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Hepatorenal tyrosinemia/fumarylacetoacetate hydrolase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The molecular defect in hepatorenal tyrosinemia is in the hepatic fumarylacetoacetic acid hydrolase (fumarylacetoacetase, EC 3.7.1.2) (see Figure 22.1). This was originally proposed on the basis of the accumulation of succinylacetone [10]. Deficiency of this enzyme was then documented by assay of activity in liver [12]. The level was 6 percent of normal in six patients with the acute disease and 20 percent in two patients with the chronic form. The activity of maleylacetoacetic acid hydrolase was also deficient in some samples of liver. A problem with enzyme assay is that in the presence of liver disease, the activities of many enzymes are reduced, but the fundamental enzyme deficiency may also be demonstrated in lymphocytes and fibroblasts [54]. The gold standard in the diagnosis of this disease is the demonstration of succinylacetone in the urine.
Native And Acquired Resistance To Infection With Cryptococcus Neoformans
Published in Hans H. Gadebusch, Phagocytes and Cellular Immunity, 2020
The mechanism for the release of lysosomal enzymes from leukocytes is apparently more complex than had hitherto been thought (reviewed by Silverstein et al.,76 Schorlemmer et al.,43 and Zurier et al.77). Acid hydrolase release into the surrounding medium usually is associated with particle ingestion, can be enhanced by compounds that elevate cyclic GMP (cGMP) levels, and is inhibited by removal of Ca2+ from the extracellular medium,72 but may also occur in the absence of ingestion. It has been postulated that free calcium locally available in the cytoplasm leads to fusion of the lysosome with a specific region of the plasma membrane78 resulting in release of enzymes. Cytochalasin B, an inhibitor of phagocytosis, is thought to potentiate this effect.78,79
Inflammation
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Intracellular levels of acid hydrolases represent the most important enzymatic correlate of mononuclear phagocyte maturation.439 Enzymes packaged in the lysosomes of macrophages57 are given in Table 5. The membrane-bound acid hydrolases exist in latent form within the membrane.150 Enzymatic activity is markedly enhanced by agents which disrupt the integrity of the lysosomal membrane, thus allowing substrate-enzyme interactions. Levels of lysosomal enzymes differ among macrophage populations, and in general, they are greater in more mature or activated cells. At the same time during maturation of the macrophage and as acid hydrolases accumulate within the cell, there is a concomitant increase in the number of cytoplasmic granules or dense bodies which have the properties of lysosomes.338
At the heart of microbial conversations: endocannabinoids and the microbiome in cardiometabolic risk
Published in Gut Microbes, 2021
Ramsha Nabihah Khan, Kristal Maner-Smith, Joshua A. Owens, Maria Estefania Barbian, Rheinallt M. Jones, Crystal R. Naudin
Through interactions with CB1 and CB2, AEA and 2-AG induce a myriad of bioactivities, known as the cannabinoid tetrad which includes hypothermia, catalepsy, hypo-locomotion and analgesia. Furthermore, activation of the cannabinoid receptors by AEA and 2-AG has been linked to a reduction in intraocular pressure and blood pressure, as well as bradycardia.32,33 Throughout various tissue types, 2-AG is detected at hundreds of times more abundant than AEA.31 Studies have shown that when fatty acid hydrolase (FAAH), an AEA-degrading enzyme, is inhibited or genetically deficient, the concentration of local AEA increases. This AEA abundance has a more potent influence in driving CB1-mediated activities than when AEA levels are low,34 suggesting divergent signaling effects based on the level of AEA present.
Putative adjunct therapies to target mitochondrial dysfunction and oxidative stress in phenylketonuria, lysosomal storage disorders and peroxisomal disorders
Published in Expert Opinion on Orphan Drugs, 2020
Nadia Turton, Tricia Rutherford, Dick Thijssen, Iain P Hargreaves
The lysosome is a vitally important organelle involved in macromolecule catabolism, recycling, and signaling, and defects in these functions, due to defects in the lysosomal acid hydrolase enzymes or cofactors, can result in the accumulation of metabolites which cause cellular toxicity [45]. There are over 70 diseases which are identified as LSDs, most of which are inherited autosomal recessively [45]. Generally, LSDs are categorized according to the type of accumulated macromolecule, with the major categories including glycogenoses, mucopolysaccharidoses, and sphingolipidoses [46]. The pathophysiology of LSDs is directly associated with the accumulated toxic metabolite with affected individuals presenting with a wide spectrum of clinical symptoms [47–49]. An accumulation of toxic metabolites may be linked with an increase in lysosomal size/number, which has been associated with an increase in cellular OS, although the mechanisms responsible have yet to be fully elucidated [50]. Alternatively, since lysosomes are essential for autophagy, lysosomal dysfunction in LSDs may result in impaired autophagic clearance of dysfunctional mitochondria [51,52]. The observed accumulation of damaged mitochondria in LSDs has been associated with ROS generation, which may cause further mitochondrial impairment.
Melatonin and alcohol-related disorders
Published in Chronobiology International, 2020
Natalia Kurhaluk, Halyna Tkachenko
The lysosomal system constitutes the major degradative mechanism of the mammalian cell (Mindell 2012). Lysosomes are ubiquitous membrane-bound organelles that contain acid hydrolases, i.e., digestive enzymes responsible for the correct degradation of lysosomal content (Kirkegaard and Jäättelä 2009; Watts 2012; Witek et al. 2014). Lysosomes play a fundamental role during autophagy, as these organelles fuse with autophagosomes to digest their content and degrade cellular components, such as damaged cell organelles or misfolded proteins (Blomgran et al. 2007; Roberg and Ollinger 1998). Compared to other organs, alcohol accumulates in the largest amount in brain tissue. Alcohol is eliminated from the brain much more slowly than from other organs. This suggests alcohol affects the brain and nervous system for a longer duration of time than other organs. High concentration of alcohol is also accumulated and eliminated relatively slowly from other organs and tissues, such as the ovaries, sperm and prostate (Cederbaum 2012; Jung and Namkoong 2014; Pohanka 2016).