NPEPPS

Puromycin-sensitive amino peptidase also known as cytosol alanyl aminopeptidase or alanine aminopeptidase (AAP) (EC 3.4.11.14) is an enzyme that in humans is encoded by the NPEPPS gene.[5][6][7] It is used as a biomarker to detect damage to the kidneys, and that may be used to help diagnose certain kidney disorders. It is found at high levels in the urine when there are kidney problems.[8]

This article is about the cytosolic alanine aminopeptidase. For the cell membrane alanyl aminopeptidase, see Alanine aminopeptidase.

NPEPPS
Identifiers
Aliases	NPEPPS, AAP-S, MP100, PSA, aminopeptidase puromycin sensitive
External IDs	OMIM: 606793 MGI: 1101358 HomoloGene: 36199 GeneCards: NPEPPS
Gene location (Human) Chr. Chromosome 17 (human)[1] Band 17q21.32 Start 47,522,942 bp[1] End 47,623,276 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11 D|11 60.95 cM Start 97,205,842 bp[2] End 97,280,638 bp[2]
Gene ontology Molecular function • peptide binding • zinc ion binding • peptidase activity • metalloaminopeptidase activity • metallopeptidase activity • hydrolase activity • metal ion binding • aminopeptidase activity Cellular component • extracellular exosome • cell nucleus • cytosol • cytoplasm Biological process • protein polyubiquitination • cellular response to hypoxia • positive regulation of protein targeting to mitochondrion • peptide catabolic process • proteolysis Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	9520	19155
Ensembl	ENSG00000141279	ENSMUSG00000001441
UniProt	P55786	Q11011
RefSeq (mRNA)	NM_006310 NM_001330257	NM_008942
RefSeq (protein)	NP_001317186 NP_006301	NP_032968
Location (UCSC)	Chr 17: 47.52 – 47.62 Mb	Chr 11: 97.21 – 97.28 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

This gene encodes the puromycin-sensitive aminopeptidase, a zinc metallopeptidase which hydrolyzes amino acids from the N-terminus of its substrate. The protein has been localized to both the cytoplasm and to cellular membranes. This enzyme degrades enkephalins in the brain, and studies in mouse suggest that it is involved in proteolytic events regulating the cell cycle.[7] It has been identified as a novel modifier of TAU-induced neurodegeneration with neuroprotective effects via direct proteolysis of TAU protein.[9][10] The loss of NPEPPS function exacerbates neurodegeneration.[11]

Structure

Gene

The NPEPPS gene is located at chromosome 17q21, consisting of 25 exons and spanning 40 kb.

Protein

NPEPPS is a ubiquitous, 100 kDa, Zn²⁺ metallopeptidase highly expressed in the brain.[12] Two isozymes have been found and they are expressed differently in the nervous system.[13] Glu 309 is one of the active site glutamates, and its mutation could convert the enzyme into an inactive binding protein.[14]

Function

NPEPPS has been proposed to function in a variety of processes, including metabolism of neuropeptidase, regulation of the cell cycle, and hydrolysis of proteasomal products to amino acids.[15][16][17] NPEPPS is a major protease to digest SOD1, similar to its role in TAU-induced neurodegeneration.[10][18] NPEPPS is also reported to play a role in creating and destroying MHC class Ⅰ-presented peptides and in limiting MHC class Ⅰ Ag presentation in dendritic cells.[19]

Clinical significance

NPEPPS is induced in neurons expressing mutant huntingtin and is critical in preventing the accumulation of polyglutamine in normal cells. It has been reported as the major peptidase digesting polyglutamine sequences in neurodegenerative diseases, such as Huntington’s disease.[20] It has been shown that elevation of NPEPPS activity in vivo could effectively block accumulation of hyperphosphorylated TAU protein and thus slow down the disease progression, suggesting increasing NPEPPS activity may be a feasible therapeutic approach to eliminate accumulation of toxic substrates, which are involved in neurodegenerative diseases.[21]

Interactions

• Cyclin-dependent kinase 5 [22]
• SOD1 [18]
• TAU [10]
• Tetrahydropyridine [23]
• β-amyloid [24]

