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J. Biol. Chem., Vol. 277, Issue 17, 14954-14964, April 26, 2002
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From the Amino acid homology
searches of the human genome revealed three members of the
metallocarboxypeptidase (metallo-CP) family that had not been
described in the literature in addition to the 14 known genes. One of
these three, named CPA5, is present in a gene
cluster with CPA1, CPA2, and CPA4
on chromosome 7. The cDNA encoding a mouse homolog of human
CPA5 was isolated from a testis library and sequenced. The
deduced amino acid sequence of human CPA5 has highest amino acid
sequence identity (60%) to CPA1. Modeling analysis shows the overall
structure to be very similar to that of other members of the A/B
subfamily of metallocarboxypeptidases. The active site of CPA5 is
predicted to cleave substrates with C-terminal hydrophobic residues, as
do CPA1, -2, and -3. Using Northern blot analysis, CPA5 mRNA is
detected in testis but not in kidney, liver, brain, or lung. In
situ hybridization analysis shows that CPA5 is localized to
testis germ cells. Mouse pro-CPA5 protein expressed in Sf9 cells
using the baculovirus system was retained in the particulate fraction
of the cells and was not secreted into the media. Pro-CPA5 was not
enzymatically active toward standard CPA substrates, but after
incubation with prohormone convertase 4 the resulting protein was able
to cleave furylacryloyl-Gly-Leu, with 3-4-fold greater activity at pH
7.4 than at 5.6. Two additional members of the human CP gene
family were also studied. Modeling analysis indicates that both contain
the necessary amino acids required for enzymatic activity. The CP on
chromosome 8 is predicted to have a CPA-like specificity for C-terminal
hydrophobic residues and was named CPA6. The CP on
chromosome 2 is predicted to cleave substrates with C-terminal acidic
residues and was named CPO.
Identification and Characterization of Three Members of the Human
Metallocarboxypeptidase Gene Family*
,, and
Department of Molecular Pharmacology, Albert
Einstein College of Medicine, Bronx, New York 10461, § Institut de Biotecnologia i Biomedicina and Departament de
Bioquímica i Biologia Molecular, Universitat Autònoma
de Barcelona, 08193 Bellaterra, Barcelona, Spain, and
¶ Departement de Pharmacologie, Institut de Pharmacologie et
Faculté de Médecine, Université de Sherbrooke,
Sherbrooke, Québec J1H 5N4, Canada
*
This work was primarily supported by National
Institutes of Health Grant R01 DK51271, and also by Grants R01 DA04494
and K02 DA00194 (to L. D. F.), by Ministerio de Ciencia y
Tecnología, Spain Grants BIO98-0362 and 2FD97-0872, the Center
de Referència en Biotecnologia of the Generalitat de Catalunya,
Spain, (to F. X. A.), and grants from the Canadian Institutes of
Health Research and a fellowship from the Fonds de la Recherche en
Santé du Québec (to R. D.). The DNA sequencing facility of
the Albert Einstein College of Medicine is supported in part by Cancer
Center Grant CA13330.The costs of publication of this
article were defrayed in part by the
payment of page charges. The 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: Dept. of Molecular
Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park
Ave., Bronx, NY 10461. Tel.: 718-430-4225; Fax: 718-430-8954; E-mail:
fricker@aecom.yu.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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