NPEPPS explained

Puromycin-sensitive amino peptidase also known as cytosol alanyl aminopeptidase or alanine aminopeptidase (AAP) is an enzyme that in humans is encoded by the NPEPPS gene.^{[1] [2] [3]} 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.^[4]

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.^[3] It has been identified as a novel modifier of TAU-induced neurodegeneration with neuroprotective effects via direct proteolysis of TAU protein.^{[5] [6]} The loss of NPEPPS function exacerbates neurodegeneration.^[7]

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.^[8] Two isozymes have been found and they are expressed differently in the nervous system.^[9] Glu 309 is one of the active site glutamates, and its mutation could convert the enzyme into an inactive binding protein.^[10]

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.^{[11] [12] [13]} NPEPPS is a major protease to digest SOD1, similar to its role in TAU-induced neurodegeneration.^[14] 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.^[15]

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.^[16] 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.^[17]

Interactions

• Cyclin-dependent kinase 5^[18]
• SOD1
• TAU
• Tetrahydropyridine^[19]
• β-amyloid^[20]

Further reading

• Thompson MW, Hersh LB . Analysis of conserved residues of the human puromycin-sensitive aminopeptidase . Peptides . 24 . 9 . 1359–65 . September 2003 . 14706550 . 10.1016/j.peptides.2003.07.012 . 24646812 .
• Bauer WO, Nanda I, Beck G, Schmid M, Jakob F . 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 . 2001 . 11435692 . 10.1159/000056907 . 28906058 .
• de Gandarias JM, Irazusta J, Gil J, Fernández D, Varona A, Casis L . Ontogeny of puromycin-sensitive and insensitive aminopeptidase activities in several subcellular fractions of the rat brain . Brain Research Bulletin . 50 . 4 . 283–90 . November 1999 . 10582526 . 10.1016/S0361-9230(99)00189-6 . 6673357 .
• Huber G, Thompson A, Grüninger F, Mechler H, Hochstrasser R, Hauri HP, Malherbe P . cDNA cloning and molecular characterization of human brain metalloprotease MP100: a beta-secretase candidate? . Journal of Neurochemistry . 72 . 3 . 1215–23 . March 1999 . 10037494 . 10.1046/j.1471-4159.1999.0721215.x . 28498743 . free .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . September 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Cussenot O, Berthon P, Cochand-Priollet B, Maitland NJ, Le Duc A . Immunocytochemical comparison of cultured normal epithelial prostatic cells with prostatic tissue sections . Experimental Cell Research . 214 . 1 . 83–92 . September 1994 . 8082751 . 10.1006/excr.1994.1236 .
• Constam DB, Tobler AR, Rensing-Ehl A, Kemler I, Hersh LB, Fontana A . Puromycin-sensitive aminopeptidase. Sequence analysis, expression, and functional characterization . The Journal of Biological Chemistry . 270 . 45 . 26931–9 . November 1995 . 7592939 . 10.1074/jbc.270.45.26931 . free .
• McLellan S, Dyer SH, Rodriguez G, Hersh LB . Studies on the tissue distribution of the puromycin-sensitive enkephalin-degrading aminopeptidases . Journal of Neurochemistry . 51 . 5 . 1552–9 . November 1988 . 3171591 . 10.1111/j.1471-4159.1988.tb01124.x . 20808131 .