References

1. GRCh38: Ensembl release 89: ENSG00000141279 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000001441 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Tobler AR, Constam DB, Schmitt-Gräff A, Malipiero U, Schlapbach R, Fontana A (March 1997). "Cloning of the human puromycin-sensitive aminopeptidase and evidence for expression in neurons". Journal of Neurochemistry. 68 (3): 889–97. doi:10.1046/j.1471-4159.1997.68030889.x. PMID 9048733.
6. Thompson MW, Tobler A, Fontana A, Hersh LB (May 1999). "Cloning and analysis of the gene for the human puromycin-sensitive aminopeptidase". Biochemical and Biophysical Research Communications. 258 (2): 234–40. doi:10.1006/bbrc.1999.0604. PMID 10329370.
7. "Entrez Gene: NPEPPS aminopeptidase puromycin sensitive".
8. Holdt B, Peters E, Nagel HR, Steiner M (2008). "An automated assay of urinary alanine aminopeptidase activity". Clinical Chemistry and Laboratory Medicine. 46 (4): 537–40. doi:10.1515/CCLM.2008.103. PMID 18302530.
9. Sengupta S, Horowitz PM, Karsten SL, Jackson GR, Geschwind DH, Fu Y, Berry RW, Binder LI (December 2006). "Degradation of tau protein by puromycin-sensitive aminopeptidase in vitro". Biochemistry. 45 (50): 15111–9. doi:10.1021/bi061830d. PMID 17154549.
10. Yanagi K, Tanaka T, Kato K, Sadik G, Morihara T, Kudo T, Takeda M (December 2009). "Involvement of puromycin-sensitive aminopeptidase in proteolysis of tau protein in cultured cells, and attenuated proteolysis of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) mutant tau". Psychogeriatrics. 9 (4): 157–66. doi:10.1111/j.1479-8301.2010.00307.x. PMID 20377816.
11. Karsten SL, Sang TK, Gehman LT, Chatterjee S, Liu J, Lawless GM, Sengupta S, Berry RW, Pomakian J, Oh HS, Schulz C, Hui KS, Wiedau-Pazos M, Vinters HV, Binder LI, Geschwind DH, Jackson GR (September 2006). "A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration". Neuron. 51 (5): 549–60. doi:10.1016/j.neuron.2006.07.019. PMID 16950154.
12. Rawson NS (November 2009). "Access to linked administrative healthcare utilization data for pharmacoepidemiology and pharmacoeconomics research in Canada: anti-viral drugs as an example". Pharmacoepidemiology and Drug Safety. 18 (11): 1072–9. doi:10.1002/pds.1822. PMID 19650154.
13. Barton S (1816-01-01). "Some Observations concerning the Medical Properties of the Pyrola Umbellata, and the Arbutus Uva Ursi, of Linnæus". Medico-Chirurgical Transactions. 7: 143–9. doi:10.1177/095952871600700108. PMC 2129051. PMID 20895273.
14. Thompson MW, Govindaswami M, Hersh LB (May 2003). "Mutation of active site residues of the puromycin-sensitive aminopeptidase: conversion of the enzyme into a catalytically inactive binding protein". Archives of Biochemistry and Biophysics. 413 (2): 236–42. doi:10.1016/s0003-9861(03)00123-1. PMID 12729622.
15. Hersh LB, Smith TE, McKelvy JF (July 1980). "Cleavage of endorphins to des-Tyr endorphins by homogeneous bovine brain aminopeptidase". Nature. 286 (5769): 160–2. doi:10.1038/286160a0. PMID 7402309.
16. Constam DB, Tobler AR, Rensing-Ehl A, Kemler I, Hersh LB, Fontana A (November 1995). "Puromycin-sensitive aminopeptidase. Sequence analysis, expression, and functional characterization". The Journal of Biological Chemistry. 270 (45): 26931–9. doi:10.1074/jbc.270.45.26931. PMID 7592939.
17. Saric T, Graef CI, Goldberg AL (November 2004). "Pathway for degradation of peptides generated by proteasomes: a key role for thimet oligopeptidase and other metallopeptidases". The Journal of Biological Chemistry. 279 (45): 46723–32. doi:10.1074/jbc.M406537200. PMID 15328361.
18. Ren G, Ma Z, Hui M, Kudo LC, Hui KS, Karsten SL (7 May 2011). "Cu, Zn-superoxide dismutase 1 (SOD1) is a novel target of Puromycin-sensitive aminopeptidase (PSA/NPEPPS): PSA/NPEPPS is a possible modifier of amyotrophic lateral sclerosis". Molecular Neurodegeneration. 6: 29. doi:10.1186/1750-1326-6-29. PMC 3113298. PMID 21548977.
19. Towne CF, York IA, Neijssen J, Karow ML, Murphy AJ, Valenzuela DM, Yancopoulos GD, Neefjes JJ, Rock KL (February 2008). "Puromycin-sensitive aminopeptidase limits MHC class I presentation in dendritic cells but does not affect CD8 T cell responses during viral infections". Journal of Immunology. 180 (3): 1704–12. doi:10.4049/jimmunol.180.3.1704. PMID 18209067.
20. Bhutani N, Venkatraman P, Goldberg AL (March 2007). "Puromycin-sensitive aminopeptidase is the major peptidase responsible for digesting polyglutamine sequences released by proteasomes during protein degradation". The EMBO Journal. 26 (5): 1385–96. doi:10.1038/sj.emboj.7601592. PMC 1817637. PMID 17318184.
21. Kudo LC, Parfenova L, Ren G, Vi N, Hui M, Ma Z, Lau K, Gray M, Bardag-Gorce F, Wiedau-Pazos M, Hui KS, Karsten SL (May 2011). "Puromycin-sensitive aminopeptidase (PSA/NPEPPS) impedes development of neuropathology in hPSA/TAU(P301L) double-transgenic mice". Human Molecular Genetics. 20 (9): 1820–33. doi:10.1093/hmg/ddr065. PMID 21320871.
22. Huber RJ, Catalano A, O'Day DH (January 2013). "Cyclin-dependent kinase 5 is a calmodulin-binding protein that associates with puromycin-sensitive aminopeptidase in the nucleus of Dictyostelium". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1833 (1): 11–20. doi:10.1016/j.bbamcr.2012.10.005. PMID 23063531.
23. Aeluri R, Ganji RJ, Marapaka AK, Pillalamarri V, Alla M, Addlagatta A (December 2015). "Highly functionalized tetrahydropyridines are cytotoxic and selective inhibitors of human puromycin sensitive aminopeptidase". European Journal of Medicinal Chemistry. 106: 26–33. doi:10.1016/j.ejmech.2015.10.026. PMID 26513642.
24. Kruppa AJ, Ott S, Chandraratna DS, Irving JA, Page RM, Speretta E, Seto T, Camargo LM, Marciniak SJ, Lomas DA, Crowther DC (December 2013). "Suppression of Aβ toxicity by puromycin-sensitive aminopeptidase is independent of its proteolytic activity". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1832 (12): 2115–26. doi:10.1016/j.bbadis.2013.07.019. PMC 3898073. PMID 23911349.

