title: Cyclolization of D-lysergic acid alkaloid peptides.
abstract: The tripeptide chains of the ergopeptines, a class of pharmacologically important D-lysergic acid alkaloid peptides, are arranged in a unique bicyclic cyclol based on an amino-terminal α-hydroxyamino acid and a terminal orthostructure. D-lysergyl-tripeptides are assembled by the nonribosomal peptide synthetases LPS1 and LPS2 of the ergot fungus Claviceps purpurea and released as N-(D-lysergyl-aminoacyl)-lactams. We show total enzymatic synthesis of ergopeptines catalyzed by a Fe²⁺/2-ketoglutarate-dependent dioxygenase (EasH) in conjunction with LPS1/LPS2. Analysis of the reaction indicated that EasH introduces a hydroxyl group into N-(D-lysergyl-aminoacyl)-lactam at α-C of the aminoacyl residue followed by spontaneous condensation with the terminal lactam carbonyl group. Sequence analysis revealed that EasH belongs to the wide and diverse family of the phytanoyl coenzyme A hydroxylases. We provide a high-resolution crystal structure of EasH that is most similar to that of phytanoyl coenzyme A hydroxylase, PhyH, from human.
authors.affiliation: Institut für Chemie, Arbeitsgruppe Biochemie und Molekulare Biologie, Technische Universität Berlin, Müller-Breslau-Strasse 10, Berlin-Charlottenburg 10623, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Havemann
authors.affiliation: Institut für Chemie, Arbeitsgruppe Biochemie und Molekulare Biologie, Technische Universität Berlin, Müller-Breslau-Strasse 10, Berlin-Charlottenburg 10623, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Vogel
authors.affiliation: Institut für Chemie und Biochemie, Abteilung Strukturbiochemie, Freie Universität Berlin, Takusstrasse 6, Berlin 14195, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Loll
authors.affiliation: Institut für Chemie, Arbeitsgruppe Biochemie und Molekulare Biologie, Technische Universität Berlin, Müller-Breslau-Strasse 10, Berlin-Charlottenburg 10623, Germany. Electronic address: ullrich.keller@tu-berlin.de.
authors.forename: Ullrich
authors.initials: U
authors.lastname: Keller
mesh_terms: D055162:Biocatalysis; D002967:Claviceps / Q000201:enzymology; D003500:Cyclization; D004087:Dihydroergotamine / Q000737:chemistry / Q000378:metabolism; D049308:Dioxygenases / Q000737:chemistry / Q000378:metabolism*; D004873:Ergolines / Q000737:chemistry / Q000378:metabolism; D004878:Ergotamine / Q000096:biosynthesis* / Q000737:chemistry*; D006801:Humans; D006900:Hydroxylation; D008237:Lysergic Acid / Q000737:chemistry* / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D010453:Peptide Synthases / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation
chemical_list: D004873:Ergolines; D010455:Peptides; C100272:ergotoxine; D004087:Dihydroergotamine; D006899:Mixed Function Oxygenases; D049308:Dioxygenases; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase; D008237:Lysergic Acid; D004878:Ergotamine