Cathepsin A is an enzyme that is classified both as a cathepsin and a carboxypeptidase. In humans, it is encoded by the CTSAgene.[5] 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. Cathespin L can activate Cathepsin A in vitro.[6][7]
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".[8]
Active site of Cathepsin A. In green is the Rebek pair. The two glutamate side chains are directed towards one another. To prevent an unfavorable charge-charge interaction the pKa of one glutamate side chain is raised to ~13.
The pairing of these carboxylic acids raises the pKa of one glutamate to ~13 while the other has a predicted pKa of ~6.[9]
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.[10]
Substrates
CTSA is part of the Renin Angiotensin System (RAS). Substrates of the enzyme that have been identified in vitro include endothelin I, angiotensin I, bradykinin, Substance P, and oxytocin.
Peptide substrates of Cathepsin A. CTSA is part of the Renin-Angiotensin System (RAS)
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.[11] After inhibition, it undergoes aging. The enzyme can be found in urine and blood.
^Rebek J, Duff RJ, Gordon WE, Parris K (September 1986). "Convergent functional groups provide a measure of stereoelectronic effects at carboxyl oxygen". Journal of the American Chemical Society. 108 (19): 6068–6069. doi:10.1021/ja00279a081. PMID22175389.
^Khavrutskii IV, Compton JR, Jurkouich KM, Legler PM (December 2019). "Paired Carboxylic Acids in Enzymes and Their Role in Selective Substrate Binding, Catalysis, and Unusually Shifted pKa Values". Biochemistry. 58 (52): 5351–5365. doi:10.1021/acs.biochem.9b00429. PMID31192586.
^Mitchell, Richard Sheppard, Kumar, Vinay, Robbins, Stanley L., Abbas, Abul K., Fausto, Nelson (2007). "Table 7-6". Robbins basic pathology (8th ed.). Saunders/Elsevier. ISBN978-1-4160-2973-1.
^Bouknight KD, Jurkouich KM, Compton JR, Khavrutskii IV, Guelta MA, Harvey SP, et al. (July 2020). "Structural and kinetic evidence of aging after organophosphate inhibition of human Cathepsin A". Biochemical Pharmacology. 177: 113980. doi:10.1016/j.bcp.2020.113980. PMID32305437.
Halal F, Chitayat D, Parikh H, Rosenblatt B, Tranchemontagne J, Vekemans M, et al. (June 1992). "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. doi:10.1002/ajmg.1320430314. PMID1605251.
Wiegant J, Galjart NJ, Raap AK, d'Azzo A (June 1991). "The gene encoding human protective protein (PPGB) is on chromosome 20". Genomics. 10 (2): 345–349. doi:10.1016/0888-7543(91)90318-9. PMID2071143.
Strisciuglio P, Sly WS, Dodson WE, McAlister WH, Martin TC (December 1990). "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. doi:10.1002/ajmg.1320370431. PMID2148053.
Kase R, Itoh K, Takiyama N, Oshima A, Sakuraba H, Suzuki Y (November 1990). "Galactosialidosis: simultaneous deficiency of esterase, carboxy-terminal deamidase and acid carboxypeptidase activities". Biochemical and Biophysical Research Communications. 172 (3): 1175–1179. doi:10.1016/0006-291X(90)91572-A. PMID2244901.
Willemsen R, Hoogeveen AT, Sips HJ, van Dongen JM, Galjaard H (March 1986). "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. PMID3084261.
Verheijen FW, Palmeri S, Galjaard H (January 1987). "Purification and partial characterization of lysosomal neuraminidase from human placenta". European Journal of Biochemistry. 162 (1): 63–67. doi:10.1111/j.1432-1033.1987.tb10542.x. PMID3102233.
Nanba E, Tsuji A, Omura K, Suzuki Y (April 1987). "Galactosialidosis: a direct evidence that a 46-kilodalton protein restores deficient enzyme activities in fibroblasts". Biochemical and Biophysical Research Communications. 144 (1): 138–142. doi:10.1016/S0006-291X(87)80486-2. PMID3107551.
Galjart NJ, Gillemans N, Harris A, van der Horst GT, Verheijen FW, Galjaard H, et al. (September 1988). "Expression of cDNA encoding the human "protective protein" associated with lysosomal beta-galactosidase and neuraminidase: homology to yeast proteases". Cell. 54 (6): 755–764. doi:10.1016/S0092-8674(88)90999-3. PMID3136930. S2CID21504892.
Chitayat D, Applegarth DA, Lewis J, Dimmick JE, McCormick AQ, Hall JG (December 1988). "Juvenile galactosialidosis in a white male: a new variant". American Journal of Medical Genetics. 31 (4): 887–901. doi:10.1002/ajmg.1320310423. PMID3149149.
Verheijen FW, Palmeri S, Hoogeveen AT, Galjaard H (June 1985). "Human placental neuraminidase. Activation, stabilization and association with beta-galactosidase and its protective protein". European Journal of Biochemistry. 149 (2): 315–321. doi:10.1111/j.1432-1033.1985.tb08928.x. PMID3922758.
van der Horst GT, Kleijer WJ, Hoogeveen AT, Huijmans JG, Blom W, van Diggelen OP (October 1983). "Morquio B syndrome: a primary defect in beta-galactosidase". American Journal of Medical Genetics. 16 (2): 261–275. doi:10.1002/ajmg.1320160215. PMID6418007.
Maire I, Nivelon-Chevallier AR (1982). "Combined deficiency of beta-galactosidase and neuraminidase: three affected siblings in a French family". Journal of Inherited Metabolic Disease. 4 (4): 221–223. doi:10.1007/BF02263656. PMID6796775. S2CID38676707.
Pshezhetsky AV, Potier M (August 1994). "Direct affinity purification and supramolecular organization of human lysosomal cathepsin A". Archives of Biochemistry and Biophysics. 313 (1): 64–70. doi:10.1006/abbi.1994.1359. PMID8053688.
Ishii N, Oshima A, Sakuraba H, Fukuyama Y, Suzuki Y (June 1994). "Normal serum beta-galactosidase in juvenile GM1 gangliosidosis". Pediatric Neurology. 10 (4): 317–319. doi:10.1016/0887-8994(94)90129-5. PMID8068159.
