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{{About|the cytosolic alanine aminopeptidase|the cell membrane alanyl aminopeptidase|Alanine aminopeptidase}}
{{PBB_Controls
{{Infobox_gene}}
| update_page = yes
'''Puromycin-sensitive amino peptidase''' also known as '''cytosol alanyl aminopeptidase''' or '''alanine aminopeptidase''' (AAP) ({{EC number|3.4.11.14}}) is an [[enzyme]] that in humans is encoded by the ''NPEPPS'' [[gene]].<ref name="pmid9048733">{{cite journal | vauthors = Tobler AR, Constam DB, Schmitt-Gräff A, Malipiero U, Schlapbach R, Fontana A | title = Cloning of the human puromycin-sensitive aminopeptidase and evidence for expression in neurons | journal = Journal of Neurochemistry | volume = 68 | issue = 3 | pages = 889–97 | date = March 1997 | pmid = 9048733 | pmc =  | doi = 10.1046/j.1471-4159.1997.68030889.x }}</ref><ref name="pmid10329370">{{cite journal | vauthors = Thompson MW, Tobler A, Fontana A, Hersh LB | title = Cloning and analysis of the gene for the human puromycin-sensitive aminopeptidase | journal = Biochemical and Biophysical Research Communications | volume = 258 | issue = 2 | pages = 234–40 | date = May 1999 | pmid = 10329370 | pmc =  | doi = 10.1006/bbrc.1999.0604 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: NPEPPS aminopeptidase puromycin sensitive| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9520| accessdate = }}</ref>  It is used as a [[biomarker]] to detect damage to the [[kidney]]s, and that may be used to help diagnose certain [[nephrology|kidney disorders]]. It is found at high levels in the [[urine]] when there are kidney problems.<ref name="pmid18302530">{{cite journal | vauthors = Holdt B, Peters E, Nagel HR, Steiner M | title = An automated assay of urinary alanine aminopeptidase activity | journal = Clinical Chemistry and Laboratory Medicine | volume = 46 | issue = 4 | pages = 537–40 | year = 2008 | pmid = 18302530 | doi = 10.1515/CCLM.2008.103 }}</ref>
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = Aminopeptidase puromycin sensitive
| HGNCid = 7900
| Symbol = NPEPPS
| AltSymbols =; PSA; MP100
| OMIM = 606793
| ECnumber = 
| Homologene = 36199
| MGIid = 1101358
| Function = {{GNF_GO|id=GO:0004177 |text = aminopeptidase activity}} {{GNF_GO|id=GO:0004179 |text = membrane alanyl aminopeptidase activity}} {{GNF_GO|id=GO:0008237 |text = metallopeptidase activity}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005829 |text = cytosol}}
| Process = {{GNF_GO|id=GO:0006508 |text = proteolysis}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 9520
    | Hs_Ensembl = ENSG00000141279
    | Hs_RefseqProtein = XP_001128588
    | Hs_RefseqmRNA = XM_001128588
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 17
    | Hs_GenLoc_start = 42963603
    | Hs_GenLoc_end = 43055634
    | Hs_Uniprot = P55786
    | Mm_EntrezGene = 19155
    | Mm_Ensembl = ENSMUSG00000001441
    | Mm_RefseqmRNA = NM_008942
    | Mm_RefseqProtein = NP_032968
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 11
    | Mm_GenLoc_start = 97021944
    | Mm_GenLoc_end = 97096666
    | Mm_Uniprot = Q3UZE0
  }}
}}
'''Aminopeptidase puromycin sensitive''', also known as '''NPEPPS''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: NPEPPS aminopeptidase puromycin sensitive| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9520| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
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 [[Enkephalin|enkephalins]] in the brain, and studies in mouse suggest that it is involved in proteolytic events regulating the cell cycle.<ref name="entrez"/> It has been identified as a novel modifier of [[Tau protein|TAU]]-induced neurodegeneration with neuroprotective effects via direct [[proteolysis]] of TAU protein.<ref>{{cite journal | vauthors = Sengupta S, Horowitz PM, Karsten SL, Jackson GR, Geschwind DH, Fu Y, Berry RW, Binder LI | title = Degradation of tau protein by puromycin-sensitive aminopeptidase in vitro | journal = Biochemistry | volume = 45 | issue = 50 | pages = 15111–9 | date = December 2006 | doi = 10.1021/bi061830d | pmid = 17154549 }}</ref><ref name=":0">{{cite journal | vauthors = Yanagi K, Tanaka T, Kato K, Sadik G, Morihara T, Kudo T, Takeda M | title = 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 | journal = Psychogeriatrics | volume = 9 | issue = 4 | pages = 157–66 | date = December 2009 | doi = 10.1111/j.1479-8301.2010.00307.x | pmid = 20377816 }}</ref> The loss of NPEPPS function exacerbates [[neurodegeneration]].<ref>{{cite journal | vauthors = 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 | title = A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration | journal = Neuron | volume = 51 | issue = 5 | pages = 549–60 | date = September 2006 | doi = 10.1016/j.neuron.2006.07.019 | pmid = 16950154 }}</ref>
{{PBB_Summary
| section_title =
| summary_text = 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 enkaphalins in the brain, and studies in mouse suggest that it is involved in proteolytic events regulating the cell cycle.<ref name="entrez">{{cite web | title = Entrez Gene: NPEPPS aminopeptidase puromycin sensitive| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9520| accessdate = }}</ref>
}}


