The only endogenous protein inhibitor known for metallocarboxypeptidases (MCPs) is latexin, a 25-kDa protein discovered in the rat brain. Latexin, alias endogenous carboxypeptidase inhibitor, inhibits human CPA4 (hCPA4), whose expression is induced in prostate cancer cells after treatment with histone deacetylase inhibitors. hCPA4 is a member of the A͞B subfamily of MCPs and displays the characteristic ␣͞-hydrolase fold. Human latexin consists of two topologically equivalent subdomains, reminiscent of cystatins, consisting of an ␣-helix enveloped by a curved -sheet. These subdomains are packed against each other through the helices and linked by a connecting segment encompassing a third ␣-helix. The enzyme is bound at the interface of these subdomains. The complex occludes a large contact surface but makes rather few contacts, despite a nanomolar inhibition constant. This low specificity explains the flexibility of latexin in inhibiting all vertebrate A͞B MCPs tested, even across species barriers. In contrast, modeling studies reveal why the N͞E subfamily of MCPs and invertebrate A͞B MCPs are not inhibited. Major differences in the loop segments shaping the border of the funnel-like access to the protease active site impede complex formation with latexin. Several sequences ascribable to diverse tissues and organs have been identified in vertebrate genomes as being highly similar to latexin. They are proposed to constitute the latexin family of potential inhibitors. Because they are ubiquitous, latexins could represent for vertebrate A͞B MCPs the counterparts of tissue inhibitors of metalloproteases for matrix metalloproteinases.metallocarboxypeptidase ͉ metalloprotease ͉ x-ray crystal structure
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