Cathepsin A Explained

Cathepsin A is an enzyme that is classified both as a cathepsin and a carboxypeptidase. In humans, it is encoded by the CTSA gene.^[1] The enzyme is also known as Human Protective Protein. It is a lysosomal serine carboxypeptidase. The enzyme is a zymogen and must be processed to produce a 32 kDa and 20 kDa large and small subunit, respectively, to become catalytically active. This cleavage can be done with Cathespin L in vitro.^{[2] [3]}

Structure

Cathepsin A contains a large and small subunit. The active site contains unusual pairs of carboxylic acids hydrogen bonded to one another, sometimes referred to as "Rebek pairs".^[4] The pairing of these carboxylic acids raises the pKa of one glutamate to ~13 while the other has a predicted pKa of ~6.^[5]

Function

This gene encodes a glycoprotein that associates with lysosomal enzymes beta-galactosidase and neuraminidase to form a complex of high-molecular-weight multimers. The formation of this complex provides a protective role for stability and activity. It is protective for β-galactosidase and neuraminidase.^[6]

Clinical significance

Deficiencies in this gene are linked to multiple forms of galactosialidosis.^[1]

Inhibition

Cathepsin A is one of 14 human enzymes commonly inhibited by organophosphate pesticides and phosphonate nerve agents. Cathepsin A can be inhibited by sarin, soman, cyclosarin, VX, and VR.^[7] After inhibition, it undergoes aging. The enzyme can be found in urine and blood.

Interactions

Cathepsin A has been shown to interact with NEU1.^[8]

Further reading

• Morreau H, Galjart NJ, Willemsen R, Gillemans N, Zhou XY, d'Azzo A . Human lysosomal protective protein. Glycosylation, intracellular transport, and association with beta-galactosidase in the endoplasmic reticulum . The Journal of Biological Chemistry . 267 . 25 . 17949–17956 . September 1992 . 1387645 . 10.1016/S0021-9258(19)37135-2 . free .
• Halal F, Chitayat D, Parikh H, Rosenblatt B, Tranchemontagne J, Vekemans M, Potier M . Ring chromosome 20 and possible assignment of the structural gene encoding human carboxypeptidase-L to the distal segment of the long arm of chromosome 20 . American Journal of Medical Genetics . 43 . 3 . 576–579 . June 1992 . 1605251 . 10.1002/ajmg.1320430314 .
• Jackman HL, Tan FL, Tamei H, Beurling-Harbury C, Li XY, Skidgel RA, Erdös EG . A peptidase in human platelets that deamidates tachykinins. Probable identity with the lysosomal "protective protein" . The Journal of Biological Chemistry . 265 . 19 . 11265–11272 . July 1990 . 1694176 . 10.1016/S0021-9258(19)38586-2 . free .
• Zhou XY, Galjart NJ, Willemsen R, Gillemans N, Galjaard H, d'Azzo A . A mutation in a mild form of galactosialidosis impairs dimerization of the protective protein and renders it unstable . The EMBO Journal . 10 . 13 . 4041–4048 . December 1991 . 1756715 . 453152 . 10.1002/j.1460-2075.1991.tb04980.x .
• Galjart NJ, Morreau H, Willemsen R, Gillemans N, Bonten EJ, d'Azzo A . Human lysosomal protective protein has cathepsin A-like activity distinct from its protective function . The Journal of Biological Chemistry . 266 . 22 . 14754–14762 . August 1991 . 1907282 . 10.1016/S0021-9258(18)98751-X . free .
• Yoshida K, Oshima A, Shimmoto M, Fukuhara Y, Sakuraba H, Yanagisawa N, Suzuki Y . Human beta-galactosidase gene mutations in GM1-gangliosidosis: a common mutation among Japanese adult/chronic cases . American Journal of Human Genetics . 49 . 2 . 435–442 . August 1991 . 1907800 . 1683306 .
• Wiegant J, Galjart NJ, Raap AK, d'Azzo A . The gene encoding human protective protein (PPGB) is on chromosome 20 . Genomics . 10 . 2 . 345–349 . June 1991 . 2071143 . 10.1016/0888-7543(91)90318-9 .
• Strisciuglio P, Sly WS, Dodson WE, McAlister WH, Martin TC . Combined deficiency of beta-galactosidase and neuraminidase: natural history of the disease in the first 18 years of an American patient with late infantile onset form . American Journal of Medical Genetics . 37 . 4 . 573–577 . December 1990 . 2148053 . 10.1002/ajmg.1320370431 .
• Kase R, Itoh K, Takiyama N, Oshima A, Sakuraba H, Suzuki Y . Galactosialidosis: simultaneous deficiency of esterase, carboxy-terminal deamidase and acid carboxypeptidase activities . Biochemical and Biophysical Research Communications . 172 . 3 . 1175–1179 . November 1990 . 2244901 . 10.1016/0006-291X(90)91572-A .
• Willemsen R, Hoogeveen AT, Sips HJ, van Dongen JM, Galjaard H . Immunoelectron microscopical localization of lysosomal beta-galactosidase and its precursor forms in normal and mutant human fibroblasts . European Journal of Cell Biology . 40 . 1 . 9–15 . March 1986 . 3084261 .
• Verheijen FW, Palmeri S, Galjaard H . Purification and partial characterization of lysosomal neuraminidase from human placenta . European Journal of Biochemistry . 162 . 1 . 63–67 . January 1987 . 3102233 . 10.1111/j.1432-1033.1987.tb10542.x .
• Nanba E, Tsuji A, Omura K, Suzuki Y . Galactosialidosis: a direct evidence that a 46-kilodalton protein restores deficient enzyme activities in fibroblasts . Biochemical and Biophysical Research Communications . 144 . 1 . 138–142 . April 1987 . 3107551 . 10.1016/S0006-291X(87)80486-2 .
• Galjart NJ, Gillemans N, Harris A, van der Horst GT, Verheijen FW, Galjaard H, d'Azzo A . Expression of cDNA encoding the human "protective protein" associated with lysosomal beta-galactosidase and neuraminidase: homology to yeast proteases . Cell . 54 . 6 . 755–764 . September 1988 . 3136930 . 10.1016/S0092-8674(88)90999-3 . 21504892 .
• Chitayat D, Applegarth DA, Lewis J, Dimmick JE, McCormick AQ, Hall JG . Juvenile galactosialidosis in a white male: a new variant . American Journal of Medical Genetics . 31 . 4 . 887–901 . December 1988 . 3149149 . 10.1002/ajmg.1320310423 .
• Verheijen FW, Palmeri S, Hoogeveen AT, Galjaard H . Human placental neuraminidase. Activation, stabilization and association with beta-galactosidase and its protective protein . European Journal of Biochemistry . 149 . 2 . 315–321 . June 1985 . 3922758 . 10.1111/j.1432-1033.1985.tb08928.x .
• van der Horst GT, Kleijer WJ, Hoogeveen AT, Huijmans JG, Blom W, van Diggelen OP . Morquio B syndrome: a primary defect in beta-galactosidase . American Journal of Medical Genetics . 16 . 2 . 261–275 . October 1983 . 6418007 . 10.1002/ajmg.1320160215 .
• Maire I, Nivelon-Chevallier AR . Combined deficiency of beta-galactosidase and neuraminidase: three affected siblings in a French family . Journal of Inherited Metabolic Disease . 4 . 4 . 221–223 . 1982 . 6796775 . 10.1007/BF02263656 . 38676707 .
• Pshezhetsky AV, Potier M . Direct affinity purification and supramolecular organization of human lysosomal cathepsin A . Archives of Biochemistry and Biophysics . 313 . 1 . 64–70 . August 1994 . 8053688 . 10.1006/abbi.1994.1359 .
• Ishii N, Oshima A, Sakuraba H, Fukuyama Y, Suzuki Y . Normal serum beta-galactosidase in juvenile GM1 gangliosidosis . Pediatric Neurology . 10 . 4 . 317–319 . June 1994 . 8068159 . 10.1016/0887-8994(94)90129-5 .
• Chakraborty S, Rafi MA, Wenger DA . Mutations in the lysosomal beta-galactosidase gene that cause the adult form of GM1 gangliosidosis . American Journal of Human Genetics . 54 . 6 . 1004–1013 . June 1994 . 8198123 . 1918177 .

