Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The NH2-terminal heterogeneity which is generated in bovine GH during its extraction from mildly acidified pituitary homogenates is attributable to a newly identified peptidase. The beta-naphthylamide of Phe-Pro-Ala, modeled after the NH2-terminal tripeptide sequence of the phenylalanyl monomer of bovine growth hormone, was cleaved by the peptidase into the tripeptide and B-naphthylamine and served as a substrate for assay of the eznyme. However, the B-naphthylamide of Ala-Phe-Pro, modeled after the NH2-terminal tripeptide sequence of the alanyl monomer, was not cleaved. In harmony with this specificity, the peptidase cleaved 11 tripeptides sequentially from the NH2-terminus of the phenylalanyl monomer of bovine GH but none from the alanyl monomer. Six of the tripeptides nearest the NH2-terminus were unequivocally identified and their sequences were consistent with the NH2-terminal octadecapeptide sequence of the phenylalanyl monomer of bovine GH. Five additional peptides were by composition consistent with their being tripeptides derived from residues 19--33. Because of the apparent specificity for the hydrolytic release of tripeptides and inability to cleave substituted tripeptidyl derivatives, the enzyme is considered to be a tripeptidyl aminopeptidase. In its hydrolysis of phenylalanyl monomers of rat growth hormone, a similar number of tripeptides was released, associated with which there was a 70% loss of biological activity but no reduction in immunological activity. The enzyme could be solubilized by extraction with 1% Triton X-100 at pH 3.0, precipitated between 2 and 3 M (NH4)2SO4, and further purified by gel filtration on G-75 in M/10 acetic acid. The enzyme has a mol wt of 57,000 and is optimally active at pH 4. It can be differentiated from cathepsin D by its insensitivity to inhibition by pepstatin.
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PMID:Identification of a tripeptidyl aminopeptidase in the anterior pituitary gland: effect on the chemical and biological properties of rat and bovine growth hormones. 74 18

To elucidate whether pesticide toxicity in higher animals involves pesticide-induced dysfunction of the intracellular protein catabolic process, we have determined the effect in vivo of the organophosphate insecticide pirimiphos-methyl on the activities of representative protein catabolising cytoplasmic and lysosomal proteases (responsible for the various stages of the protein degradation cascade and essential for normal cell functioning) in heart, kidney, brain and liver target tissues in the rat. In liver tissue (the major site of pesticide metabolism), the activities of all of the cytoplasmic proteases investigated (alanyl-, arginyl-, leucyl aminopeptidases, dipeptidyl aminopeptidase IV, tripeptidyl aminopeptidase, proline endopeptidase) were significantly inhibited (by 20-40% of control activity) following administration of 10 mg pirimiphos-methyl/kg bodyweight, whereas of the lysosomal proteases investigated, only the activities of dipeptidyl aminopeptidase I and cathepsin D were significantly reduced (by 15-20% of control activity). In contrast, there was no insecticide-induced inhibition of protease activities in heart, kidney or brain tissues; some lysosomal enzymes (dipeptidyl aminopeptidase I, cathepsins L and D) showed significantly increased activities in these tissues (the reason for which remains to be determined). We conclude that the effect of pirimiphos-methyl on proteolytic enzyme activities differs in different target tissues, and that pirimiphos-methyl induced inhibition of proteases in liver tissue may represent a previously unrecognised toxicity hazard in higher animals.
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PMID:Effect of pirimiphos-methyl on proteolytic enzyme activities in rat heart, kidney, brain and liver tissues in vivo. 920 12

Neuronal ceroid lipofuscinoses (NCL) form a distinct group of storage diseases where the normal development of the central nervous system is interrupted and neurons of the neocortex begin to degenerate. Mutations in genes encoding three lysosomal enzymes are the causes for three early-onset forms of NCLs: palmitoyl-protein thioesterase 1 (PPT1) is deficient in human infantile NCL, tripeptidyl peptidase 1 (TTP1) in late-infantile NCL, and cathepsin D in congenital ovine NCL. We wanted to compare the developmental expression profiles of these enzymes in rat brain. In conclusion, the PPT1 expression pattern differed from the two other lysosomal enzymes implicated in NCL diseases, thus suggesting a distinctive role for PPT1 in brain development.
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PMID:Developmental changes in the expression of neuronal ceroid lipofuscinoses-linked proteins. 1100 10

