Disease relevance of ENPEP

• Soluble and particulate pyroglutamyl peptidase I activities, aminopeptidase A activity, and soluble aminopeptidase B activity do not vary in renal cancer [1].
• gp160 is a cell surface differentiation-related glycoprotein of 160 kDa expressed by epithelial cells of the glomerulus and proximal tubule cells of the human nephron but only by a subset of renal cell carcinomas (RCCs) [2].
• We performed a phase I trial of the safety and immunogenicity of a vaccine prepared from molecularly cloned envelope protein, gp160, in 30 volunteer subjects with HIV infection in Walter Reed stage 1 or 2 [3].
• However, the gp160 polyprotein was not cleaved and the mutated virions were biologically inactive, until and unless they were exposed to limiting concentrations of chymotrypsin [4].
• Chimpanzees were immunized with recombinant forms of the HIV-1 glycoproteins gp120 and gp160 produced in Chinese hamster ovary cells, and then challenged with HIV-1 [5].

Psychiatry related information on ENPEP

• This paper examines existing statutes and the APA resource document, considers the variety of ways in which the goals of reform can be achieved, and recommends approaches that balance desires for public safety with the legitimate needs and concerns of the mental health professions [6].
• Concerns about APA questionnaire on personality disorders [7].
• Comments on the APA Panic Disorder Guideline. American Psychiatric Association [8].
• Pathological gambling was officially defined as a psychiatric illness by APA in 1980 [9].
• IgG to gp160 and to four peptides (gp41 immunodominant DI domain, gp41/Id; EDLKWA epitope of DIII domain, gp41/K; gp120 C-terminus, gp120/Ct; V3 loop, gp120/V3) were evaluated in all samples [10].

High impact information on ENPEP

• Seroconversion to selected envelope epitopes was observed, as were new T-cell proliferative responses to gp160 [3].
• In 19 of the 30 subjects both humoral and cellular immunity to HIV envelope proteins increased in response to vaccination with gp160 [3].
• Protection of chimpanzees from infection by HIV-1 after vaccination with recombinant glycoprotein gp120 but not gp160 [5].
• For the primary vaccination recombinant vaccinia virus (V25) expressing the complete gp160 env protein of the HTLV-IIIB strain of HIV-1 was introduced by scarification [11].
• Finally, skin tests showed both immediate and delayed hypersensitivity to gp160 in vivo [11].

Chemical compound and disease context of ENPEP

• We have described a new variety of aldosterone-producing adenoma which is responsive to angiotensin II (AII-responsive APA), consists of at least 20% zona glomerulosa-like cells, and does not make "hybrid steroids" in excess [12].
• PATIENTS AND METHODS: Twenty-six consecutive assessable patients with potentially resectable adenocarcinoma of the esophagus or gastroesophageal junction were treated with two preoperative courses of intensive chemotherapy (etoposide, doxorubicin, and cisplatin [EAP]) with granulocyte-macrophage CSF (GM-CSF) [13].
• The APA Task Force report on benzodiazepine dependence, toxicity, and abuse [14].
• Enhancement of aminopeptidase A expression during angiotensin II-induced choriocarcinoma cell proliferation through AT1 receptor involving protein kinase C- and mitogen-activated protein kinase-dependent signaling pathway [15].
• In the present study we examined the effects of Ang II on proliferation and APA expression in trophoblast-like BeWo choriocarcinoma cells [15].

Biological context of ENPEP

• The linkage of ENPEP to complement factor I (IF) confirms the human chromosome band 4q25 localization predicted from the chromosomal location of murine ENPEP [16].
• Human ENPEP thus provides an additional marker for the long arm of chromosome 4 that should facilitate studies of this genomic region [16].
• Using a radiation hybrid panel, the gene order around ENPEP was determined to be centromere-D4S1236-(570 kb)-ENPEP-(210 kb)-D4S262-(270 kb)-D4S953-(270 kb)-D4S474-(570 kb)-IF [16].
• Aminopeptidase A (glutamyl aminopeptidase; EC 3.4.11.7) has been cloned from porcine brain and kidney cortex cDNA libraries and the complete primary sequence of the enzyme deduced [17].
• Finally, APA cDNA-transfected APA-overexpressing TCS cells significantly reduced the Ang II-induced cell invasion ability as compared with parental or control vector-transfected TCS cells, although there was no significant difference in cellular proliferation among them [18].

