7e37 | pdb_00007e37

Crystal structure of deoxypodophyllotoxin synthase from Sinopodophyllum hexandrum in complex with 2-oxoglutarate

spinqualitylabelsall models 7e37, resolution 2.09Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7e37 is a 2 chain structure with sequence from Sinopodophyllum hexandrum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.09Å Ligands: AKG, FE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function 2ODD_SINHE Publication Abstract from PubMed Deoxypodophyllotoxin contains a core of four fused rings (A to D) with three consecutive chiral centers, the last being created by the attachment of a peripheral trimethoxyphenyl ring (E) to ring C. Previous studies have suggested that the iron(II)- and 2-oxoglutarate-dependent (Fe/2OG) oxygenase, deoxypodophyllotoxin synthase (DPS), catalyzes the oxidative coupling of ring B and ring E to form ring C and complete the tetracyclic core. Despite recent efforts to deploy DPS in the preparation of deoxypodophyllotoxin analogs, the mechanism underlying the regio- and stereoselectivity of this cyclization event has not been elucidated. Herein, we report 1) two structures of DPS in complex with 2OG and (+/-)-yatein, 2) in vitro analysis of enzymatic reactivity with substrate analogs, and 3) model reactions addressing DPS's catalytic mechanism. The results disfavor a prior proposal of on-pathway benzylic hydroxylation. Rather, the DPS-catalyzed cyclization likely proceeds by hydrogen atom abstraction from C7', oxidation of the benzylic radical to a carbocation, Friedel-Crafts-like ring closure, and rearomatization of ring B by C6 deprotonation. This mechanism adds to the known pathways for transformation of the carbon-centered radical in Fe/2OG enzymes and suggests what types of substrate modification are likely tolerable in DPS-catalyzed production of deoxypodophyllotoxin analogs. Mechanistic analysis of carbon-carbon bond formation by deoxypodophyllotoxin synthase.,Tang H, Wu MH, Lin HY, Han MR, Tu YH, Yang ZJ, Chien TC, Chan NL, Chang WC Proc Natl Acad Sci U S A. 2022 Jan 4;119(1). pii: 2113770119. doi:, 10.1073/pnas.2113770119. PMID:34969844 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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