon proteolytic domain (Lon PD) contains a conserved lysine (Lys722), located 43 residues beyond the catalytic serine (Ser679) to carry out catalytic activities.26 To understand how Lon protease is involved in the degradation of KatG, we investigated whether KatG physically interacts with the proteolytic active site of Lon protease. We used a bacterial two-hybrid assay to assess the interaction between KatG and the PD of Lon protease by expressing the katG gene with a C-terminal fusion of the cyaA-T18 fragment and lon PD genes with N-terminal fusions of the cyaA-T25 fragment in an E. coli strain lacking CyaA adenylate cyclase. We then spotted cells on a MacConkey agar plate containing maltose and measured β-galactosidase production from a cAMP-dependent promoter produced when T18 and T25 fragments of the cyaA gene are functionally complemented by a physical interaction between fused KatG and the PD of Lon protease. The strain expressing KatG-T18 and the T25-Lon proteolytic domain showed a strong red color on the MacConkey-maltose plate, indicating that KatG interacts with Lon PD (Figure 3a). By contrast, no interaction was observed in KatG-T18 co-expressing the empty T25 fragment. The interaction was confirmed by measuring the β-galactosidase activity. The KatG-Lon PD interaction was further analyzed by in vitro cross-linking of purified proteins. We observed an additional band corresponding to roughly 99 kDa (79 + 20) on polyacrylamide gel when KatG and the Lon proteolytic domain were incubated with a cross-linker (Figure 3a).