Notes and References

1. Tobler AR, Constam DB, Schmitt-Gräff A, Malipiero U, Schlapbach R, Fontana A . Cloning of the human puromycin-sensitive aminopeptidase and evidence for expression in neurons . Journal of Neurochemistry . 68 . 3 . 889–97 . March 1997 . 9048733 . 10.1046/j.1471-4159.1997.68030889.x . 30408265 . free .
2. Thompson MW, Tobler A, Fontana A, Hersh LB . Cloning and analysis of the gene for the human puromycin-sensitive aminopeptidase . Biochemical and Biophysical Research Communications . 258 . 2 . 234–40 . May 1999 . 10329370 . 10.1006/bbrc.1999.0604 .
3. Web site: Entrez Gene: NPEPPS aminopeptidase puromycin sensitive.
4. Holdt B, Peters E, Nagel HR, Steiner M . An automated assay of urinary alanine aminopeptidase activity . Clinical Chemistry and Laboratory Medicine . 46 . 4 . 537–40 . 2008 . 18302530 . 10.1515/CCLM.2008.103 . 45057277 .
5. Sengupta S, Horowitz PM, Karsten SL, Jackson GR, Geschwind DH, Fu Y, Berry RW, Binder LI . Degradation of tau protein by puromycin-sensitive aminopeptidase in vitro . Biochemistry . 45 . 50 . 15111–9 . December 2006 . 10.1021/bi061830d . 17154549 .
6. Yanagi K, Tanaka T, Kato K, Sadik G, Morihara T, Kudo T, Takeda M . 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 . December 2009 . 10.1111/j.1479-8301.2010.00307.x . 20377816 . free .
7. 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 . A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration . Neuron . 51 . 5 . 549–60 . September 2006 . 10.1016/j.neuron.2006.07.019 . 16950154 . 8389733 . free .
8. Rawson NS . 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 . November 2009 . 10.1002/pds.1822 . 19650154 . 22999576 .
9. Barton S . Some Observations concerning the Medical Properties of the Pyrola Umbellata, and the Arbutus Uva Ursi, of Linnæus . Medico-Chirurgical Transactions . 7 . 143–9 . 1816-01-01 . 10.1177/095952871600700108 . 20895273 . 2129051 .
10. Thompson MW, Govindaswami M, Hersh LB . 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 . May 2003 . 12729622 . 10.1016/s0003-9861(03)00123-1.
11. Hersh LB, Smith TE, McKelvy JF . Cleavage of endorphins to des-Tyr endorphins by homogeneous bovine brain aminopeptidase . Nature . 286 . 5769 . 160–2 . July 1980 . 7402309 . 10.1038/286160a0. 1980Natur.286..160H . 4257825 .
12. Constam DB, Tobler AR, Rensing-Ehl A, Kemler I, Hersh LB, Fontana A . Puromycin-sensitive aminopeptidase. Sequence analysis, expression, and functional characterization . The Journal of Biological Chemistry . 270 . 45 . 26931–9 . November 1995 . 7592939 . 10.1074/jbc.270.45.26931. free .
13. Saric T, Graef CI, Goldberg AL . 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 . November 2004 . 15328361 . 10.1074/jbc.M406537200 . free .
14. Ren G, Ma Z, Hui M, Kudo LC, Hui KS, Karsten SL . 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 . 7 May 2011 . 21548977 . 10.1186/1750-1326-6-29 . 3113298 . free .
15. Towne CF, York IA, Neijssen J, Karow ML, Murphy AJ, Valenzuela DM, Yancopoulos GD, Neefjes JJ, Rock KL . 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 . February 2008 . 18209067 . 10.4049/jimmunol.180.3.1704. free .
16. Bhutani N, Venkatraman P, Goldberg AL . 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 . March 2007 . 1817637 . 10.1038/sj.emboj.7601592 . 17318184 .
17. 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 . Puromycin-sensitive aminopeptidase (PSA/NPEPPS) impedes development of neuropathology in hPSA/TAU(P301L) double-transgenic mice . Human Molecular Genetics . 20 . 9 . 1820–33 . May 2011 . 10.1093/hmg/ddr065 . 21320871 . free .
18. Huber RJ, Catalano A, O'Day DH . 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 . January 2013 . 10.1016/j.bbamcr.2012.10.005 . 23063531 . free .
19. Aeluri R, Ganji RJ, Marapaka AK, Pillalamarri V, Alla M, Addlagatta A . Highly functionalized tetrahydropyridines are cytotoxic and selective inhibitors of human puromycin sensitive aminopeptidase . European Journal of Medicinal Chemistry . 106 . 26–33 . December 2015 . 10.1016/j.ejmech.2015.10.026 . 26513642 .
20. Kruppa AJ, Ott S, Chandraratna DS, Irving JA, Page RM, Speretta E, Seto T, Camargo LM, Marciniak SJ, Lomas DA, Crowther DC . 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 . December 2013 . 3898073 . 10.1016/j.bbadis.2013.07.019 . 23911349 .