Role of Aminopeptidases in the Blood Pressure Regulation

Mitsui, Takashi; Nomura, Seiji; Itakura, Atsuo; Mizutani, Shigehiko

doi:10.1248/bpb.27.768

Cited by 25 publications

(23 citation statements)

References 38 publications

(35 reference statements)

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“…This result would support the possibility that the cleavage of N-terminal Arg residues catalyzed by AP-O could also be of in vivo relevance. This possibility, together with the expression of the AP-O gene in the heart and testis, tissues in which the renin-angiotensin system plays important roles (5,69), prompted us to investigate the putative involvement of AP-O in the processing of peptides of this system. The renin-angiotensin system regulates the homeostasis, blood pressure, endocrine processes, and behavior at the systemic level as well as at the local tissue level (5,69).…”

Section: Discussionmentioning

confidence: 99%

“…These enzymes are widely distributed in multiple organisms from bacteria to human and play essential roles in protein maturation and regulation of the metabolism of bioactive peptides (1,2). Furthermore, alterations in the function and regulation of aminopeptidases underlie several human diseases, including cancer and cardiovascular disorders (3)(4)(5). Among the different families of human aminopeptidases, there has been a growing interest in the analysis of the biological and pathological relevance of members of the M1 family of zinc metallopeptidases or gluzincins (6,7).…”

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confidence: 99%

“…The expression of the AP-O gene in heart and testis prompted us to evaluate the possibility that this aminopeptidase could participate in the proteolytic processing of peptides involved in the regulation of cardiac and male reproductive physiology (5,69). To this purpose, we incubated angiotensins I, II, and III with 2.5 nM recombinant AP-O or the commercially available aminopeptidases APN and PAP (2.5 pM), and the resulting fragments were analyzed by mass spectrometry.…”

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confidence: 99%

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Identification of Human Aminopeptidase O, a Novel Metalloprotease with Structural Similarity to Aminopeptidase B and Leukotriene A4 Hydrolase

Díaz‐Perales

Quesada

Sánchez

et al. 2005

Journal of Biological Chemistry

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We have cloned and characterized a human brain cDNA encoding a new metalloprotease that has been called aminopeptidase O (AP-O). AP-O exhibits a series of structural features characteristic of aminopeptidases, including a conserved catalytic domain with a zinc-binding site (HEXXHX 18 E) that allows its classification in the M1 family of metallopeptidases or gluzincins. The structural complexity of AP-O is further increased by the presence of an additional C-terminal domain 170 residues long, which is predicted to have an ARM repeat fold originally identified in the Drosophila segment polarity gene product Armadillo. This ARM repeat domain is also present in aminopeptidase B, aminopeptidase B-like, and leukotriene A 4 hydrolase and defines a novel subfamily of aminopeptidases that we have called ARM aminopeptidases. Northern blot analysis revealed that AP-O is mainly expressed in the pancreas, placenta, liver, testis, and heart. Human AP-O was produced in Escherichia coli, and the purified recombinant protein hydrolyzed synthetic substrates used for assaying aminopeptidase activity. This activity was abolished by general inhibitors of metalloproteases and specific inhibitors of aminopeptidases. Recombinant AP-O also cleaved angiotensin III to generate angiotensin IV, a bioactive peptide of the renin-angiotensin pathway with multiple actions on diverse tissues, including brain, testis, and heart. On the basis of these results we suggest that AP-O could play a role in the proteolytic processing of bioactive peptides in those tissues where it is expressed.Aminopeptidases are exopeptidases that have the ability to catalyze the hydrolysis of amino acid residues from the N terminus of peptide or protein substrates. These enzymes are widely distributed in multiple organisms from bacteria to human and play essential roles in protein maturation and regulation of the metabolism of bioactive peptides (1, 2). Furthermore, alterations in the function and regulation of aminopeptidases underlie several human diseases, including cancer and cardiovascular disorders (3-5). Among the different families of human aminopeptidases, there has been a growing interest in the analysis of the biological and pathological relevance of members of the M1 family of zinc metallopeptidases or gluzincins (6, 7). To date, 12 members of this family have been identified in human tissues (www.uniovi.es/degradome) (8). Aminopeptidase A (APA or ENPEP) is a type II membranebound protease that cleaves N-terminal amino acid residues from peptides such as cholecystokinin-8 and angiotensin II (9, 10) and contributes to the control of blood pressure and angiogenesis (11-13). Aminopeptidase N (APN, 1 ANPEP, or CD13) is also a membrane-bound exopeptidase associated with angiogenesis regulation (14 -16) that acts as a receptor for the coronavirus and tumor-homing peptides (17, 18). Aminopeptidase Q (APQ or laeverin) is structurally related to APN and participates in regulation of the extravillous trophoblast invasion of maternal decidual tissues (8, 19). The thyr...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Identification of Human Aminopeptidase O, a Novel Metalloprotease with Structural Similarity to Aminopeptidase B and Leukotriene A4 Hydrolase

Díaz‐Perales

Quesada

Sánchez

et al. 2005

Journal of Biological Chemistry

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“…Ang II is a cytokine that participates in renal damage and has vasoactive and profibrotic properties and contributes to kidney injury by causing hypertension and glomerulosclerosis. Impairment of Ang II degradation may influence Ang II action and, indeed, animal studies have suggested a role for APA in blood pressure regulation (Mitsui et al 2003(Mitsui et al ,2004. All components of the RAS are highly expressed in the developing kidney.…”

Section: Discussionmentioning

confidence: 99%

Expression and Effect of Inhibition of Aminopeptidase-A during Nephrogenesis

Dijkman

Assmann

Steenbergen

et al. 2006

J Histochem Cytochem.

