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)

Pepstatin is a low molecular weight, potent inhibitor specific for acid proteases with a Ki value of about 10(-10)M for pepsin. The chemical structure of pepstatin is essentially a hexapeptide which contains two residues of an unusual amino acid, 4-amino-3-hydroxy-6-methylheptanoic acid (statine). The complete structure of pepstatin is isovaleryl-L-valyl-L-valyl-statyl-L-alanyl-statine. To study its mode of inhibition, we prepared several derivatives and measured their kinetics of inhibition. Both N-acetyl-statine and N-acetyl-alanyl-statine are competitive inhibitors for pepsin with Ki values of 1.2 x 10(-4)M and 5.65 x 10(-6)M, respectively. The Ki value for N-acetyl-valyl-statine is 4.8 x 10(-6)M. These statyl derivatives, therefore, are very strong inhibitors. The Ki value for N-acetyl-statine is 600-fold smaller than that of its structural analog N-acetyl-leucine. The derivative which contains two statyl residues in a tetrapeptide exhibits inhibitory properties which approach those of pepstatin itself. Other acid proteases, human pepsin, human gastricsin, renin, cathepsin D, the acid protease from R. chinensis and bovine chymosin, also are inhibited by pepstatin and its derivatives. We suggest that the statyl residue is responsible for the unusual inhibitory capability of pepstatin and that statine is an analog of the previously proposed transition state for catalysis by pepsin and other acid proteases.
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PMID:Pepstatin inhibition mechanism. 33 90

Four derivatives of pepstatin, each of which contains the unusual amino acid 4-amino-3-hydroxy-6-methylheptanoic acid (statine) have been prepared. All four are porcine pepsin inhibitors. Both N-acetylstatine and N-acetyl-alanyl-statine are competitive inhibitors for pepsin with Ki values of 1.2 X 10(-4) M and 5.65 X 10(-6) M, respectively. The Ki values for N-acetyl-valyl-statine is 4.8 X 10(-6) M. These statyl derivatives, therefore, are very strong inhibitors. The Ki value for N-acetyl-statine is 600-fold smaller than that of its structural analog N-acetyl-leucine. The derivative which contains two statyl residues in a tetrapeptide exhibits inhibitory properties which approach those of pepstatin itself. Other acid proteases, human pepsin, human gastricsin, renin, cathepsin D, the acid protease from Rhizopus chinensis and bovine chymosin, also are inhibited by pepstatin and its derivatives. It is suggested that the statyl residue is responsible for the unusual inhibitory capability of pepstatin and that statine is an analog of the previously proposed transition state for catalysis by pepsin and other acid proteases.
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PMID:Mode of inhibition of acid proteases by pepstatin. 99 6

1. Five synthetic peptides which together spanned the propart segment of human prorenin were tested for their ability to interact with human renin, pepsin, gastricsin, cathepsin D, cathepsin E, calf chymosin and the aspartic proteinase from Endothia parasitica. 2. While two peptides showed no significant effect with any of the enzymes, a further two were cleaved by several enzymes. 3. Only one (corresponding to the 32P-43P residues in the propart sequence) acted as a weak competitive inhibitor of most of the enzymes.
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PMID:Inhibition of aspartic proteinases by synthetic peptides derived from the propart region of human prorenin. 173 96

The effect of alpha 2-macroglobulin, one of the major antiproteinases in the plasma of vertebrates, on the action of the aspartic proteinases chymosin, cathepsin D and cathepsin E towards peptide and protein substrates at pH 6.2 was examined. Activities towards protein substrates were blocked, thus demonstrating that alpha 2-macroglobulin can inhibit aspartic proteinases, in addition to serine proteinases, cysteine proteinases and metalloproteinases.
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PMID:Inhibition of aspartic proteinases by alpha 2-macroglobulin. 247 14

The amino acid sequence of endothiapepsin, the aspartic protease from Endothia parasitica has been determined. The enzyme consists of 330 residues. The sequence determination was performed exclusively at the protein level. The homology of this fungal milk-clotting enzyme with aspartic proteases is demonstrated by alignment with pepsin, chymosin, gastricsin, renin, and cathepsin D from various vertebrates and proteinase A from Saccharomyces cerevisiae showing 25-30% identity. The identity with mucor rennin from Mucor pucillus was 21% and with penicillopepsin from Penicillium janthinellum 53%, the fungal enzymes thus representing the lowest as well as the highest degree of homology.
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PMID:Amino acid sequence of endothiapepsin. Complete primary structure of the aspartic protease from Endothia parasitica. 330 16

Cathepsin D (EC 3.4.23.4) was purified from rabbit skeletal muscle using acetone-dried muscle powder as starting material. After the acetone-dried powder was extracted with 0.2 mM ATP, the extract was fractionated with acetone an subjected to DEAE-Sephadex A-50 and Sephadex G-100 column chromatography. Rechromatography on a Sephadex G-100 column resulted in a purified preparation. SDS-polyacrylamide gel electrophoresis of the purified enzyme showed one major band of 42,000 daltons and some bands of contaminants. Since gel filtration also indicated a value of 42,000 daltons for the enzyme, it was concluded that muscle cathepsin D has no subunit structure. The enzyme acted optimally towards myofibrils around pH3, resulting in the degradation of the myosin heavy chain and production of a 30,000-dalton component.
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PMID:Purification of cathepsin D from rabbit skeletal muscle and its action towards myofibrils. 731 36

