1. Cyclolization of D-lysergic acid alkaloid peptides.
- Author
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Havemann J, Vogel D, Loll B, and Keller U
- Subjects
- Biocatalysis, Claviceps enzymology, Cyclization, Dihydroergotamine chemistry, Dihydroergotamine metabolism, Dioxygenases chemistry, Ergolines chemistry, Ergolines metabolism, Humans, Hydroxylation, Mixed Function Oxygenases chemistry, Mixed Function Oxygenases metabolism, Models, Molecular, Peptide Synthases metabolism, Protein Conformation, Dioxygenases metabolism, Ergotamine biosynthesis, Ergotamine chemistry, Lysergic Acid chemistry, Lysergic Acid metabolism, Peptides chemistry, Peptides metabolism
- 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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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