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J. Biol. Chem., Vol. 280, Issue 14, 14310-14317, April 8, 2005

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

Araceli Díaz-Perales, Víctor Quesada, Luis M. Sánchez, Alejandro P. Ugalde, María F. Suárez, Antonio Fueyo, and Carlos López-Otín¶

From the Departamento de Bioquímica y Biología Molecular and Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain

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 (HEXXHX₁₈E) 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 A₄ 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.

Received for publication, November 23, 2004 , and in revised form, January 27, 2005.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AJ560639, AJ810420, and AJ810421.

^* This work was supported by grants from Comisión Interministerial de Ciencia y Tecnología-Spain, Gobierno del Principado de Asturias, Fundación La Caixa, European Union (FP5 and FP6), and Daiichi Fine Chemical Co, Ltd (Toyama, Japan). The Instituto Universitario de Oncología is supported by Obra Social Cajastur-Asturias and Red de Centros de Cáncer-Instituto Carlos III, Spain. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 34-985-104201; Fax: 34-985-103564; E-mail: clo{at}uniovi.es.

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