Disease relevance of Enpep

• Hypertension and angiotensin II hypersensitivity in aminopeptidase A-deficient mice [1].
• Efficacy was tested in a melanoma cancer tumor model by treating tumor induced by B16-F0/neu tumor cells in mice with myoblasts secreting angiostatin from either the standard or enhanced APA microcapsules [2].
• A nephritogenic rat monoclonal antibody to mouse aminopeptidase A. Induction of massive albuminuria after a single intravenous injection [3].
• In autoimmune prostatitis (EAP) of the day-3 thymectomized (d3tx) mice, male Tregs suppressed EAP 3 times better than Tregs from female mice or male mice without prostates [4].
• The binding of antibodies to podocytic antigens such as the Heymann antigen or aminopeptidase A may lead to the induction of a membranous glomerulonephritis in several species [5].

Psychiatry related information on Enpep

• Lack of angiotensin II conversion to angiotensin III increases water but not alcohol consumption in aminopeptidase A-deficient mice [6].

High impact information on Enpep

• We previously reported that in the murine brain, aminopeptidase A (APA) is involved in the conversion of angiotensin II (AngII) to AngIII and that AngIII is one of the main effector peptides of the brain RAS in the control of vasopressin release [7].
• A single dose of systemic RB150 (15 mg/kg, i.v.) in conscious DOCA-salt rats inhibited brain APA activity and markedly reduced blood pressure for up to 24 h [7].
• Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: a potential treatment of salt-dependent hypertension [7].
• RB150 given i.v. is able to cross the blood-brain barrier, to inhibit brain APA, and to block the formation of central AngIII [7].
• These results demonstrate for the first time that (i) APA and APN are involved in vivo in the metabolism of brain Ang II and Ang III, respectively, and that (ii) the action of Ang II on vasopressin release depends upon the prior conversion of Ang II to Ang III [8].

Chemical compound and disease context of Enpep

• There was no clear relation between the inhibition of glomerular APA activity and albuminuria, yet it was evident that intrarenal Ang II levels were significantly increased in albuminuric mice and not in nonalbuminuric mice [9].
• We have investigated the effects of glucose concentration on the bioenergetic status and on the metabolic and secretory functions exhibited by mouse insulinoma betaTC3 cells entrapped in calcium alginate/poly-L-lysine/alginate (APA) beads [10].
• Both enalapril and losartan treatment reduced the acute albuminuria, measured 1 day after injection of a monoclonal antibody against aminopeptidase A, by 91% and 83%, respectively [11].
• The effects of alginate composition on cell growth as well as the metabolic and secretory profile of transformed beta-cells entrapped in alginate/poly-L-lysine/alginate (APA) solid beads were investigated following entrapment of beta TC3 mouse insulinoma cells in alginate composed of either high mannuronic acid or high guluronic acid residues [12].
• Amastatin, an inhibitor of aminopeptidase A, produced by actinomycetes [13].

Biological context of Enpep

• Aminopeptidase A, which generates one of the main effector peptides of the brain renin-angiotensin system, angiotensin III, has a key role in central control of arterial blood pressure [14].
• In the absence of such compounds for APA, we first explored the organization of the APA active site by site-directed mutagenesis [14].
• Aminopeptidase A (EC 3.4.11.7; APA) is a 130 kDa membrane-bound zinc enzyme that contains the consensus sequence HEXXH (residues 385-389) conserved among the zinc metalloprotease family [15].
• To evaluate the physiological role of APA, we examined BP homeostasis in APA-deficient mice [1].
• The full-length cDNA encoding aminopeptidase A (APAL) was cloned from a rat hippocampus cDNA library [16].

Anatomical context of Enpep

• Aminopeptidase A activity of the murine B-lymphocyte differentiation antigen BP-1/6C3 [17].
• From brush border preparations of the small intestine, a rich source of many endopeptidases and exopeptidases, the BP-1 antibody selectively removed aminopeptidase A [APA; L-alpha-aspartyl(L-alpha-glutamyl)-peptide hydrolase, EC 3.4.11.7] activity [17].
• The APA activity of a panel of cell lines correlated in linear fashion with cell-surface levels of the BP-1/6C3 antigen [17].
• Thus APA, the enzyme responsible for the formation of brain AngIII, represents a potential central therapeutic target that justifies the development of APA inhibitors, crossing the blood-brain barrier, as central anti-hypertensive agents [14].
• Activity of APM and APA was found mostly in the fibrocytes which adhered to the basal membrane of the epithelium and glands [18].

Associations of Enpep with chemical compounds

• This activity was enhanced by alkaline earth metals such as Ca2+ and was abrogated by amastatin and angiotensin, which are known competitive inhibitors of APA [17].
• The data indicate that the murine BP-1/6C3 antigen is active APA, an enzyme that catalyzes specifically the removal of unsubstituted, N-terminal glutamic acid and aspartic acid residues from peptides [17].
• Contribution of molecular modeling and site-directed mutagenesis to the identification of a new residue, glutamate 215, involved in the exopeptidase specificity of aminopeptidase A [19].
• In female mice, cholesterol-enriched diet produced a significant increase in soluble aspartyl- and membrane-bound aspartyl- and glutamyl-aminopeptidase activities, and a significant decrease in membrane-bound alanyl-, arginyl- and cystinyl-aminopeptidase activities [20].
• BP-1/6C3/APA expression by early B lineage cells is up-regulated by IL-7, an important growth factor for pre-B cells and T cells [21].

Other interactions of Enpep

• Secondly, we developed a specific and selective APA inhibitor, compound EC33 [(S)-3-amino-4-mercaptobutylsulphonic acid], as well as a potent and selective APN inhibitor, PC18 (2-amino-4-methylsulphonylbutane thiol) [14].
• These properties distinguish the brain acidic aminopeptidase from aminopeptidase A isolated from human serum or pig kidney and the aspartyl aminopeptidase of dog kidney [22].
• The thymic cortical reticular cells showed increased aminopeptidase A activity accompanied by a generalized aminopeptidase M and alkaline phosphatase reaction [23].
• In contrast, most of the APP, alkaline phosphodiesterase I, aminopeptidase A and clathrin was effectively solubilized at all of the protein/detergent ratios examined [24].
• Organ distribution of aminopeptidase A and dipeptidyl peptidase IV in normal mice [25].

Analytical, diagnostic and therapeutic context of Enpep

• Previous site-directed mutagenesis studies and the recent molecular modeling of the APA zinc metallopeptidase domain have shown that all the amino acids involved in catalysis are located between residues 200 and 500 [26].
• A tyrosine residue was previously proposed to be involved in the enzymic activity of aminopeptidase N. Furthermore sequence alignment of mouse APA with other monozinc aminopeptidases indicates the presence of a conserved tyrosine (Tyr-471 in APA) [15].
• Rat aminopeptidase A mRNAs were detected in the kidney, liver, heart and brain by Northern blot analysis [16].
• Molecular cloning and expression of aminopeptidase A isoforms from rat hippocampus [16].
• In conclusion, this study shows that mouse pancreatic islets survive and remain functionally competent for at least 2 weeks in vitro after microencapsulation in APA capsules generated in an electrostatic field [27].

References