Biology:NPEPPS

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Short description: Protein-coding gene in the species Homo sapiens


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

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. ↑ "Cloning of the human puromycin-sensitive aminopeptidase and evidence for expression in neurons". Journal of Neurochemistry 68 (3): 889–97. March 1997. doi:10.1046/j.1471-4159.1997.68030889.x. PMID 9048733. 
  2. ↑ "Cloning and analysis of the gene for the human puromycin-sensitive aminopeptidase". Biochemical and Biophysical Research Communications 258 (2): 234–40. May 1999. doi:10.1006/bbrc.1999.0604. PMID 10329370. 
  3. ↑ 3.0 3.1 "Entrez Gene: NPEPPS aminopeptidase puromycin sensitive". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9520. 
  4. ↑ "An automated assay of urinary alanine aminopeptidase activity". Clinical Chemistry and Laboratory Medicine 46 (4): 537–40. 2008. doi:10.1515/CCLM.2008.103. PMID 18302530. 
  5. ↑ "Degradation of tau protein by puromycin-sensitive aminopeptidase in vitro". Biochemistry 45 (50): 15111–9. December 2006. doi:10.1021/bi061830d. PMID 17154549. 
  6. ↑ 6.0 6.1 6.2 "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. doi:10.1111/j.1479-8301.2010.00307.x. PMID 20377816. 
  7. ↑ "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. doi:10.1016/j.neuron.2006.07.019. PMID 16950154. 
  8. ↑ "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. doi:10.1002/pds.1822. PMID 19650154. 
  9. ↑ "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. doi:10.1177/095952871600700108. PMID 20895273. 
  10. ↑ "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. doi:10.1016/s0003-9861(03)00123-1. PMID 12729622. 
  11. ↑ "Cleavage of endorphins to des-Tyr endorphins by homogeneous bovine brain aminopeptidase". Nature 286 (5769): 160–2. July 1980. doi:10.1038/286160a0. PMID 7402309. Bibcode: 1980Natur.286..160H. 
  12. ↑ "Puromycin-sensitive aminopeptidase. Sequence analysis, expression, and functional characterization". The Journal of Biological Chemistry 270 (45): 26931–9. November 1995. doi:10.1074/jbc.270.45.26931. PMID 7592939. 
  13. ↑ "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. doi:10.1074/jbc.M406537200. PMID 15328361. 
  14. ↑ 14.0 14.1 "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. doi:10.1186/1750-1326-6-29. PMID 21548977. 
  15. ↑ "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. doi:10.4049/jimmunol.180.3.1704. PMID 18209067. 
  16. ↑ "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. doi:10.1038/sj.emboj.7601592. PMID 17318184. 
  17. ↑ "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. doi:10.1093/hmg/ddr065. PMID 21320871. 
  18. ↑ "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. doi:10.1016/j.bbamcr.2012.10.005. PMID 23063531. 
  19. ↑ "Highly functionalized tetrahydropyridines are cytotoxic and selective inhibitors of human puromycin sensitive aminopeptidase". European Journal of Medicinal Chemistry 106: 26–33. December 2015. doi:10.1016/j.ejmech.2015.10.026. PMID 26513642. 
  20. ↑ "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. doi:10.1016/j.bbadis.2013.07.019. PMID 23911349. 

Further reading

  • "Analysis of conserved residues of the human puromycin-sensitive aminopeptidase". Peptides 24 (9): 1359–65. September 2003. doi:10.1016/j.peptides.2003.07.012. PMID 14706550. 
  • "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. doi:10.1159/000056907. PMID 11435692. 
  • "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. doi:10.1016/S0361-9230(99)00189-6. PMID 10582526. 
  • "cDNA cloning and molecular characterization of human brain metalloprotease MP100: a beta-secretase candidate?". Journal of Neurochemistry 72 (3): 1215–23. March 1999. doi:10.1046/j.1471-4159.1999.0721215.x. PMID 10037494. 
  • "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research 6 (9): 791–806. September 1996. doi:10.1101/gr.6.9.791. PMID 8889548. 
  • "Immunocytochemical comparison of cultured normal epithelial prostatic cells with prostatic tissue sections". Experimental Cell Research 214 (1): 83–92. September 1994. doi:10.1006/excr.1994.1236. PMID 8082751. 
  • "Puromycin-sensitive aminopeptidase. Sequence analysis, expression, and functional characterization". The Journal of Biological Chemistry 270 (45): 26931–9. November 1995. doi:10.1074/jbc.270.45.26931. PMID 7592939. 
  • "Studies on the tissue distribution of the puromycin-sensitive enkephalin-degrading aminopeptidases". Journal of Neurochemistry 51 (5): 1552–9. November 1988. doi:10.1111/j.1471-4159.1988.tb01124.x. PMID 3171591. 




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