4nao
From Proteopedia
Crystal structure of EasH
Structural highlights
FunctionEASH_CLAP2 Dioxygenase; part of the gene cluster that mediates the biosynthesis of fungal ergot alkaloid (PubMed:14732265, PubMed:14700635, PubMed:15904941, PubMed:17308187, PubMed:17720822). DmaW catalyzes the first step of ergot alkaloid biosynthesis by condensing dimethylallyl diphosphate (DMAP) and tryptophan to form 4-dimethylallyl-L-tryptophan (PubMed:14732265). The second step is catalyzed by the methyltransferase easF that methylates 4-dimethylallyl-L-tryptophan in the presence of S-adenosyl-L-methionine, resulting in the formation of 4-dimethylallyl-L-abrine (By similarity). The catalase easC and the FAD-dependent oxidoreductase easE then transform 4-dimethylallyl-L-abrine to chanoclavine-I which is further oxidized by easD in the presence of NAD(+), resulting in the formation of chanoclavine-I aldehyde (PubMed:20118373, PubMed:21409592). Agroclavine dehydrogenase easG then mediates the conversion of chanoclavine-I aldehyde to agroclavine via a non-enzymatic adduct reaction: the substrate is an iminium intermediate that is formed spontaneously from chanoclavine-I aldehyde in the presence of glutathione (PubMed:20735127, PubMed:21494745). The presence of easA is not required to complete this reaction (PubMed:21494745). Further conversion of agroclavine to paspalic acid is a two-step process involving oxidation of agroclavine to elymoclavine and of elymoclavine to paspalic acid, the second step being performed by the elymoclavine oxidase cloA (PubMed:16538694, PubMed:17720822). Paspalic acid is then further converted to D-lysergic acid (PubMed:15904941). Ergopeptines are assembled from D-lysergic acid and three different amino acids by the D-lysergyl-peptide-synthetases composed each of a monomudular and a trimodular nonribosomal peptide synthetase subunit (PubMed:14700635, PubMed:15904941). LpsB and lpsC encode the monomodular subunits responsible for D-lysergic acid activation and incorporation into the ergopeptine backbone (PubMed:14700635). LpsA1 and A2 subunits encode the trimodular nonribosomal peptide synthetase assembling the tripeptide portion of ergopeptines (PubMed:14700635). LpsA1 is responsible for formation of the major ergopeptine, ergotamine, and lpsA2 for alpha-ergocryptine, the minor ergopeptine of the total alkaloid mixture elaborated by C.purpurea (PubMed:17560817, PubMed:19139103). D-lysergyl-tripeptides are assembled by the nonribosomal peptide synthetases and released as N-(D-lysergyl-aminoacyl)-lactams (PubMed:24361048). Cyclolization of the D-lysergyl-tripeptides is performed by the Fe(2+)/2-ketoglutarate-dependent dioxygenase easH which 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 (PubMed:24361048).[UniProtKB:Q50EL0][1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Publication Abstract from PubMedThe 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. Cyclolization of D-Lysergic Acid Alkaloid Peptides.,Havemann J, Vogel D, Loll B, Keller U Chem Biol. 2013 Dec 18. pii: S1074-5521(13)00417-1. doi:, 10.1016/j.chembiol.2013.11.008. PMID:24361048[14] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||