==References==
==Structure==
{{reflist|2}}
 
==Further reading==
===Gene===
{{refbegin | 2}}
The ''NPEPPS'' gene is located at [[chromosome 17]]q21, consisting of 25 [[exons]] and spanning 40 kb.
{{PBB_Further_reading
 
| citations =  
===Protein===
*{{cite journal | author=Ewing RM, Chu P, Elisma F, ''et al.'' |title=Large-scale mapping of human protein-protein interactions by mass spectrometry. |journal=Mol. Syst. Biol. |volume=3 |issue= |pages= 89 |year= 2007 |pmid= 17353931 |doi= 10.1038/msb4100134 }}
NPEPPS is a ubiquitous , 100 kDa, Zn<sup>2+</sup> [[metallopeptidase]] highly expressed in the brain.<ref>{{cite journal | vauthors = Rawson NS | title = Access to linked administrative healthcare utilization data for pharmacoepidemiology and pharmacoeconomics research in Canada: anti-viral drugs as an example | journal = Pharmacoepidemiology and Drug Safety | volume = 18 | issue = 11 | pages = 1072–9 | date = November 2009 | doi = 10.1002/pds.1822 | pmid = 19650154 }}</ref> Two [[isozymes]] have been found and they are expressed differently in the nervous system.<ref>{{cite journal | vauthors = Barton S | title = Some Observations concerning the Medical Properties of the Pyrola Umbellata, and the Arbutus Uva Ursi, of Linnæus | journal = Medico-Chirurgical Transactions | volume = 7 | pages = 143–9 | date = 1816-01-01 | pmid = 20895273 | pmc = 2129051 }}</ref> [[Glutamic acid|Glu]] 309 is one of the active site [[glutamates]], and its [[mutation]] could convert the enzyme into an inactive binding protein.<ref>{{cite journal | vauthors = Thompson MW, Govindaswami M, Hersh LB | title = Mutation of active site residues of the puromycin-sensitive aminopeptidase: conversion of the enzyme into a catalytically inactive binding protein | journal = Archives of Biochemistry and Biophysics | volume = 413 | issue = 2 | pages = 236–42 | date = May 2003 | pmid = 12729622 | doi=10.1016/s0003-9861(03)00123-1}}</ref>
*{{cite journal | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
 
*{{cite journal | author=Thompson MW, Hersh LB |title=Analysis of conserved residues of the human puromycin-sensitive aminopeptidase. |journal=Peptides |volume=24 |issue= 9 |pages= 1359-65 |year= 2005 |pmid= 14706550 |doi= }}
== Function ==
*{{cite journal | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40-5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
 
