Hydrolases lysosomal

The mannose 6-phosphate receptor is the cargo/coat-receptor for trans-Golgi network (TGN)-derived cla-thrin vesicles. The receptor recognizes the mannose 6-phosphate tag of lysosomal hydrolases on the luminal side and the adaptor-1 complex of clathrin on the cytoplasmic face. 

Genetic Deficiencies of Glycoprotein Lysosomal Hydrolases Cause Diseases Such as a-Mannosidosis... 

Figure 48-12. Schematic illustration of some aspects of the role of the osteoclast in bone resorption. Lysosomal enzymes and hydrogen ions are released into the confined microenvironment created by the attachment between bone matrix and the peripheral clear zone of the osteoclast. The acidification of this confined space facilitates the dissolution of calcium phosphate from bone and is the optimal pH for the activity of lysosomal hydrolases. Bone matrix is thus removed, and the products of bone resorption are taken up into the cytoplasm of the osteoclast, probably digested further, and transferred into capillaries. The chemical equation shown in the figure refers to the action of carbonic anhydrase II, described in the text. (Reproduced, with permission, from Jun-queira LC, Carneiro J BasicHistology. Text Atlas, 10th ed. McGraw-Hill, 2003.)...

The GAGs are synthesized by the sequential actions of a battery of specific enzymes (glycosyltransferases, epimerases, suhotransferases, etc) and are degraded by the sequential action of lysosomal hydrolases. Genetic deficiencies of the latter result in mucopolysaccharidoses (eg, Hurler syndrome). 

The retrieval mechanism for the M6P receptor resembles the one previously described for the H/KDEL receptor [53]. Optimal binding of M6P receptor to M6P occurs at pH 6.5-6.7, the pH found in the TGN. When transport vesicles arrive at late endosomes, the pH is lowered by the action of H+ pumps. The affinity of the M6P receptor for its ligands is reduced at acid pHs, resulting in M6P receptor releasing the M6P in the late endosome. As a result, transport of lysosomal hydrolases occurs unidirectionally. Once the M6P receptor releases M6P-bearing hydrolases, the receptor can be returned to the TGN for reuse. Transport of the M6P receptor to either TGN or late endosome relies on signal peptides on the cytoplasmic tail region of the M6P receptor. 

Under some circumstances, lysosomal hydrolases may fail to be properly packaged in the TGN, so they enter the default pathway to the cell surface, where they are secreted. Although these hydrolases do little harm at the nearly neutral pH of most extracellular fluids, they can also be returned to lysosomes by a pathway known as receptor-mediated endocytosis. In this pathway, M6P receptors are sent to the plasma membrane, where they bind escaped lysosomal hydrolases and bring them back to lysosomes through the early and late endosomes. Receptor-mediated endocytosis is a major component of the endocytic pathways for trafficking of membrane proteins and merit more detailed consideration. 

Primary lysosomal hydrolase defects 685 Other types of lysosomal disorder 688... 

Primary lysosomal hydrolase defects. Two-thirds of the lysosomal storage diseases involve defects in genes that code for acid hydrolases. Table 41-2 lists 29 defects that have been defined so far. They have an autosomal recessive mode of inheritance, except for Hunter s syndrome and Fabry s disease, where the mode is X-linked recessive. The defective genes have been identified and mutations have been defined for nearly all. The nervous system is involved in most. Many of the disorders show a wide range of clinical severity, which may range from death in early childhood to a moderate disability in adulthood. 

Canine submaxillary mucins (34) Glycopeptide hormones (99,109) Lysosomal hydrolases (110)... 

The weak base chloroquine (30-300 pM, 30 minutes, either in the presence or absence of serum) increases the endosomal pH (83) within a few minutes (45), leading to pH values close to 6.3 in both endosomes and lysosomes and therefore preventing lysosomal degradation. As a mechanism of action, a direct inhibition of lysosomal hydrolases (cathepsin B1 and some phospholipases and lysophospholipases) is reported (82). In Kupffer cells, effects are tolerated at concentrations of 40 pM or less for up to four hours and are irreversible within two hours after medium replacement (82). 

In contradistinction to the decrease in lysosomal enzyme activity observed in alveolar macrophages and bronchial lavage fluid, Dillard et al. reported that continuous ozone exposure (0.70-0.79 ppm for 5-7 days) resulted in an increase in the activity of some lysosomal hydrolases in rat whole-lung homogenates and lung fractions, including the soluble supernatant. The tocopherol concentrations of the diet had no effect on the findings. 

