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Asparagine endopeptidase

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Asparagine endopeptidase (AEP)

AEP is asparagine endopeptidase and it is an proteolytic enzyme from C13 peptidase family, which means that that hydrolyses a peptide bond using the thiol group of a cysteine residue as a nucleophile. It hydrolyzes substrates at the C-terminus of asparagine residues. It is also called a mammalian legumain and it was found in 1996. First it was found in beans but than homologues have been identified in plants, protozoa, vertebrates, and helminths. The expression of this enzyme is connected with many pathological conditions such as cancer, atherosclerosis and inflammation [1]. In body it can be detected in spleen, liver, brain, testis tissue and heart [2] and it is localised mostly in lysosomes and endosomes. It is also interesting that AEP is activated in age-dependent manner [3].

Activation

Adenosine endopeptidase is synthesized as inactive zymogen [4]. AEP and other cystein peptidase are activated when pH changes from neutral to acidic. It underegoes autoproteolytic maturation for catalytic activation. It appears to be autocatalytically cleaved after asparagine or asparatare residue. Activation begins at pH 4.5. The chemical structure at this pH is really interesting. The breaks which occurs at 4.5 can be healed under the basic crystalization cinditions. C-terminal fragments (∼13 kDa) generated during autoproteolysis were gradually re-ligated to form the proenzyme when the pH was increased towards 7.5, which means that proteolytic activation of AEP can be reversible [3].

AEP in neurodegenerative diseases

AEP is activated during brain ischemia or brain acidosis and epilepsia seizure. It cuts SET protein, which is an inhibitor of DNase, so without inhibitor DNA in the brain is damaged. AEP is connected with Alzheimer disease and Parkinson disease. In this cases the AEP is more active than in normal, healthy brain. In brain it cleaves tau protein and amyloid precursor protein. Both disease are characterised by creating a toxic clumps i neuronal cells . In PD it is an alpha synuclein which is cut by AEP into toxic chunks [5].

AEP in Alzeheimer disease

Active AEP was found at increased levels and translocated to the cytoplasm of neuronal cells of AD patients [6]. In AD the plaques are composed of amyloid beta, intracellular neurofibrillary tangles and tau protein. The dysfunction of APP proteolysis and the abnormal phosphorylation of tau lead to the formation of neuritic plaques and neurofibrillary tangles(NFTs), respectively which causes neuronal degeneration and dementia [7] It also play a crucial role in behavior disorders connected wit AD such as anxiety and depression. It also plays a role in stroke. Since stroke elicits acidity AEP became active. Then as said it cleaves SET which causes brain cells death [8]. Targeting of AEP might help with AD. Developement of small molecules of AEP selective inhibitors is crucial for helping with diseases. These inhibotors are for example Cbz-L-Ala-L-Ala-AzaAsnchloromethylketone, and aza-peptidyl AEP inhibitors [5].

AEP in immune system

There are many regulators which affects immune system and help to keep it balanced. If the immune system is too active there is a danger of developing an autoimmune disease if the immune system is too pasive infections and cancer are free to grow. Antigen presenting is a key role in activation of immune system [5]. It has been discovered that AEP plays role in this criticall moment. AEP is involved is presenting of foreign and self proteing using MHCII protein complex [9]. The main role of AEP in immunity is not clear but it seems, that it is connected with checkpoint inhibitors such as PD-1, which downregulates AEP which is key to shifting the balance between cancer fighting cells and regulatory T cells. In the absence of AEP inhibitory checkpoints may not have a beneficial response. Measuring of this enzyme in patients could predict, which one of them may provide better response to treatment [10].

Antimicrobial activity

AEP or legumain is used in African medicine. In plant called Oldenlandia affinis it has proven an antimicrobial activity by generating of cyclic peptides which are important for defence against pathogens in plants. The immunological relevance of these cyclic peptides can be prooved by using actice components of the plant to accelerate child birth [11][12].

Signalling

In innate immunity TLRs play an important role. These TLRs can be proteolytically activated by AEP mainly TLR7 and TLR9 [13]. The reduction of proinflammatory cytokines by stimulating TLR9 was found in myeloid cells and plasmacytoid dendritic cells which had lack of AEP[14]. Enzyme is also important in processing of influneza virus and immune response using TLR7[15]. AEP plays a critical role in TLR processing. and AEP can initiate removal of invariant chain in MHCII complex, which can be critically influence peptide generation and activity of MHCII [16].