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
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]].<ref name="PMID7402309">{{cite journal | vauthors = Hersh LB, Smith TE, McKelvy JF | title = Cleavage of endorphins to des-Tyr endorphins by homogeneous bovine brain aminopeptidase | journal = Nature | volume = 286 | issue = 5769 | pages = 160–2 | date = July 1980 | pmid = 7402309 | doi=10.1038/286160a0}}</ref><ref>{{cite journal | vauthors = Constam DB, Tobler AR, Rensing-Ehl A, Kemler I, Hersh LB, Fontana A | title = Puromycin-sensitive aminopeptidase. Sequence analysis, expression, and functional characterization | journal = The Journal of Biological Chemistry | volume = 270 | issue = 45 | pages = 26931–9 | date = November 1995 | pmid = 7592939 | doi=10.1074/jbc.270.45.26931}}</ref><ref name="PMID15328361">{{cite journal | vauthors = Saric T, Graef CI, Goldberg AL | title = Pathway for degradation of peptides generated by proteasomes: a key role for thimet oligopeptidase and other metallopeptidases | journal = The Journal of Biological Chemistry | volume = 279 | issue = 45 | pages = 46723–32 | date = November 2004 | pmid = 15328361 | doi = 10.1074/jbc.M406537200 }}</ref> NPEPPS is a major protease to digest [[SOD1]], similar to its role in TAU-induced neurodegeneration.<ref name=":0" /><ref name="PMID21548977">{{cite journal | vauthors = Ren G, Ma Z, Hui M, Kudo LC, Hui KS, Karsten SL | title = 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 | journal = Molecular Neurodegeneration | volume = 6 | pages = 29 | date = 7 May 2011 | pmid = 21548977 | doi = 10.1186/1750-1326-6-29 | pmc=3113298}}</ref> NPEPPS is also reported to play a role in creating and destroying [[Myosin heavy chain|MHC]] class Ⅰ-presented peptides and in limiting MHC class Ⅰ Ag presentation in dendritic cells.<ref>{{cite journal | vauthors = Towne CF, York IA, Neijssen J, Karow ML, Murphy AJ, Valenzuela DM, Yancopoulos GD, Neefjes JJ, Rock KL | title = Puromycin-sensitive aminopeptidase limits MHC class I presentation in dendritic cells but does not affect CD8 T cell responses during viral infections | journal = Journal of Immunology | volume = 180 | issue = 3 | pages = 1704–12 | date = February 2008 | pmid = 18209067 | doi=10.4049/jimmunol.180.3.1704}}</ref>
*{{cite journal | author=Bauer WO, Nanda I, Beck G, ''et al.'' |title=Human puromycin-sensitive aminopeptidase: cloning of 3' UTR, evidence for a polymorphism at a.a. 140 and refined chromosomal localization to 17q21. |journal=Cytogenet. Cell Genet. |volume=92 |issue= 3-4 |pages= 221-4 |year= 2001 |pmid= 11435692 |doi= }}
 
*{{cite journal | author=de Gandarias JM, Irazusta J, Gil J, ''et al.'' |title=Ontogeny of puromycin-sensitive and insensitive aminopeptidase activities in several subcellular fractions of the rat brain. |journal=Brain Res. Bull. |volume=50 |issue= 4 |pages= 283-90 |year= 1999 |pmid= 10582526 |doi=  }}
==Clinical significance==
*{{cite journal  | author=Thompson MW, Tobler A, Fontana A, Hersh LB |title=Cloning and analysis of the gene for the human puromycin-sensitive aminopeptidase. |journal=Biochem. Biophys. Res. Commun. |volume=258 |issue= 2 |pages= 234-40 |year= 1999 |pmid= 10329370 |doi= 10.1006/bbrc.1999.0604 }}
 