Ozone might interfere with the intracellular bactericidal capabilities of alveolar macrophages by inactivating lysosomal hydrolases, or perhaps through the destruction of heme-containing enzymes that are apparentiy involved in producing superoxide anion radical. Further evaluation of the process by which relatively low concentrations of ozone potentiate bacterial infection would be of value. 

Continuous for 5-7 days Increased activity of lysosomal hydrolases in whole-lung homogenates Rat 48... 

Hurst, D. J., and D. L. Coffin. Ozone effect on lysosomal hydrolases of alveolar macrophages in vitro. Arch. Intern. Med. 127 1059-1063, 1971. 

Krabbe disease is caused by inherited deficiency of the lysosomal hydrolase galactocerebrosidase, the enzyme responsible for degradation of gaiactosyiceramide, a component of the myelin sheath, and other galactosphingosines (eg, psychosine). 

Cataldo AM, Paskevich PA, Kominami E, et al Lysosomal hydrolases of different classes are abnormally distributed in brains of patients with Alzheimer s disease. Proc Natl Acad Sci U S A 88 10998-11002, 1991... 

In mouse liver and kidney and in rat liver, a-D-mannosidase activity appeared to be equally distributed between the two cytoplasmic-granule fractions. With mouse spleen and cancer tissue, a considerable proportion of the enzyme was found free in the cytoplasm. Rat spleen, on the other hand, lacked this cytoplasmic fraction. Inasmuch as the enzyme within the cytoplasmic granules was not fully active in a sucrose homogenate until the membranes had been disintegrated, a-D-mannosidase conforms to the definition of a lysosomal hydrolase. 

Any dialogue on meat flavor development and deterioration requires a brief discussion of muscle structure. Muscle has a highly compact and complex multicellular structural organization (Figure 2). Individual muscle cells contain numerous mitochondria and nuclei. They also contain contractile elements as the bulk of their structure. While the sarcoplasm of muscle (the aqueous non-organellar component) is small compared to the cytoplasm of non-muscle cells, it does have a highly evolved system of membranes called the SR/L representing an acronym for sarcoplasmic reticulum/lysosomal membrane system (11). The SR/L surrounds each contractile element (Fig. 9-13 in 12 Fig. 7-10 in 13). The close proximity of the SR/L to the contractile proteins situates the proteins in a location that is optimal for their hydrolysis by lysosomal hydrolases (12, 13). 

Previous studies have shown that muscle lysosomal hydrolases are released early in the postmortem period due to a decrease in intracellular ATP concentrations. The decreased intracellular ATP level causes the rupture of the lysosomal membrane (14), releasing hydrolytic enzymes (proteases, lipases, and glycosidases) that further potentiate the weakening of membrane integrity and cellular function. Furthermore, as the acidosis increases (due to the anaerobic conditions associated with cellular death) the intramuscular pH to levels reach that which are optimal for the activity of several lysosomal thiol proteinases. 

Genetic defects in the degradation of glycoproteins are representative of lysosomal storage disorders. Each disease is caused by a deficiency of a lysosomal hydrolase, accumulation and urinary excretion of substrates, a progressive clinical course and considerable phenotypic variation. These disorders also manifest the clinical symptoms normally associated with genetic mucopolysaccharidoses, namely coarse facies, dysostosis multiplex and/or ocular involvement. 

The attention of biochemists has been drawn to the importance of pathways of degradation of complex polysaccharides through the existence of at least 35 inherited lysosomal storage diseases 347-351 In many of these diseases one of the 40-odd lysosomal hydrolases is defective or absent. 

Various natural, chemically modified and mixtures of flavonoids are widely used therapeutically as venous protective or venotonic drugs in chronic venous insufficiency and haemorrhoidal attacks. Flavonoids have been found to inhibit increased vessel wall permeability, fluid changes in the capillary bed and diffusion of plasma proteins. In addition, they may exert a protective effect on the perivascular tissues due to their antihyaluronidase effect and the inhibition of lysine oxidase (producing crosslinks in collagen and elastin) and lysosomal hydrolases (degrade glycosamines). All these effects may account for the venotonic effects of these drugs [5]. However, the venous effects of flavonoids are out of the scope of the present review. 

The process whereby newly synthesized proteins are directed to specific locations is referred to as protein targeting. Soluble lysosomal hydrolases are targeted to lysosomes... 

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