Dipeptidyl aminopeptidases (DPPs: EC 3.4.14) are a group of enzymes that cleave dipeptides from the N-terminal ends of peptides. In the nervous system, DPPs regulate the biological activities of various peptides that function as neurotransmitters, neuromodulators, or hormones (McDonald and Barret 1986;McKelvy and Blumberg 1986). Previous biochemical studies found at least five different enzyme proteins (DPPI through DPPV)that account for DPP activity in mammalian tissues on the basis of substrate specificity (McDonald and Barret 1986;Hui 1988). However, in spite of extensive biochemical characterization, little is known about DPPs at the molecular biological level. Only cDNAs for DPPIV have been characterized thus far (Ogata et al. 1989;Darmoul et al. 1990; Marguet et al. 1992). Recently we isolated and characterized two distinct cDNAs encoding new dipeptidyl aminopeptidase-like proteins (designated DPPXs) in rat and bovine brain by molecular cloning (Wada et al. 1992). The two DPPXs, which share an identical transmembrane domain and a long C-terminal extracellular domain but have different C-terminal cytoplasmic domains, show substantial sequence similarity to DPPIV (Ogata et al. 1989;Darmoul et al. 1990Darmoul et al. , 1992;;Marguet et al. 1992). However, DPPX appears to be functionally distinct from the classical DPPI-DPPIV, since cells transfected with expressible DPPX cDNAs do not show enzyme activity with the artificial substrates used to differentiate DPPI-DPPIV (N. Yokotani and K. Wada, unpublished observation). Both DPPX