Cathepsin A

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".{{cite journal | vauthors = Rebek J, Duff RJ, Gordon WE, Parris K | title = Convergent functional groups provide a measure of stereoelectronic effects at carboxyl oxygen | journal = Journal of the American Chemical Society | volume = 108 | issue = 19 | pages = 6068–6069 | date = September 1986 | pmid = 22175389 | doi = 10.1021/ja00279a081 }}

File:CatA.jpg The pairing of these carboxylic acids raises the pKa of one glutamate to ~13 while the other has a predicted pKa of ~6.{{cite journal | vauthors = Khavrutskii IV, Compton JR, Jurkouich KM, Legler PM | title = Paired Carboxylic Acids in Enzymes and Their Role in Selective Substrate Binding, Catalysis, and Unusually Shifted pK_a Values | journal = Biochemistry | volume = 58 | issue = 52 | pages = 5351–5365 | date = December 2019 | pmid = 31192586 | doi = 10.1021/acs.biochem.9b00429 }}

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.{{cite book | author = Mitchell, Richard Sheppard | author2 = Kumar, Vinay | author3 = Robbins, Stanley L. | author4 = Abbas, Abul K. | author5 = Fausto, Nelson | title = Robbins basic pathology | edition = 8th | publisher = Saunders/Elsevier | year = 2007 | chapter = Table 7-6 | isbn = 978-1-4160-2973-1 }}

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.

File:CatASubstrate.jpg

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.{{cite journal | vauthors = Bouknight KD, Jurkouich KM, Compton JR, Khavrutskii IV, Guelta MA, Harvey SP, Legler PM | title = Structural and kinetic evidence of aging after organophosphate inhibition of human Cathepsin A | journal = Biochemical Pharmacology | volume = 177 | pages = 113980 | date = July 2020 | pmid = 32305437 | doi = 10.1016/j.bcp.2020.113980 }} After inhibition, it undergoes aging. The enzyme can be found in urine and blood.

Deficiencies in this gene are linked to multiple forms of galactosialidosis and CARASAL.{{cite journal | vauthors = Budhdeo S, de Paiva AR, Wade C, Lopes LC, Della-Ripa B, Davagnanam I, Lucato L, Mummery CJ, Kok F, Houlden H, Werring DJ, Lynch DS | title = A rare cause of monogenic cerebral small vessel disease and stroke: Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL) | journal = Journal of Neurology | volume = 269 | issue = 12 | pages = 6673–6677 | date = December 2022 | pmid = 35904593 | doi = 10.1007/s00415-022-11302-9 }}

Cathepsin A has been shown to interact with NEU1 and GLB1.{{cite journal | vauthors = van der Spoel A, Bonten E, d'Azzo A | title = Transport of human lysosomal neuraminidase to mature lysosomes requires protective protein/cathepsin A | journal = The EMBO Journal | volume = 17 | issue = 6 | pages = 1588–1597 | date = March 1998 | pmid = 9501080 | pmc = 1170506 | doi = 10.1093/emboj/17.6.1588 }}