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Aminopeptidase-A (APA) is a metalloprotease that cleaves N-terminal aspartyl and glutamyl residues from peptides. Its best-known substrate is angiotensin II (Ang II), the most active compound of the renin-angiotensin system (RAS). The RAS is involved in renal development. Most components of the RAS system are expressed in the developing kidney. Thus far, APA has not been studied in detail. In the present study we have evaluated the expression of APA at the protein, mRNA, and enzyme activity (EA) level in the kidney during nephrogenesis. Furthermore, we have studied the effect of inhibiting APA EA by injection of anti-APA antibodies into 1-day-old mice. APA expression was observed from the comma stage onwards, predominantly in the developing podocytes and brush borders of proximal tubular cells. Notably, APA was absent in the medulla or the renal arterioles. Inhibition of APA EA caused temporary podocyte foot-process effacement, suggesting a minimum role for APA during nephrogenesis.

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“…It is well known that the M1 aminopeptidases play important roles in the metabolism of vasoactive peptide hormones, such as angiotensins and kallidin in the placenta (39). In brief, APA degrades angiotensin II to angiotensin III, and then APN, P-LAP, and LVRN/APQ can generate angiotensin IV from angiotensin III and bradykinin from kallidin.…”

Section: Discussionmentioning

confidence: 99%

Histidine 379 of Human Laeverin/Aminopeptidase Q, a Nonconserved Residue within the Exopeptidase Motif, Defines Its Distinctive Enzymatic Properties

Maruyama

Arisaka

Goto

et al. 2009

Journal of Biological Chemistry

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Human laeverin/aminopeptidase Q (LVRN/APQ) is a novel member of the M1 family of zinc aminopeptidases and is specifically expressed on the cell surface of human extravillous trophoblasts. Multiple sequence alignment of human M1 aminopeptidase revealed that the first Gly residue within the conserved exopeptidase motif of the M1 family, GXMEN motif, is uniquely substituted for His in human LVRN/APQ. In this study, we evaluated the roles of nonconserved His 379 , comprising the exopeptidase motif in the enzymatic properties of human LVRN/APQ. We revealed that the substitution of His 379 with Gly caused significant changes in substrate specificity both toward fluorogenic substrates and natural peptide hormones. In addition, the susceptibilities of bestatin, a sensitive inhibitor for human LVRN/ APQ, and natural inhibitory peptides were decreased in the H379G mutant. A molecular model suggested a conformational difference between wild-type and H379G human LVRN/APQs. These results indicate that His 379 of the enzyme plays essential roles in its distinctive enzymatic properties and contributes to maintaining the appropriate structure of the catalytic cavity of the enzyme. Our data may bring new insight into the biological significance of the unique exopeptidase motif of LVRN/APQ obtained during the evolution of primates.The M1 family of mono-zinc aminopeptidases is widely distributed in bacteria, fungi, plants, and animals (1, 2). They hydrolyze peptide bonds linking to the N-terminal amino acids of peptide or protein substrates. The human M1 family consists of 11 enzymes that participate in many important physiological events, such as reproduction (3), angiogenesis (4 -6), antigen presentation (7-10), blood pressure control (11-13), and memory retention (14), and thus play essential roles in the maintenance of homeostasis.M1 aminopeptidases share two conserved domains: HEXXH(X) 18 E gluzincin motif and the exopeptidase motif, which is conserved as a GAMEN sequence in most members. The function of each conserved residue within these motifs has been elucidated using site-directed mutagenesis. For instance, two His residues and the second Glu within the HEXXH(X) 18 E motif coordinate the zinc atom essential for catalytic activity. The first Glu in the motif polarizes to the water molecule that coordinates the zinc atom and promotes nucleophilic attack of the carbonyl carbon of the peptide bond forming a tetrahedral intermediate in water (15). The conserved Glu within the exopeptidase motif, the GAMEN sequence, was shown to be involved in recognition of the ␣-amino group of substrates (16,17).Laeverin (LVRN) 4 was originally identified as a cell-surface protein specifically expressed on human extravillous trophoblasts (18). The cDNA cloning of human LVRN revealed that it contains both consensus motifs and is a novel member of the family. Another group predicted the existence of the LVRN gene in the human genome through a genomic search and named it aminopeptidase Q (APQ) (19); however, its exopeptidase motif is uniquely c...

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Role of Aminopeptidases in the Blood Pressure Regulation

Cited by 25 publications

References 38 publications

Identification of Human Aminopeptidase O, a Novel Metalloprotease with Structural Similarity to Aminopeptidase B and Leukotriene A4 Hydrolase

Identification of Human Aminopeptidase O, a Novel Metalloprotease with Structural Similarity to Aminopeptidase B and Leukotriene A4 Hydrolase

Expression and Effect of Inhibition of Aminopeptidase-A during Nephrogenesis

Histidine 379 of Human Laeverin/Aminopeptidase Q, a Nonconserved Residue within the Exopeptidase Motif, Defines Its Distinctive Enzymatic Properties

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