Further reading

• Thompson MW, Hersh LB (September 2003). "Analysis of conserved residues of the human puromycin-sensitive aminopeptidase". Peptides. 24 (9): 1359–65. doi:10.1016/j.peptides.2003.07.012. PMID 14706550.
• Bauer WO, Nanda I, Beck G, Schmid M, Jakob F (2001). "Human puromycin-sensitive aminopeptidase: cloning of 3' UTR, evidence for a polymorphism at a.a. 140 and refined chromosomal localization to 17q21". Cytogenetics and Cell Genetics. 92 (3–4): 221–4. doi:10.1159/000056907. PMID 11435692.
• de Gandarias JM, Irazusta J, Gil J, Fernández D, Varona A, Casis L (November 1999). "Ontogeny of puromycin-sensitive and insensitive aminopeptidase activities in several subcellular fractions of the rat brain". Brain Research Bulletin. 50 (4): 283–90. doi:10.1016/S0361-9230(99)00189-6. PMID 10582526.
• Huber G, Thompson A, Grüninger F, Mechler H, Hochstrasser R, Hauri HP, Malherbe P (March 1999). "cDNA cloning and molecular characterization of human brain metalloprotease MP100: a beta-secretase candidate?". Journal of Neurochemistry. 72 (3): 1215–23. doi:10.1046/j.1471-4159.1999.0721215.x. PMID 10037494.
• Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Cussenot O, Berthon P, Cochand-Priollet B, Maitland NJ, Le Duc A (September 1994). "Immunocytochemical comparison of cultured normal epithelial prostatic cells with prostatic tissue sections". Experimental Cell Research. 214 (1): 83–92. doi:10.1006/excr.1994.1236. PMID 8082751.
• Constam DB, Tobler AR, Rensing-Ehl A, Kemler I, Hersh LB, Fontana A (November 1995). "Puromycin-sensitive aminopeptidase. Sequence analysis, expression, and functional characterization". The Journal of Biological Chemistry. 270 (45): 26931–9. doi:10.1074/jbc.270.45.26931. PMID 7592939.
• McLellan S, Dyer SH, Rodriguez G, Hersh LB (November 1988). "Studies on the tissue distribution of the puromycin-sensitive enkephalin-degrading aminopeptidases". Journal of Neurochemistry. 51 (5): 1552–9. doi:10.1111/j.1471-4159.1988.tb01124.x. PMID 3171591.