Anatomical context of ENPEP

• The APA was strongly immunolocalized in pericytes [19].
• Enzymatic assays on human RCC cell lines indicated a 100% concordance between APA activity and gp160 expression [2].
• The gp160 cDNA possesses 78% homology to the murine BP-1/6C3 antigen, a B-lymphocyte differentiation protein that exhibits aminopeptidase A (APA; EC 3.4.11.7) activity [2].
• Immunohistochemical staining in high-grade CIN and SCC tissues showed that APA was strongly expressed at the edge of lesions adjacent to cervical stromal cells [18].
• Furthermore, APA expression and enzymatic activity were enhanced by addition of the conditioned medium (CM) from fibroblast culture, but not by heat-treated CM [18].

Associations of ENPEP with chemical compounds

• These data indicate that the gp160 human kidney/RCC glycoprotein is human APA [2].
• HIgher concentrations (1-10 microM) of aldosterone (ALD) stimulated APA activity to a lesser extent (x 1.25) [20].
• APA activity was calcium-dependent and was inhibited by amastatin [20].
• Treatment of HGECs by dexamethasone (DEX) increased ecto-APA activity in a dose- and time-dependent manner [20].
• These results suggested the importance of tumor-stromal interaction for the regulation of APA expression in the microenvironment of cervical carcinoma and the potential role for this peptidase in regulating tumor invasion through inactivation of Ang II activity [18].

Physical interactions of ENPEP

• In cells expressing recombinant human immunodeficiency virus (HIV) envelope glycoprotein, gp160 bound transiently to calreticulin with a peak at 10 min after its synthesis [21].
• Here we show that CD4 binding to gp120 induces the formation and/or exposure of the gp41 HR1 coiled coil in a process that does not involve gp120 shedding and that depends on the proteolytic maturation of the gp160 envelope glycoprotein precursor [22].
• The gp120 and gp160 specifically recognize the C-terminal heparin-binding domain of Fn (Fn-CTHBD) with a calculated KD of 2.8 x 10(-7) M for gp160 [23].
• There was, however, a temporal association between CD4 down-modulation and the accumulation of intracellular HIV-1 gp 160/120; in addition, intracellular CD4-gp 160 complexes were identifiable in OM-10.1 cell lysates at time points following TNF-alpha induction after surface CD4 was no longer detectable [24].
• These results provide supporting evidence that envelope-specific, complement-activating antibodies induced by infection or gp160 immunization can target HIV-1 immune complexes to CR1 [25].

Regulatory relationships of ENPEP

• This gp160 treatment adversely affects the functional capabilities of T cells: pre-treatment of CD4+ T cells with gp160 for 4 h at 37 degrees C inhibited anti-CD3-induced interleukin-2 secretion [26].
• The gp160-induced AP-1 complex is dependent upon protein tyrosine phosphorylation and is protein synthesis-independent [26].
• Pre-incubation of CD4+ T lymphocytes in the presence of anti-CD4 mAb or gp160 inhibits the activation of JNK in response to phorbol 12-myristate 13-acetate and ionomycin [27].
• When ICAM-1 was coexpressed with gp160, syncytium formation between the transfected kidney cells and uninfected CD$+ T cells was markedly enhanced [28].
• In this study, we observed that HIV gp160 could induce significant TGF-beta secretion and TGF-beta mRNA expression in PBMC from HIV-seronegative healthy donors [29].

Other interactions of ENPEP

• In this system, angiotensin II is converted to angiotensin III (Ang III) by glutamyl aminopeptidase (GluAP) and Ang III is further metabolised to angiotensin IV by alanyl aminopeptidase or arginine-aminopeptidase [30].
• Using genomic DNA encoding for human EAP as a probe, we identified the ENPEP gene location on human chromosome 4q25 by polymerase chain reaction analysis of a human/rodent somatic cell hybrid mapping panel and by fluorescence in situ hybridization [16].
• Actinomycin D and cycloheximide prevented and RU 38486, a glucocorticoid receptor antagonist, suppressed the DEX-induced increase in APA activity [20].
• Regulation of aminopeptidase A expression in cervical carcinoma: role of tumor-stromal interaction and vascular endothelial growth factor [18].
• METHODS: Immunohistochemical analysis using anti-P-LAP and anti-APA antibodies was performed on ultrathin frozen sections of fixed human placental villi [31].

Analytical, diagnostic and therapeutic context of ENPEP

• Molecular cloning of the human kidney differentiation antigen gp160: human aminopeptidase A [2].
• Fluorescence-activated cell sorting analysis demonstrated that cell surface APA expression was extremely low in three human SCC cell lines, SiHa, TCS and CaSki, under basal conditions [18].
• However, both contact and noncontact cocultures with human cervical fibroblasts resulted in the induction of APA expression in these SCC cells [18].
• Maximal increase of APA activity (x 2) occurred after treatment with 0.5 microM DEX for 5 days [20].
• Microsomal PAP was separated from aminopeptidase A (AAP) by affinity chromatography [32].

References