*{{cite journal | author=Huber G, Thompson A, Grüninger F, ''et al.'' |title=cDNA cloning and molecular characterization of human brain metalloprotease MP100: a beta-secretase candidate? |journal=J. Neurochem. |volume=72 |issue= 3 |pages= 1215-23 |year= 1999 |pmid= 10037494 |doi= }}
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]].<ref>{{cite journal | vauthors = Bhutani N, Venkatraman P, Goldberg AL | title = Puromycin-sensitive aminopeptidase is the major peptidase responsible for digesting polyglutamine sequences released by proteasomes during protein degradation | journal = The EMBO Journal | volume = 26 | issue = 5 | pages = 1385–96 | date = March 2007 | pmc = 1817637 | doi = 10.1038/sj.emboj.7601592 | pmid = 17318184 }}</ref> 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.<ref>{{cite journal | vauthors = 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 | title = Puromycin-sensitive aminopeptidase (PSA/NPEPPS) impedes development of neuropathology in hPSA/TAU(P301L) double-transgenic mice | journal = Human Molecular Genetics | volume = 20 | issue = 9 | pages = 1820–33 | date = May 2011 | doi = 10.1093/hmg/ddr065 | pmid = 21320871 }}</ref>
*{{cite journal  | author=Tobler AR, Constam DB, Schmitt-Gräff A, ''et al.'' |title=Cloning of the human puromycin-sensitive aminopeptidase and evidence for expression in neurons. |journal=J. Neurochem. |volume=68 |issue= 3 |pages= 889-97 |year= 1997 |pmid= 9048733 |doi=  }}
 
*{{cite journal | author=Bonaldo MF, Lennon G, Soares MB |title=Normalization and subtraction: two approaches to facilitate gene discovery. |journal=Genome Res. |volume=6 |issue= 9 |pages= 791-806 |year= 1997 |pmid= 8889548 |doi= }}
== Interactions ==
*{{cite journal | author=Cussenot O, Berthon P, Cochand-Priollet B, ''et al.'' |title=Immunocytochemical comparison of cultured normal epithelial prostatic cells with prostatic tissue sections. |journal=Exp. Cell Res. |volume=214 |issue= 1 |pages= 83-92 |year= 1994 |pmid= 8082751 |doi= 10.1006/excr.1994.1236 }}
 
*{{cite journal | author=Constam DB, Tobler AR, Rensing-Ehl A, ''et al.'' |title=Puromycin-sensitive aminopeptidase. Sequence analysis, expression, and functional characterization. |journal=J. Biol. Chem. |volume=270 |issue= 45 |pages= 26931-9 |year= 1995 |pmid= 7592939 |doi= }}
*[[Cyclin-dependent kinase 5]] <ref>{{cite journal | vauthors = Huber RJ, Catalano A, O'Day DH | title = Cyclin-dependent kinase 5 is a calmodulin-binding protein that associates with puromycin-sensitive aminopeptidase in the nucleus of Dictyostelium | journal = Biochimica et Biophysica Acta | volume = 1833 | issue = 1 | pages = 11–20 | date = January 2013 | doi = 10.1016/j.bbamcr.2012.10.005 | pmid = 23063531 }}</ref>
*{{cite journal | author=McLellan S, Dyer SH, Rodriguez G, Hersh LB |title=Studies on the tissue distribution of the puromycin-sensitive enkephalin-degrading aminopeptidases. |journal=J. Neurochem. |volume=51 |issue= 5 |pages= 1552-9 |year= 1988 |pmid= 3171591 |doi= }}
*SOD1 <ref name="PMID21548977" />
}}
*TAU <ref name=":0" />
*[[Tetrahydropyridine]] <ref>{{cite journal | vauthors = Aeluri R, Ganji RJ, Marapaka AK, Pillalamarri V, Alla M, Addlagatta A | title = Highly functionalized tetrahydropyridines are cytotoxic and selective inhibitors of human puromycin sensitive aminopeptidase | journal = European Journal of Medicinal Chemistry | volume = 106 | pages = 26–33 | date = December 2015 | doi = 10.1016/j.ejmech.2015.10.026 | pmid = 26513642 }}</ref>
*[[β-amyloid]] <ref>{{cite journal | vauthors = Kruppa AJ, Ott S, Chandraratna DS, Irving JA, Page RM, Speretta E, Seto T, Camargo LM, Marciniak SJ, Lomas DA, Crowther DC | title = Suppression of Aβ toxicity by puromycin-sensitive aminopeptidase is independent of its proteolytic activity | journal = Biochimica et Biophysica Acta | volume = 1832 | issue = 12 | pages = 2115–26 | date = December 2013 | pmc = 3898073 | doi = 10.1016/j.bbadis.2013.07.019 | pmid = 23911349 }}</ref>
 
