Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of recombinant lysosomal enzymes for enzyme replacement therapy (ERT) is likely to be a necessary component of effective treatment regimens for lysosomal storage diseases (LSDs). The mechanism and rate of uptake into target cells, rate of disappearance of the enzyme from plasma, and its tissue distribution are important factors to assess the need for possible modifications to the enzyme, particularly for LSDs that affect the central nervous system (CNS). Two recombinant lysosomal enzymes, caprine N-acetylglucosamine-6-sulfatase (rc6S) and human N-acetylgalactosamine-4-sulfatase (rh4S), deficient in MPS IIID and MPS VI, respectively, were radiolabeled and purified. The major portion (>77%) of each recombinant enzyme contained the mannose-6-phosphate (M6P) recognition marker as demonstrated by their ability to bind to a M6P receptor affinity column. The uptake of 3H-rc6S and 3H-rh4S into cultured rat brain cells was also inhibited by the addition of 5 mM M6P to the culture medium. After iv administration of 0.4-0.5 mg/kg of 3H-rc6S and 1 mg/kg of 3H-rh4S to the rat, both enzymes were rapidly lost from the circulation in a biphasic fashion (t1/2 for 3H-rc6S = 1.25+/-0.15 min and 37.17+/-23.29 min; t1/2 for 3H-rh4S = 0.41 and 5.3 min). At this dose, about 6% of 3H-rc6S, but only 0.49% of 3H-rh4S, remained in the plasma 4 h after administration, whereas approx 30% of 3H-rc6S and more than 50% of 3H-rh4S was found in the liver. At doses of 1.6-2.0 mg/kg of 3H-rc6S and 1 mg/kg 3H-rh4S, but not at the lower dose of 3H-rc6S, trace levels of both 3H-rc6S and 3H-rh4S were detected in the brain. The low level of enzyme recovered from the brain suggests that modification of rc6S will be necessary to achieve sufficient enzyme uptake into the CNS for effective therapy of MPS IIID.
J Mol Neurosci 1998 Dec
PMID:Recombinant caprine 3H-[N-acetylglucosamine-6-sulfatase] and human 3H-[N-acetylgalactosamine-4-sulfatase]: plasma clearance, tissue distribution, and cellular uptake in the rat. 1034 92

Mucopolysaccharidosis type IIID (MPS IIID) is a lysosomal storage disorder resulting from lack of activity of the lysosomal hydrolase N-acetylglucosamine 6-sulfatase (6S) (EC 3.1.6.14). The syndrome is associated with systemic and central nervous system (CNS) heparan sulfate glycosaminoglycan (HS-GAG) accumulation, secondary storage of lipids, and severe, progressive dementia. In this investigation, caprine MPS IIID, established as a large animal model for the human disease, was used to evaluate the efficacy of enzyme replacement therapy (ERT). Recombinant caprine 6S (rc6S) (1 mg/kg/dose) was administered intravenously to one MPS IIID goat kid at 2, 3, and 4 wks of age. Five days after the last dose, the uronic acid (UA) content and the composition of uncatabolized HS-GAG fractions in the brain of the ERT-treated MPS IIID kid were similar to those from a control, untreated MPS IIID animal. However, hepatic uronic acid levels in the treated MPS IIID kid were approximately 90% lower than those in the untreated MPS IIID control; whereas the composition of the residual hepatic HS-GAG was identical to that in the untreated animal. Marked reduction of lysosomal storage vacuoles in hepatic cells of the treated MPS IIID kid was observed, but ERT had no effect on CNS lesions. No residual 6S activity was detected in brain or liver. This preliminary investigation indicates that other treatment regimens will be necessary to ameliorate MPS III-related CNS lesions.
J Mol Neurosci 2000 Dec
PMID:Caprine mucopolysaccharidosis IIID: a preliminary trial of enzyme replacement therapy. 1130 88

During fasting of animals, there is decreased content of skin glycosaminoglycans (GAGs) accompanied by decrease in their biosynthesis. Since tissue GAG content depends on both synthesis and degradation of these molecules, we asked whether fasting affects the activity of several tissue glycosidases. Therefore we measured the activity of skin neutral and acidic endoglycosidases, some exoglycosidases: beta-N-acetylhexosaminidase [EC 3.2.1.30], beta-galactosidase [EC 2.1.23], beta-glucuronidase [EC 3.2.1.31], alpha-iduronidase [EC 3.2.1.76], and two sulfatases: arylsulfatase B [EC 3.1.6.1] and 6-sulfatase [EC 3.1.6.14] in the skin of control and fasted rats. Although fasting was accompanied by distinct decrease in the activity of most neutral endoglycosidases, no characteristic changes in the activity of exoglycosidases were found. In contrast, we found that fasting is associated with increase in the activity of acidic endoglycosidases (of lysosomal origin) which degraded hyaluronic acid, chondroitin-4-sulfate, chondroitin-6-sulfate and heparin. The same GAGs were decreased in the skin of fasted rats. Our data suggest that the phenomenon is a result of increased intracellular degradation of these molecules. Therefore, not only decreased biosynthesis of GAGs during fasting, but also increased their intracellular degradation may contribute to decrease in GAG skin content.
Comp Biochem Physiol B Biochem Mol Biol 2002 Mar
PMID:Glycosaminoglycan-degrading enzymes in the skin of fasted rats. 1195 38

Mucopolysaccharidosis IIID (MPS IIID) is a lysosomal storage disease associated with deficient activity of the enzyme N-acetylglucosamine 6-sulfatase (EC 3.1.6.14), a lysosomal hydrolase in the heparan sulfate glycosaminoglycan (HS-GAG) degradation pathway. In caprine MPS IIID, enzyme replacement therapy reversed early postnatal systemic but not primary or secondary central nervous system (CNS) substrate accumulations. The caprine MPS IIID large animal model system was used in this investigation to define the developmental profile of morphological and biochemical perturbations to estimate a time frame for therapeutic intervention. Light and electron microscopy were used to compare the CNS, liver, and kidney of normal +/+, MPS IIID carrier +/-, and MPS IIID-affected -/- goat kids (kids), at 60, 113-114, 128-129, and 135 d gestation (dg) of a 150-d gestational period, at birth, and at 59-64 d of postnatal (d-pn) age. In the CNS of -/- kids, morphological correlations of HS-GAG and glycolipid accumulations were evident in early differentiating neurons at 60 dg. CNS and systemic developmental, regional, and cellular differences in -/- kids at all time points included more prominent and earlier accumulation of lucent, putative HS-GAG substrates in lysosomes of meningeal and perivascular macrophages and hepatic sinusoidal cells than in CNS, hepatic, or renal parenchymal cells. The amounts and compositions of HS-GAG substrates in the brain and liver of +/+, +/-, and -/- kids were determined at 60, 65, 113-114, and 128-135 dg, at birth, and 53-78 d-pn. In the CNS of -/- kids, HS-GAG concentrations were variable and exceeded those of age-matched control tissue samples in the third but not the second trimester. In contrast, hepatic HS-GAG levels in -/- kids exceeded control values at all time points evaluated and paralleled the progressive morphological alterations. CNS and hepatic HS-GAG compositions in -/- kids were similar to each other and were more complex at all pre- and postnatal ages than those from control kids. Based on the time frame of development of CNS lesions and biochemical perturbations, prenatal therapeutic intervention in caprine MPS IIID is likely to be necessary to prevent or ameliorate substantive CNS and systemic lesions.
J Mol Neurosci 2004
PMID:Caprine mucopolysaccharidosis IIID: fetal and neonatal brain and liver glycosaminoglycan and morphological perturbations. 1545 41