Adverse effects of doxorubicin (adriamycin) have been reported to be due to iron-catalyzed free radical formation, which can be prevented with the cytoprotective chelating agent [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)]propane (dexrazoxane; ICRF-187). Affected tissues include the heart, gastrointestinal tract, and kidney. However, there is very little information on the effects of adriamycin on skeletal muscle, despite the fact that there is direct and indirect evidence to show that both adriamycin and ICRF-187 are myotoxic. To investigate the mechanisms of cytotoxicity of these agents in skeletal muscle, we have conducted a systematic investigation of the activities of the major lysosomal (dipeptidyl aminopeptidase I and II and cathepsins B, D, H, and L) and cytoplasmic (alanyl-, arginyl-, and leucyl aminopeptidase, dipeptidyl aminopeptidase IV, tripeptidyl aminopeptidase, and proline endopeptidase) muscle proteases. These enzymes play an important role in normal cellular function and represent potential targets for toxic and protective agents. Male Wistar rats (approx. 0.2 kg) were subjected to a pretreatment phase of 30 min followed by a treatment stage of either 2.5 or 24 h. The pretreatment involved injection of a single bolus of either saline (0.15 mol/l NaCl; 5 ml/kg ip) or ICRF-187 (100 mg/kg; 5 ml/kg ip). After 30 min, rats were injected again with a single bolus of either adriamycin (5 mg/kg; 10 ml/kg ip) or saline (0.15 mol/l NaCl; 10 ml/kg ip) in the treatment phase. At either 2.5 or 24 h after the last adriamycin or saline injection, rats were killed for subsequent dissection of the gastrocnemius muscle for analysis. In the 2.5-h study, there were significant reductions in cathepsin D activities of adriamycin-treated rats compared to saline injected control (p = 0.02). In both 2.5- and 24-h studies there were also significant differences (p = 0.05) in cathepsin H activities between rats treated with adriamycin and ICRF-187, although these differences were not significant when data were compared with corresponding saline-injected rats. There were no other overt effects for any of the other proteases at either 2.5 or 24 h. We conclude that both adriamycin and ICRF-187 have very little effect on the activities of muscle proteases and that altered proteolysis is not involved in the reported pathological reactions induced by these agents.
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PMID:Effects of Doxorubicin (Adriamycin) and [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)]propane (ICRF-187) on skeletal muscle protease activities. 1124 12

The neuronal ceroid lipofuscinoses (NCL, also known as Batten disease) is a devastating neurodegenerative diseases caused by mutations in either soluble enzymes or membrane-associated structural proteins that result in lysosome dysfunction. Different forms of NCL were defined initially by age of onset, affected population and/or type of storage material but collectively represent the most prevalent pediatric hereditary neurovisceral storage disorder. Specific gene mutations are now known for each subclass of NCL in humans that now largely define the disease: cathepsin D (CTSD) for congenital (CLN10 form); palmitoyl protein thioesterase 1 (PPT1) for infantile (CLN1 form); tripeptidyl peptidase 1 (TPP1) for classic late infantile (CLN2 form); variant late infantile-CLN5, CLN6 or CLN8 for variant late infantile forms; and CLN3 for juvenile (CLN3 form). Several mouse models of NCL have been developed, or in some cases exist sporadically, that exhibit mutations producing a progressive neurodegenerative phenotype similar to that observed in human NCL. The study of these mouse models of NCL has dramatically advanced our knowledge of NCL pathophysiology and in some cases has helped delineate the function of proteins mutated in human NCL. In addition, NCL mutant mice have been tested for several different therapeutic approaches and as such they have become important pre-clinical models for validating treatment options. In this review we will assess the current state of mouse models of NCL with regards to their unique pathophysiology and how these mice have helped investigators achieve a better understanding of human NCL disease and therapy.
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PMID:Mouse models of neuronal ceroid lipofuscinoses: useful pre-clinical tools to delineate disease pathophysiology and validate therapeutics. 2250 4