{{reflist}}

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• {{cite journal | vauthors = Morreau H, Galjart NJ, Willemsen R, Gillemans N, Zhou XY, d'Azzo A | title = Human lysosomal protective protein. Glycosylation, intracellular transport, and association with beta-galactosidase in the endoplasmic reticulum | journal = The Journal of Biological Chemistry | volume = 267 | issue = 25 | pages = 17949–17956 | date = September 1992 | pmid = 1387645 | doi = 10.1016/S0021-9258(19)37135-2 | doi-access = free }}
• {{cite journal | vauthors = Halal F, Chitayat D, Parikh H, Rosenblatt B, Tranchemontagne J, Vekemans M, Potier M | title = 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 | journal = American Journal of Medical Genetics | volume = 43 | issue = 3 | pages = 576–579 | date = June 1992 | pmid = 1605251 | doi = 10.1002/ajmg.1320430314 }}
• {{cite journal | vauthors = Jackman HL, Tan FL, Tamei H, Beurling-Harbury C, Li XY, Skidgel RA, Erdös EG | title = A peptidase in human platelets that deamidates tachykinins. Probable identity with the lysosomal "protective protein" | journal = The Journal of Biological Chemistry | volume = 265 | issue = 19 | pages = 11265–11272 | date = July 1990 | pmid = 1694176 | doi = 10.1016/S0021-9258(19)38586-2 | doi-access = free }}
• {{cite journal | vauthors = Zhou XY, Galjart NJ, Willemsen R, Gillemans N, Galjaard H, d'Azzo A | title = A mutation in a mild form of galactosialidosis impairs dimerization of the protective protein and renders it unstable | journal = The EMBO Journal | volume = 10 | issue = 13 | pages = 4041–4048 | date = December 1991 | pmid = 1756715 | pmc = 453152 | doi = 10.1002/j.1460-2075.1991.tb04980.x }}
• {{cite journal | vauthors = Galjart NJ, Morreau H, Willemsen R, Gillemans N, Bonten EJ, d'Azzo A | title = Human lysosomal protective protein has cathepsin A-like activity distinct from its protective function | journal = The Journal of Biological Chemistry | volume = 266 | issue = 22 | pages = 14754–14762 | date = August 1991 | pmid = 1907282 | doi = 10.1016/S0021-9258(18)98751-X | doi-access = free }}
• {{cite journal | vauthors = Yoshida K, Oshima A, Shimmoto M, Fukuhara Y, Sakuraba H, Yanagisawa N, Suzuki Y | title = Human beta-galactosidase gene mutations in GM1-gangliosidosis: a common mutation among Japanese adult/chronic cases | journal = American Journal of Human Genetics | volume = 49 | issue = 2 | pages = 435–442 | date = August 1991 | pmid = 1907800 | pmc = 1683306 }}
• {{cite journal | vauthors = Wiegant J, Galjart NJ, Raap AK, d'Azzo A | title = The gene encoding human protective protein (PPGB) is on chromosome 20 | journal = Genomics | volume = 10 | issue = 2 | pages = 345–349 | date = June 1991 | pmid = 2071143 | doi = 10.1016/0888-7543(91)90318-9 }}
• {{cite journal | vauthors = Strisciuglio P, Sly WS, Dodson WE, McAlister WH, Martin TC | title = 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 | journal = American Journal of Medical Genetics | volume = 37 | issue = 4 | pages = 573–577 | date = December 1990 | pmid = 2148053 | doi = 10.1002/ajmg.1320370431 }}
• {{cite journal | vauthors = Kase R, Itoh K, Takiyama N, Oshima A, Sakuraba H, Suzuki Y | title = Galactosialidosis: simultaneous deficiency of esterase, carboxy-terminal deamidase and acid carboxypeptidase activities | journal = Biochemical and Biophysical Research Communications | volume = 172 | issue = 3 | pages = 1175–1179 | date = November 1990 | pmid = 2244901 | doi = 10.1016/0006-291X(90)91572-A }}
• {{cite journal | vauthors = Willemsen R, Hoogeveen AT, Sips HJ, van Dongen JM, Galjaard H | title = Immunoelectron microscopical localization of lysosomal beta-galactosidase and its precursor forms in normal and mutant human fibroblasts | journal = European Journal of Cell Biology | volume = 40 | issue = 1 | pages = 9–15 | date = March 1986 | pmid = 3084261 }}