Notes and References

1. Web site: Entrez Gene: CTSA cathepsin A.
2. Kolli N, Garman SC . Proteolytic activation of human cathepsin A . The Journal of Biological Chemistry . 289 . 17 . 11592–11600 . April 2014 . 24599961 . 10.1074/jbc.M113.524280 . free . 4002070 .
3. Web site: R&D Systems . Recombinant Human Cathepsin A/Lysosom Carboxypeptidase A . Catalog #: 1049-SE .
4. Rebek J, Duff RJ, Gordon WE, Parris K . Convergent functional groups provide a measure of stereoelectronic effects at carboxyl oxygen . Journal of the American Chemical Society . 108 . 19 . 6068–6069 . September 1986 . 22175389 . 10.1021/ja00279a081 .
5. Khavrutskii IV, Compton JR, Jurkouich KM, Legler PM . Paired Carboxylic Acids in Enzymes and Their Role in Selective Substrate Binding, Catalysis, and Unusually Shifted pK_a Values . Biochemistry . 58 . 52 . 5351–5365 . December 2019 . 31192586 . 10.1021/acs.biochem.9b00429 .
6. Book: Mitchell, Richard Sheppard . Kumar, Vinay . Robbins, Stanley L. . Abbas, Abul K. . Fausto, Nelson . Robbins basic pathology . 8th . Saunders/Elsevier . 2007 . Table 7-6 . 978-1-4160-2973-1 .
7. Bouknight KD, Jurkouich KM, Compton JR, Khavrutskii IV, Guelta MA, Harvey SP, Legler PM . Structural and kinetic evidence of aging after organophosphate inhibition of human Cathepsin A . Biochemical Pharmacology . 177 . 113980 . July 2020 . 32305437 . 10.1016/j.bcp.2020.113980 .
8. van der Spoel A, Bonten E, d'Azzo A . Transport of human lysosomal neuraminidase to mature lysosomes requires protective protein/cathepsin A . The EMBO Journal . 17 . 6 . 1588–1597 . March 1998 . 9501080 . 1170506 . 10.1093/emboj/17.6.1588 .