Cathepsin A/protective protein: an unusual lysosomal multifunctional protein

Abstract

Cathepsin A/protective protein [3.4.16.5], carboxypeptidase A, is a lysosomal serine protease with structural homology to yeast (Saccharomyces cerevisiae) carboxypeptidase Y. Cathepsin A is a member of the alpha/beta hydrolase fold family and has been suggested to share a common ancestral relationship with other alpha/beta hydrolase fold enzymes, such as cholinesterases. Several lines of evidence indicate that cathepsin A is a multicatalytic enzyme with deamidase and esterase in addition to carboxypeptidase activities. Cathepsin A was recently identified in human platelets as deamidase. In vitro, it hydrolyzes a variety of bioactive peptide hormones including tachykinins, suggesting that extralysosomal cathepsin A plays a role in regulation of bioactive peptide functions. Recent reports emphasize the lysosomal protective function of cathepsin A rather than its protease function. The protective function of cathepsin A is distinct from its catalytic function. Human lysosomal beta-galactosidase and neuraminidase exist as a high molecular weight enzyme complex, in which there is a 54-kDa glycoprotein termed 'lysosomal protective protein'. Based on cell culture studies, protective protein was found to protect both beta-galactosidase and neuraminidase from intralysosomal proteolysis by forming a multienzyme complex and was shown to be deficient in patients with galactosialidosis, a combined deficiency of beta-galactosidase and neuraminidase. Molecular cloning and gene expression studies have disclosed that protective protein is cathepsin A. The cathepsin A precursor has the potential to restore both beta-galactosidase and neuraminidase activities in fibroblasts from patients with galactosialidosis. Cathepsin A knockout mice showed a phenotype similar to human galactosialidosis and the deficient phenotype found in the mutant mice was corrected by transplanting erythroid precursor cells overexpressing cathepsin A. Collectively, these findings demonstrate the significance of cathepsin A as a key molecule in the onset of galactosialidosis and also highlight the therapeutic potential of the cathepsin A precursor for patients with galactosialidosis.

Cathepsin A Is the Major Hydrolase Catalyzing the Intracellular Hydrolysis of the Antiretroviral Nucleotide Phosphonoamidate Prodrugs GS-7340 and GS-9131

“…In addition, the specific activities of the purified enzyme and the recombinant CatA towards GS-7340 were virtually identical (35 nmol ⅐ min Ϫ1 ⅐ g). DFP and 3,4-DCI are effective inhibitors of serine hydrolases, including CatA (6,11,17,22,26,32). Purified prodrug hydrolase and the recombinant CatA were both inhibited by 3,4-DCI and DFP with IC 50 s of ϳ0.5 M and 5 to 10 M, respectively (Table 2).…”

Mechanism of Activation of PSI-7851 and Its Diastereoisomer PSI-7977

“…Interestingly, our enzyme studies showed that CatA preferentially hydrolyzes PSI-7977, although CES1 prefers PSI-7976 as a substrate. The stereo-selective hydrolysis of an acyclovir phosphoramidate prodrug was previously demonstrated by using carboxypeptidase Y, a structural homolog of cathepsin A (31,32). A computer model of carboxypeptidase Y docked with a phosphoramidate prodrug in the active site suggested that positioning of the carbonyl moiety of the carboxyl ester with the R-phosphate diastereoisomer was more preferable for catalysis than with the S-diastereoisomer (31).…”

Familial Danish Dementia

“…8, the proteolytic degradation of ADan and A␤ reflects the activity of more than a single enzyme. A potential candidate for the C-terminal detyrosination of ADan is cathepsin A (carboxypeptidase A) (40), which is widely distributed in lysosomes and has broad specificity, releasing the C-terminal amino acid at optimum pH of 4.5-6.0. The cleavage at the ADan Ala 2 -Ser 3 peptide bond seems to be catalyzed by a dipeptidyl-peptidase, in a similar fashion as deposited ABri amyloid in FBD (6).…”