Journal
CHEMISTRY & BIOLOGY
Volume 21, Issue 1, Pages 146-155Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2013.11.008
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Funding
- Deutsche Forschungsgemeinschaft [SPP1152 (Ke 452/11-5)]
- Unicat Center of Excellence at TU Berlin
- Helmholtz Zentrum Berlin fur Materialien und Energie
- Freie Universitat Berlin
- Humboldt-Universitet zu Berlin
- Max-Del-bruck Centrum
- Leibniz-Institut fur Molekulare Pharmakologie
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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 alpha-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 alpha-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.
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