title: Cathepsin L and Arg/Lys aminopeptidase: a distinct prohormone processing pathway for the biosynthesis of peptide neurotransmitters and hormones.
abstract: Peptide neurotransmitters and hormones are synthesized as protein precursors that require proteolytic processing to generate smaller, biologically active peptides that are secreted to mediate neurotransmission and hormone actions. Neuropeptides within their precursors are typically flanked by pairs of basic residues, as well as by monobasic residues. In this review, evidence for secretory vesicle cathepsin L and Arg/Lys aminopeptidase as a distinct proteolytic pathway for processing the prohormone proenkephalin is presented. Cleavage of prohormone processing sites by secretory vesicle cathepsin L occurs at the NH2-terminal side of dibasic residues, as well as between the dibasic residues, resulting in peptide intermediates with Arg or Lys extensions at their NH2-termini. A subsequent Arg/Lys aminopeptidase step is then required to remove NH2-terminal basic residues to generate the final enkephalin neuropeptide. The cathepsin L and Arg/Lys aminopeptidase prohormone processing pathway is distinct from the proteolytic pathway mediated by the subtilisin-like prohormone convertases 1/3 and 2 (PC1/3 and PC2) with carboxypeptidase E/H. Differences in specific cleavage sites at paired basic residue sites distinguish these two pathways. These two proteolytic pathways demonstrate the increasing complexity of regulatory mechanisms for the production of peptide neurotransmitters and hormones.
authors.affiliation: Buck Institute for Age Research, Novato, CA 94945, USA. vhook@ucsd.edu
authors.forename: Vivian
authors.initials: V
authors.lastname: Hook
authors.forename: Sukkid
authors.initials: S
authors.lastname: Yasothornsrikul
authors.forename: Doron
authors.initials: D
authors.lastname: Greenbaum
authors.forename: Katalin F
authors.initials: KF
authors.lastname: Medzihradszky
authors.forename: Katie
authors.initials: K
authors.lastname: Troutner
authors.forename: Thomas
authors.initials: T
authors.lastname: Toneff
authors.forename: Richard
authors.initials: R
authors.lastname: Bundey
authors.forename: Anna
authors.initials: A
authors.lastname: Logrinova
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinheckel
authors.forename: Christoph
authors.initials: C
authors.lastname: Peters
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
mesh_terms: D000626:Aminopeptidases / Q000378:metabolism*; D000818:Animals; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism*; D003546:Cysteine Endopeptidases; D006728:Hormones / Q000096:biosynthesis*; D018377:Neurotransmitter Agents / Q000096:biosynthesis*; D011498:Protein Precursors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
chemical_list: D006728:Hormones; D018377:Neurotransmitter Agents; D011498:Protein Precursors; D002403:Cathepsins; D000626:Aminopeptidases; D003546:Cysteine Endopeptidases; D056668:Cathepsin L