NPEPPS

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

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]

NPEPPS
Identifiers
Aliases	NPEPPS, AAP-S, MP100, PSA, aminopeptidase puromycin sensitive
External IDs	OMIM: 606793; MGI: 1101358; HomoloGene: 36199; GeneCards: NPEPPS; OMA:NPEPPS - orthologs
Gene location (Human) Chr. Chromosome 17 (human)[1] Band 17q21.32 Start 47,522,942 bp[1] End 47,624,665 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11 D|11 60.95 cM Start 97,096,668 bp[2] End 97,171,464 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right hemisphere of cerebellum vagina epithelium of colon ganglionic eminence skin of leg gastric mucosa muscle of thigh skin of abdomen left ovary right ovary Top expressed in Rostral migratory stream neural layer of retina retinal pigment epithelium ciliary body facial motor nucleus granulocyte supraoptic nucleus dentate gyrus of hippocampal formation granule cell nucleus of stria terminalis anterior horn of spinal cord More reference expression data BioGPS n/a
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 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: 97.1 – 97.17 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]