Disease relevance of ANPEP

• Biological significance of aminopeptidase N/CD13 in thyroid carcinomas [1].
• Human cytomegalovirus infection downregulates expression of the cellular aminopeptidases CD10 and CD13 [2].
• Functional and phenotypic upregulation of CD13/aminopeptidase-N on precursor-B acute lymphoblastic leukemia after in vitro stimulation [3].
• CONCLUSIONS: These data show that cell-surface peptidases are differentially expressed by normal prostatic stromal and epithelial cells, with increased expression of APA in the stroma surrounding prostate cancer cells, absent APN expression in most tumor cells, and a decreased frequency of DPP IV expression in metastatic tumors [4].
• METHODS: We studied the relationship between the expression of neutral endopeptidase and aminopeptidase N by quantitative reverse transcript-polymerase chain reaction analysis in 132 patients with non-small cell lung cancer undergoing radical surgery from 1991 to 1996 [5].

Psychiatry related information on ANPEP

• Moreover, APN inhibitors and mutations in the catalytic site had no obvious effect on permissiveness for virus, thus providing evidence that the APN enzymatic activity is not involved in the process of infection [6].
• After a short period (48 h) of wakefulness and feeding following 10 days of starvation during the hibernation period, the activities of the disaccharidases and of aminopeptidase N returned to values measured in active animals [7].

High impact information on ANPEP

• Deficiency of a granulocyte-membrane glycoprotein (gp150) in a boy with recurrent bacterial infections [8].
• A monoclonal antibody, RBS, blocked HCV-229E virus infection of human lung fibroblasts, immunoprecipitated aminopeptidase N and inhibited its enzymatic activity [9].
• Here we report that human aminopeptidase N, a cell-surface metalloprotease on intestinal, lung and kidney epithelial cells, is a receptor for human coronavirus strain HCV-229E, but not for HCV-OC43 [9].
• Immunofluorescence analysis revealed a myelomonocytoid immunophenotype (expression of CD13 and CD68, and lack of lymphoid markers) [10].
• NB4, a human promyelocytic leukemic cell line that expresses high levels of cell-surface CD13/aminopeptidase N, does not undergo endothelial IL-8-induced apoptosis [11].

Chemical compound and disease context of ANPEP

• DNA from a tertiary mouse cell transformant containing amplified human sequences encoding a human myeloid membrane glycoprotein, gp150, was used to construct a bacteriophage lambda library [12].
• CD13, a receptor for human coronavirus 229E (HCoV-229E), was identified as a major component of the Triton X-100-resistant membrane microdomain in human fibroblasts [13].
• Even a minor disruption in the normal proteolytic equilibrium can influence tumor progression, and a range of ectopeptidases, including neutral endopeptidase 24.11, aminopeptidase N, dipeptidyl peptidase IV, angiotensin-converting enzyme, and the disintegrin-metalloproteinases, have been shown to be involved in tumour development and metastasis [14].
• While the DPIV inhibitor Lys-[Z(NO])(2)]-pyrrolidide or the APN-inhibitor Actinonin alone had marked but no significant therapeutic effects, the simultaneous administration of both inhibitors reduced colitis activity in comparison to placebo treated mice, significantly (DAI 4.8 vs. 7.7, p<0.005) [15].
• Addition of a single glycosylation site to hAPN blocks human coronavirus-229E receptor activity [16].

Biological context of ANPEP

• This refined the localization of a previously identified breakpoint in the linkage map between regions with orthology to human chromosome 15q (represented by CYP1A1 and ANPEP) and 14q (represented by SSTR1) [17].
• FTC-133 cells stably transfected with an expression vector for APN-enhanced green fluorescent protein showed a higher migration rate than FTC-133 cells transfected with the enhanced green fluorescent protein-control plasmid [1].
• Indeed, treatment of cells with an inhibitor of viral DNA synthesis blocks downregulation of CD13, whilst downregulation of CD10 is unaffected [2].
• While aminopeptidase N and neutral endopeptidase exhibit no significant sequence homology, both are expressed on the cell surface and have very similar enzymatic properties [2].
• The analysis of mRNA by competitive polymerase chain reaction (PCR) confirmed our results with respect to the APN increase at the level of gene expression [18].

Anatomical context of ANPEP

• In the undifferentiated thyroid carcinoma cell line 1736, APN/CD13 mRNA expression could be increased by epidermal growth factor, basic fibroblast growth factor, interleukin-6, and tumor necrosis factor alpha [1].
• Monocytes responded to C5a with increases in CD13 and CD45/CD45Ro [19].
• Early passage intralobular fibroblasts were positive for APN but negative for DPP IV, as seen in the intact tissue [20].
• In co-culture experiments with T-lymphocytes, cholesterol depletion of synoviocytes greatly reduced their capability to induce an early lymphocytic expression of aminopeptidase N/CD13 [21].
• Cholesterol depletion of synoviocytes by methyl-beta-cyclodextrin disrupted >90% of the caveolae and reduced the raft localization of aminopeptidase N/CD13 without affecting Ala-p-nitroanilide-cleaving activity of confluent cell cultures [21].