The gene organization and nucleotide sequence of an aspartic proteinase (AP) of plant origin were first disclosed by cDNA and genomic DNA cloning of a rice AP (oryzasin). The deduced amino acid sequence of oryzasin 1 was significantly similar to those of other APs (34-85%), with highest similarity (85%) to barley AP (HvAP). Oryzasin 1, as well as HvAP, is distinct from animal and microbial APs in that the plant APs contain a unique 104-amino-acid insertion in the C-terminal region. The oryzasin 1 gene spans approximately 6.6 kbp and is composed of 14 exons and 13 introns. The exon-intron organization of the oryzasin 1 gene is totally different from those of genes for animal and microbial APs such as human cathepsin D, rat renin, bovine chymosin, aspergillopepsin A of Aspergillus awamori, proteinase A of Saccharomyces cerevisiae and rhizopuspepsin of Rhizopus niveus, despite the fact that oryzasin 1 shows overall sequence similarity to these APs.
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PMID:Rice aspartic proteinase, oryzasin, expressed during seed ripening and germination, has a gene organization distinct from those of animal and microbial aspartic proteinases. 755 74

Aspartic proteinases are produced in the human body by a variety of cells. Some of these proteins, examples of which are pepsin, gastricsin, and renin, are secreted and exert their effects in the extracellular spaces. Cathepsin D and cathepsin E on the other hand are intracellular enzymes. The least characterized of the human aspartic proteinases is cathepsin E. Presented here are results of studies designed to characterize the binding specificities in the active site of human cathepsin E with comparison to other mechanistically similar enzymes. A peptide series based on Lys-Pro-Ala-Lys-Phe*Nph-Arg-Leu was generated to elucidate the specificity in the individual binding pockets with systematic substitutions in the P5-P2, and P2'-P3' based on charge, hydrophobicity, and hydrogen bonding. Also, to explore the S2 binding preferences, a second series of peptides based on Lys-Pro-Ile-Glu-Phe*Nph-Arg-Leu was generated with systematic replacements in the P2 position. Kinetic parameters were determined for both sets of peptides. The results were correlated to a rule-based structural model of human cathepsin E, constructed on the known three-dimensional structures of several highly homologous aspartic proteinases; porcine pepsin, bovine chymosin, yeast proteinase A, human cathepsin D, and mouse and human renin. Important specificity-determining interactions were found in the S3 (Glu-13) and S2 (Thr-222, Gln-287, Leu-289, Ile-300) subsites.
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PMID:Exploring the binding preferences/specificity in the active site of human cathepsin E. 756 64

The ability of cathepsin D, chymosin, pepsin and renin to produce endothelin-1 (ET-1) from proendothelin-1 (proET-1) was compared. No significant conversion was observed when proET-1 was incubated with up to 1 U of renin for 15 min at 37 degrees C. Cathepsin D generated, as well as degraded, ET-1 rapidly. Net production of ET-1 reached a maximum when 0.003 U of cathepsin D was used, and about 16% of the initial proET-1 was detected as ET-1 by HPLC. Pepsin up to 1 U converted proET-1 into ET-1 dose-dependently with a maximum of 71% conversion. A further increase of the amount of pepsin in the reaction mixture produced nonspecific cleavage of ET-1. Less than 10% of ET-1 remained in the presence of 15 U of pepsin. Chymosin also generated ET-1 dose-dependently, and a complete conversion was obtained at 1 U of enzyme. Greater than 1 U of chymosin only slightly degraded ET-1; at least 80% of ET-1 was still present when 15 U of chymosin was included in the assay. Other properties associated with the conversion of proET-1 into ET-1 by chymosin were investigated. Similar to authentic ET-1, the product of chymosin treatment caused contraction of isolated rabbit aortic rings, and pre-incubation of chymosin with pepstatin A abolished this contractile response.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Conversion of proendothelin-1 into endothelin-1 by aspartylproteases. 822 77

Cathepsin D is an indigenous aspartic proteinase in bovine milk. By competitive enzyme-linked immunosorbent assay the amount of immunoreactive cathepsin D and procathepsin D in bovine skim milk was estimated to be 0.4 microgram/ml. Immunoreactive cathepsin D purified from whey consisted of a small fraction of mature cathepsin D, but the major form was the proenzyme procathepsin D. A preparation of bovine milk procathepsin D was, like mature cathepsin D, able to degrade purified alpha s1-, alpha s2-, beta- and kappa-casein and alpha-lactalbumin, while beta-lactoglobulin was resistant to cleavage. The cleavage sites in these proteins were determined and compared with those of chymosin. Cathepsin D was capable of generating the alpha s1-I, beta-I, beta-II and beta-III fragments originally described from the action of chymosin on the respective caseins, and these fragments were subjected to further proteolysis. Cathepsin D was also able to liberate the caseinomacropeptide from purified kappa-casein, and to coagulate bovine skim milk. This demonstrated that milk contains an indigenous coagulation enzyme present mainly in the whey fraction.
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PMID:Bovine milk procathepsin D and cathepsin D: coagulation and milk protein degradation. 865 37


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