Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.2.1.31 (beta-glucuronidase)
 7,680 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. A partially purified lysosomal preparation was obtained from adult mouse livers by sucrose-density-gradient centrifugation of a large-granule fraction. 2. This lysosome-enriched subfraction was contaminated approx. 10% by mitochondrial cytochrome c oxidase and malate dehydrogenase. 3. Free acid phosphohydrolase and beta-glucuronidase contributed less than 10% of the total (Triton X-100-solubilized) activity in contrast with approx. 30% free N-acetyl-beta-d-glucosaminidase when assayed in an iso-osmotic incubation system. 4. Exposure of the lysosomal preparation to inorganic Hg(2+) ions and organic mercurials (p-chloromercuribenzoate, phenylmercuric acetate) induced an irreversible loss of structure-linked latency with resulting enzyme activation. 5. Maximal activation was related to log [Hg(2+)] and pH. The response was all-or-none for individual particles; the dose-response curve portrayed the variation in particle resistance within the lysosomal population. 6. l-Cysteine and GSH totally prevented Hg(2+) ion-induced hydrolase activation. Ascorbate provided approx. 50% protection. 7. The three lysosomal hydrolases were differentially activated at constant [Hg(2+)], suggesting a different pattern of binding, unique for each enzyme studied.
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PMID:Effect of mercurial compounds on structure-linked latency of lysosomal hydrolases. 429 23

Granules from rabbit peritoneal leucocytes were prepared in 0.3 M sucrose as an optically homogeneous suspension with the aid of heparin. Lysis of the granules in vitro was followed by measurement of decreases in the apparent absorbance of the suspensions at 520 mmicro and was accompanied by solubilization of beta-glucuronidase from the particles. Streptolysins O and S from hemolytic streptococci lysed the granules at 20 degrees C; the initial rate of lysis by streptolysin O was greater than that by streptolysin S. Cysteine activated, and specific antibody inhibited, streptolysin O; antimycin and bovine serum albumin inhibited streptolysin S. The granules were not lysed by any other streptococcal exotoxins. Lysis was irreversible and depended neither upon oxidative phosphorylation, nor upon intact respiration. The granules were also lysed by lysolecithin, at concentrations from 2 x 10(-6)M to 1 x 10(-4)M; bovine serum albumin and antimycin also inhibited this lytic agent. Such other hemolytic agents and procedures as vitamin A, non-ionic detergents, and ultraviolet irradiation also disrupted leucocyte granules. In susceptibility to lysis and other properties, the granules of white cells resembled erythrocytes. Leucocyte granules differed from mitochondria in that they did not appear to take up or extrude water reversibly; they were unaffected by thyroxine, phosphate, or metabolic substrate. The studies are compatible with the hypotheses that white cell granules are similar to lysosomes isolated from other tissues, and that they share common surface properties with erythrocytes.
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PMID:STUDIES ON LYSOSOMES. V. THE EFFECTS OF STREPTOLYSINS AND OTHER HEMOLYTIC AGENTS ON ISOLATED LEUCOCYTE GRANULES. 1419 5

A beta-glucuronide-based linker for attaching cytotoxic agents to monoclonal antibodies (mAbs) was designed and evaluated. We employed the cytotoxic auristatin derivatives MMAE (1a) and MMAF (1b) and doxorubicin propyloxazoline (DPO, 2) to give the beta-glucuronide drug-linkers 9a, 9b, and 17, respectively. Cysteine-quenched derivatives of 9b and 17 were determined to be substrates for E. coli beta-glucuronidase, resulting in facile drug release. The beta-glucuronide MMAF drug-linker 9b was highly stable in rat plasma with an extrapolated half-life of 81 days. Each drug-linker when conjugated to mAbs c1F6 (anti-CD70) and cAC10 (anti-CD30) gave monomeric antibody-drug conjugates (ADCs) with as many as eight drugs per mAb and had high levels of immunologically specific cytotoxic activity on cancer cell lines. cAC10-9a displayed pronounced antitumor activity in a subcutaneous Karpas 299 lymphoma tumor model. A single dose treatment led to cures in all animals at the 0.5 mg/kg dose level and above, and the conjugate was well tolerated at 100 mg/kg. In mice with subcutaneous renal cell carcinoma xenografts, the MMAF conjugate c1F6-9b was tolerated at 25 mg/kg and efficacious at 0.75 mg/kg. These results demonstrate that the beta-glucuronide linker system is an effective strategy for targeting cytotoxic agents providing ADCs with high degrees of efficacy at well-tolerated doses.
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PMID:Development and properties of beta-glucuronide linkers for monoclonal antibody-drug conjugates. 1670 24