Associations of ANPEP with chemical compounds

• Among the herein described and evaluated compounds, the 2',3-dinitroflavone-8-acetic acid (19b) proved to be the most efficient and exhibited an IC(50) of 25 microM which is 2.5 times higher than that of bestatin (1), the natural known inhibitor of APN/CD13 [22].
• Synthesis and biological evaluation of novel flavone-8-acetic acid derivatives as reversible inhibitors of aminopeptidase N/CD13 [22].
• The link between met-enkephalin-induced down-regulation of APN activity and the release of superoxide anion [23].
• DEX strongly increased NEP and APN expression and activity, both in the absence and in the presence of cytokines [24].
• Aminopeptidase-P removes the N-terminal tyrosine from PYY, but the intact peptide is not a substrate for aminopeptidase-N [25].

Physical interactions of ANPEP

• Alanine methyl ketone-Sepharose (AMK-Sepharose) is introduced as affinity support for the purification of a bacterial alanyl aminopeptidase (AAP) from a membrane protein extract and Arginine-Agarose as support for the preparation of a membrane-bound proteinase of myeloma cells (MP-1) [26].
• Aminopeptidase N has been reported to be a Bacillus thuringiensis (Bt) Cry1A toxin-binding protein in several lepidopteran insects. cDNAs of aminopeptidase-like proteins from both Bt-susceptible RC688s and Bt-resistant HD198r strains of the Indianmeal moth, Plodia interpunctella, were cloned and sequenced [27].

Co-localisations of ANPEP

• The aggregated labeling of CD13 colocalized with caveolin-1 in most cells [13].

Regulatory relationships of ANPEP

• Involvement of insulin-regulated aminopeptidase and/or aminopeptidase N in the angiotensin IV-induced effect on dopamine release in the striatum of the rat [28].
• EGF stimulated 5'-nucleotidase and aminopeptidase N activities in intact human mesangial cells in a time- (24-72 h) and dose-dependent (0.1-50 ng ml(-1)) manner [29].
• However, we did find that the HIV-2 ST envelope glycoprotein (gp150) was not as efficient at blocking CD4 as the glycoprotein (gp140) derived from HIV-2 ROD [30].

Other interactions of ANPEP

• In our study, we quantified the expression of APN/CD13 and additionally dipeptidyl peptidase IV (DPIV)/CD26 in thyroid carcinoma cell lines and in tissues of patients with thyroid carcinomas [1].
• A 5-day incubation with interferon-gamma (IFN-gamma) increased protein expression, especially of APN and, to a lesser extent, also of DPIV, whereas no significant increase in enzymatic activity could be observed [18].
• OBJECTIVES: Neutral endopeptidase modulates the growth of lung cancer, while aminopeptidase N degrades the extracellular matrix and is involved in cell motility [5].
• Both DP IV and APN serve as targets of efficient enzymatic inhibitors which induce autocrine production of TGF-beta1 and subsequent suppression of T cell proliferation and cytokine release [31].
• Puromycin-sensitive aminopeptidase activity in the tumor increases [tumor (t) = 10,775 vs. nontumor (n) = 7,635 units of peptidase (UP)/mg protein; P < 0.05], whereas aminopeptidase N decreases (t = 6,664 vs. n = 33,381 UP/mg protein; P < 0.001) [32].

Analytical, diagnostic and therapeutic context of ANPEP

• CD13 was analyzed phenotypically using a specific monoclonal antibody (mAb) by flow cytometry, and also with a spectrophotometric enzyme assay to measure the cleavage of specific peptide substrates [3].
• Transcription and expression of CD10, CD13, and CD143 were studied by quantitative RT-PCR, Western blotting, and immunohistochemistry [33].
• In vivo, targeting DP IV and APN provided a potent therapeutic approach for the treatment of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis [31].
• Aminopeptidase-N is a membrane-bound metalloprotease catalyzing the removal of N-terminal amino acids from peptides and was detected by immunofluorescence staining on theca interna cells in secondary follicles and on luteinized thecal cells in preovulatory follicles and corpora lutea [34].
• Indirect immunofluorescence staining revealed that both endometrial stromal cells and decidual cells during the first trimester of pregnancy expressed cluster of differentiation (CD) 13 antigen and CD10 antigen, which are identical to aminopeptidase N and neutral endopeptidase, respectively [35].

References