References

  1. ^ Zhang, Zhentao; Xie, Manling; Ye, Keqiang (2016). "Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases". undefined. Retrieved 2018-08-27.
  2. ^ CHEN, Jinq-May; DANDO, Pam M.; STEVENS, Richard A. E.; FORTUNATO, Mara; BARRETT, Alan J. (1998-10-01). "Cloning and expression of mouse legumain, a lysosomal endopeptidase". Biochemical Journal. 335 (1): 111–117. doi:10.1042/bj3350111. ISSN 0264-6021.
  3. ^ a b Zhao, Lixia; Hua, Tian; Crowley, Christopher; Ru, Heng; Ni, Xiangmin; Shaw, Neil; Jiao, Lianying; Ding, Wei; Qu, Lu (2014-03). "Structural analysis of asparaginyl endopeptidase reveals the activation mechanism and a reversible intermediate maturation stage". Cell Research. 24 (3): 344–358. doi:10.1038/cr.2014.4. ISSN 1001-0602. PMC 3945893. PMID 24407422. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  4. ^ Li, Dongtao Ni; Matthews, Stephen P.; Antoniou, Antony N.; Mazzeo, Daniela; Watts, Colin (2003-07-14). "Multistep Autoactivation of Asparaginyl Endopeptidasein Vitroandin Vivo". Journal of Biological Chemistry. 278 (40): 38980–38990. doi:10.1074/jbc.m305930200. ISSN 0021-9258.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ a b c Zhang, Zhentao; Xie, Manling; Ye, Keqiang (2016-05-13). "Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases". Expert Opinion on Therapeutic Targets. 20 (10): 1237–1245. doi:10.1080/14728222.2016.1182990. ISSN 1472-8222.
  6. ^ Basurto-Islas, Gustavo; Grundke-Iqbal, Inge; Tung, Yunn Chyn; Liu, Fei; Iqbal, Khalid (2013-06-14). "Activation of asparaginyl endopeptidase leads to Tau hyperphosphorylation in Alzheimer disease". The Journal of Biological Chemistry. 288 (24): 17495–17507. doi:10.1074/jbc.M112.446070. ISSN 1083-351X. PMC 3682549. PMID 23640887.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  7. ^ Zhang, Zhentao; Song, Mingke; Liu, Xia; Kang, Seong Su; Kwon, Il-Sun; Duong, Duc M.; Seyfried, Nicholas T.; Hu, William T.; Liu, Zhixue (2014-11). "Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease". Nature Medicine. 20 (11): 1254–1262. doi:10.1038/nm.3700. ISSN 1546-170X. PMC 4224595. PMID 25326800. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  8. ^ Gao, Jing; Li, Kai; Du, Lingfang; Yin, Hongqiang; Tan, Xiaoyue; Yang, Zhuo (2018-07-17). "Deletion of asparagine endopeptidase reduces anxiety- and depressive-like behaviors and improves abilities of spatial cognition in mice". Brain Research Bulletin. 142: 147–155. doi:10.1016/j.brainresbull.2018.07.010. ISSN 1873-2747. PMID 30030107.
  9. ^ Matthews, Stephen P.; Werber, Ingrid; Deussing, Jan; Peters, Christoph; Reinheckel, Thomas; Watts, Colin (2010-02-17). "Distinct Protease Requirements for Antigen Presentation In Vitro and In Vivo". The Journal of Immunology. 184 (5): 2423–2431. doi:10.4049/jimmunol.0901486. ISSN 0022-1767.
  10. ^ "Enzyme AEP's importance to immunity discovered". Retrieved 2018-08-28.
  11. ^ Gillon, Amanda D.; Saska, Ivana; Jennings, Cameron V.; Guarino, Rosemary F.; Craik, David J.; Anderson, Marilyn A. (2007-10-30). "Biosynthesis of circular proteins in plants". The Plant Journal. 53 (3): 505–515. doi:10.1111/j.1365-313x.2007.03357.x. ISSN 0960-7412.
  12. ^ Craik, David J. (2012-02-15). "Host-Defense Activities of Cyclotides". Toxins. 4 (2): 139–156. doi:10.3390/toxins4020139. ISSN 2072-6651.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  13. ^ Maschalidi, Sophia; Hässler, Signe; Blanc, Fany; Sepulveda, Fernando E.; Tohme, Mira; Chignard, Michel; van Endert, Peter; Si-Tahar, Mustapha; Descamps, Delphyne (2012-08-16). "Asparagine Endopeptidase Controls Anti-Influenza Virus Immune Responses through TLR7 Activation". PLoS Pathogens. 8 (8): e1002841. doi:10.1371/journal.ppat.1002841. ISSN 1553-7374.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  14. ^ Sepulveda, Fernando E.; Maschalidi, Sophia; Colisson, Renaud; Heslop, Lea; Ghirelli, Cristina; Sakka, Emna; Lennon-Duménil, Ana-Maria; Amigorena, Sebastian; Cabanie, Lucien (2009-11). "Critical Role for Asparagine Endopeptidase in Endocytic Toll-like Receptor Signaling in Dendritic Cells". Immunity. 31 (5): 737–748. doi:10.1016/j.immuni.2009.09.013. ISSN 1074-7613. {{cite journal}}: Check date values in: |date= (help); no-break space character in |title= at position 46 (help)
  15. ^ Maschalidi, Sophia; Hässler, Signe; Blanc, Fany; Sepulveda, Fernando E.; Tohme, Mira; Chignard, Michel; van Endert, Peter; Si-Tahar, Mustapha; Descamps, Delphyne (2012-08-16). "Asparagine Endopeptidase Controls Anti-Influenza Virus Immune Responses through TLR7 Activation". PLoS Pathogens. 8 (8): e1002841. doi:10.1371/journal.ppat.1002841. ISSN 1553-7374.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  16. ^ Manoury, Bénédicte; Mazzeo, Daniela; Li, Dongtao Ni; Billson, Jeremy; Loak, Kylie; Benaroch, Philippe; Watts, Colin (2003-04). "Asparagine Endopeptidase Can Initiate the Removal of the MHC Class II Invariant Chain Chaperone". Immunity. 18 (4): 489–498. doi:10.1016/s1074-7613(03)00085-2. ISSN 1074-7613. {{cite journal}}: Check date values in: |date= (help)
                                                                             

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