Biology:Cathepsin A

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Short description: Enzyme known as Human Protective Protein

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[2] 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.[3][4]

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".[5]

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.[6]

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.[7]

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.[8] After inhibition, it undergoes aging. The enzyme can be found in urine and blood.

Clinical significance

Deficiencies in this gene are linked to multiple forms of galactosialidosis and CARASAL.[1][9]

Interactions

Cathepsin A has been shown to interact with NEU1 and GLB1.[10]

References

  1. ↑ 1.0 1.1 "Entrez Gene: CTSA cathepsin A". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=5476. 
  2. ↑ "The atomic model of the human protective protein/cathepsin A suggests a structural basis for galactosialidosis". Proc Natl Acad Sci U S A 95 (2): 621–5. January 1998. doi:10.1073/pnas.95.2.621. PMID 9435242. Bibcode: 1998PNAS...95..621R. 
  3. ↑ "Proteolytic activation of human cathepsin A". The Journal of Biological Chemistry 289 (17): 11592–11600. April 2014. doi:10.1074/jbc.M113.524280. PMID 24599961. 
  4. ↑ "Recombinant Human Cathepsin A/Lysosom Carboxypeptidase A". R&D Systems. https://www.rndsystems.com/products/recombinant-human-cathepsin-a-lysosom-carboxypeptidase-a-cf_1049-se. 
  5. ↑ "Convergent functional groups provide a measure of stereoelectronic effects at carboxyl oxygen". Journal of the American Chemical Society 108 (19): 6068–6069. September 1986. doi:10.1021/ja00279a081. PMID 22175389. Bibcode: 1986JAChS.108.6068R. 
  6. ↑ "Paired Carboxylic Acids in Enzymes and Their Role in Selective Substrate Binding, Catalysis, and Unusually Shifted pKa Values". Biochemistry 58 (52): 5351–5365. December 2019. doi:10.1021/acs.biochem.9b00429. PMID 31192586. 
  7. ↑ Mitchell, Richard Sheppard; Kumar, Vinay; Robbins, Stanley L.; Abbas, Abul K.; Fausto, Nelson (2007). "Table 7-6". Robbins basic pathology (8th ed.). Saunders/Elsevier. ISBN 978-1-4160-2973-1. 
  8. ↑ "Structural and kinetic evidence of aging after organophosphate inhibition of human Cathepsin A". Biochemical Pharmacology 177. July 2020. doi:10.1016/j.bcp.2020.113980. PMID 32305437. 
  9. ↑ "A rare cause of monogenic cerebral small vessel disease and stroke: Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL)". Journal of Neurology 269 (12): 6673–6677. December 2022. doi:10.1007/s00415-022-11302-9. PMID 35904593. https://discovery.ucl.ac.uk/id/eprint/10153709/. 
  10. ↑ "Transport of human lysosomal neuraminidase to mature lysosomes requires protective protein/cathepsin A". The EMBO Journal 17 (6): 1588–1597. March 1998. doi:10.1093/emboj/17.6.1588. PMID 9501080. 

Further reading



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