ORIGINAL RESEARCH ARTICLE published: 17 December 2013 doi: 10.3389/fgene.2013.00293 A tale of two drug targets: the evolutionary history of BACE1 and BACE2 Christopher Southan 1 and John M. Hancock 2* 1 IUPHAR Database and Guide to Pharmacology Web Portal Group, University/BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK 2 Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK Edited by: The beta amyloid (APP) cleaving enzyme (BACE1) has been a drug target for Alzheimer’s Christian M. Zmasek, Washington Disease (AD) since 1999 with lead inhibitors now entering clinical trials. In 2011, the University, USA paralog, BACE2, became a new target for type II diabetes (T2DM) having been identified Reviewed by: as a TMEM27 secretase regulating pancreatic β cell function. However, the normal Victor P.Andreev, University of Miami, USA roles of both enzymes are unclear. This study outlines their evolutionary history and Dapeng Wang, Beijing Institute of new opportunities for functional genomics. We identified 30 homologs (UrBACEs) in Genomics, China basal phyla including Placozoans, Cnidarians, Choanoflagellates, Porifera, Echinoderms, *Correspondence: Annelids, Mollusks and Ascidians (but not Ecdysozoans). UrBACEs are predominantly John M. Hancock, Department of single copy, show 35–45% protein sequence identity with mammalian BACE1, are ∼100 Physiology, Development and Neuroscience, University of residues longer than cathepsin paralogs with an aspartyl protease domain flanked by Cambridge, Downing Street, a signal peptide and a C-terminal transmembrane domain. While multiple paralogs in Cambridge CB2 3EG, UK Trichoplax and Monosiga pre-date the nervous system, duplication of the UrBACE in fish e-mail:
[email protected] gave rise to BACE1 and BACE2 in the vertebrate lineage.