Chapter 6 Arginyl Aminopeptidase

Aminopeptidase B (Ap-B; EC.3.4.11.6) was originally defined as an exopeptidase able to trim out basic amino acid residues from the Nt2-terminus of peptides. Purification of Ap-B from rat testes showed that this enzyme is a monomeric 72 kDa Zn2+-dependent exopeptidase, which selectively removes Arg and/or Lys residues from the NH2-terminus of various peptides. In vitro, Ap-B exhibits a weak ability to hydrolyze leukotriene A4 into leukotriene B4, a lipid mediator of inflammation. The in vivo bi-functionality of Ap-B remains to be demonstrated. Elucidation of the rat, human and mouse Ap-B primary structures allows its classification in the Ml family of Zn2+-aminopeptidases and reveals a structural relationship with leukotriene A4 hydrolase, an important enzyme of the arachidonic pathway. The human Ap-B gene (rnpep) is localized on chromosome 1 band q32 in a high transcript density chromosomal region. The gene is bracketed by tim17a and elf3, which encode a pre-protein translocase of the inner mitochondrial membrane and an ETS family transcription factor, respectively. The recent description of the mouse genome allows to localize the mouse Ap-B encoding gene on chromosome 1, in a putative inversed synthenic region. Ap-B is widely distributed in a number of rat and human tissues. Ap-B expression level varies depending on the cells or tissues considered and likely in a species-dependent manner. Both the constitutive and the regulated pathways secrete the enzyme. Moreover, in PC12 cells, the protein is associated, as an active form, to the external face of the plasma membrane. Although the physiological function of Ap-B remains an open question, several data strongly support the hypothesis that Ap-B could participate in the final stages of precursor processing mechanisms and thereby in some inflammatory processes and tumour developments.