== References ==
{{reflist|33em}}
 
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Thompson MW, Hersh LB | title = Analysis of conserved residues of the human puromycin-sensitive aminopeptidase | journal = Peptides | volume = 24 | issue = 9 | pages = 1359–65 | date = September 2003 | pmid = 14706550 | doi = 10.1016/j.peptides.2003.07.012 }}
* {{cite journal | vauthors = Bauer WO, Nanda I, Beck G, Schmid M, Jakob F | title = Human puromycin-sensitive aminopeptidase: cloning of 3' UTR, evidence for a polymorphism at a.a. 140 and refined chromosomal localization to 17q21 | journal = Cytogenetics and Cell Genetics | volume = 92 | issue = 3-4 | pages = 221–4 | year = 2001 | pmid = 11435692 | doi = 10.1159/000056907 }}
* {{cite journal | vauthors = de Gandarias JM, Irazusta J, Gil J, Fernández D, Varona A, Casis L | title = Ontogeny of puromycin-sensitive and insensitive aminopeptidase activities in several subcellular fractions of the rat brain | journal = Brain Research Bulletin | volume = 50 | issue = 4 | pages = 283–90 | date = November 1999 | pmid = 10582526 | doi = 10.1016/S0361-9230(99)00189-6 }}
* {{cite journal | vauthors = Huber G, Thompson A, Grüninger F, Mechler H, Hochstrasser R, Hauri HP, Malherbe P | title = cDNA cloning and molecular characterization of human brain metalloprotease MP100: a beta-secretase candidate? | journal = Journal of Neurochemistry | volume = 72 | issue = 3 | pages = 1215–23 | date = March 1999 | pmid = 10037494 | doi = 10.1046/j.1471-4159.1999.0721215.x }}
* {{cite journal | vauthors = Bonaldo MF, Lennon G, Soares MB | title = Normalization and subtraction: two approaches to facilitate gene discovery | journal = Genome Research | volume = 6 | issue = 9 | pages = 791–806 | date = September 1996 | pmid = 8889548 | doi = 10.1101/gr.6.9.791 }}
* {{cite journal | vauthors = Cussenot O, Berthon P, Cochand-Priollet B, Maitland NJ, Le Duc A | title = Immunocytochemical comparison of cultured normal epithelial prostatic cells with prostatic tissue sections | journal = Experimental Cell Research | volume = 214 | issue = 1 | pages = 83–92 | date = September 1994 | pmid = 8082751 | doi = 10.1006/excr.1994.1236 }}
* {{cite journal | vauthors = Constam DB, Tobler AR, Rensing-Ehl A, Kemler I, Hersh LB, Fontana A | title = Puromycin-sensitive aminopeptidase. Sequence analysis, expression, and functional characterization | journal = The Journal of Biological Chemistry | volume = 270 | issue = 45 | pages = 26931–9 | date = November 1995 | pmid = 7592939 | doi = 10.1074/jbc.270.45.26931 }}
* {{cite journal | vauthors = McLellan S, Dyer SH, Rodriguez G, Hersh LB | title = Studies on the tissue distribution of the puromycin-sensitive enkephalin-degrading aminopeptidases | journal = Journal of Neurochemistry | volume = 51 | issue = 5 | pages = 1552–9 | date = November 1988 | pmid = 3171591 | doi = 10.1111/j.1471-4159.1988.tb01124.x }}
{{refend}}
{{refend}}
{{protein-stub}}
{{WikiDoc Sources}}

Latest revision as of 03:09, 27 October 2017

This article is about the cytosolic alanine aminopeptidase. For the cell membrane alanyl aminopeptidase, see Alanine aminopeptidase.
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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
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Wikidata
View/Edit Human

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.[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.[6][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

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 3.0 3.1 "Entrez Gene: NPEPPS aminopeptidase puromycin sensitive".
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 6.0 6.1 6.2 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.
  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 (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.
  8. ↑ 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.
  9. ↑ 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. PMC 2129051. PMID 20895273.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 14.0 14.1 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.
  15. ↑ 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.
  16. ↑ 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.
  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 (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.
  18. ↑ 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. 1833 (1): 11–20. doi:10.1016/j.bbamcr.2012.10.005. PMID 23063531.
  19. ↑ 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.
  20. ↑ 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. 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.
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