• {{cite journal | vauthors = Verheijen FW, Palmeri S, Galjaard H | title = Purification and partial characterization of lysosomal neuraminidase from human placenta | journal = European Journal of Biochemistry | volume = 162 | issue = 1 | pages = 63–67 | date = January 1987 | pmid = 3102233 | doi = 10.1111/j.1432-1033.1987.tb10542.x | doi-access = }}
• {{cite journal | vauthors = Nanba E, Tsuji A, Omura K, Suzuki Y | title = Galactosialidosis: a direct evidence that a 46-kilodalton protein restores deficient enzyme activities in fibroblasts | journal = Biochemical and Biophysical Research Communications | volume = 144 | issue = 1 | pages = 138–142 | date = April 1987 | pmid = 3107551 | doi = 10.1016/S0006-291X(87)80486-2 }}
• {{cite journal | vauthors = Galjart NJ, Gillemans N, Harris A, van der Horst GT, Verheijen FW, Galjaard H, d'Azzo A | title = Expression of cDNA encoding the human "protective protein" associated with lysosomal beta-galactosidase and neuraminidase: homology to yeast proteases | journal = Cell | volume = 54 | issue = 6 | pages = 755–764 | date = September 1988 | pmid = 3136930 | doi = 10.1016/S0092-8674(88)90999-3 | s2cid = 21504892 }}
• {{cite journal | vauthors = Chitayat D, Applegarth DA, Lewis J, Dimmick JE, McCormick AQ, Hall JG | title = Juvenile galactosialidosis in a white male: a new variant | journal = American Journal of Medical Genetics | volume = 31 | issue = 4 | pages = 887–901 | date = December 1988 | pmid = 3149149 | doi = 10.1002/ajmg.1320310423 }}
• {{cite journal | vauthors = Verheijen FW, Palmeri S, Hoogeveen AT, Galjaard H | title = Human placental neuraminidase. Activation, stabilization and association with beta-galactosidase and its protective protein | journal = European Journal of Biochemistry | volume = 149 | issue = 2 | pages = 315–321 | date = June 1985 | pmid = 3922758 | doi = 10.1111/j.1432-1033.1985.tb08928.x | doi-access = }}
• {{cite journal | vauthors = van der Horst GT, Kleijer WJ, Hoogeveen AT, Huijmans JG, Blom W, van Diggelen OP | title = Morquio B syndrome: a primary defect in beta-galactosidase | journal = American Journal of Medical Genetics | volume = 16 | issue = 2 | pages = 261–275 | date = October 1983 | pmid = 6418007 | doi = 10.1002/ajmg.1320160215 }}
• {{cite journal | vauthors = Maire I, Nivelon-Chevallier AR | title = Combined deficiency of beta-galactosidase and neuraminidase: three affected siblings in a French family | journal = Journal of Inherited Metabolic Disease | volume = 4 | issue = 4 | pages = 221–223 | year = 1982 | pmid = 6796775 | doi = 10.1007/BF02263656 | s2cid = 38676707 }}
• {{cite journal | vauthors = Pshezhetsky AV, Potier M | title = Direct affinity purification and supramolecular organization of human lysosomal cathepsin A | journal = Archives of Biochemistry and Biophysics | volume = 313 | issue = 1 | pages = 64–70 | date = August 1994 | pmid = 8053688 | doi = 10.1006/abbi.1994.1359 }}
• {{cite journal | vauthors = Ishii N, Oshima A, Sakuraba H, Fukuyama Y, Suzuki Y | title = Normal serum beta-galactosidase in juvenile GM1 gangliosidosis | journal = Pediatric Neurology | volume = 10 | issue = 4 | pages = 317–319 | date = June 1994 | pmid = 8068159 | doi = 10.1016/0887-8994(94)90129-5 }}
• {{cite journal | vauthors = Chakraborty S, Rafi MA, Wenger DA | title = Mutations in the lysosomal beta-galactosidase gene that cause the adult form of GM1 gangliosidosis | journal = American Journal of Human Genetics | volume = 54 | issue = 6 | pages = 1004–1013 | date = June 1994 | pmid = 8198123 | pmc = 1918177 }}

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• {{MeshName|Cathepsin+A}}

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{{Proteases}}

{{Enzymes}}

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Category:EC 3.4.16

Category:Proteases

Category:Cathepsins

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