7mbf | pdb_00007mbf
codeinone reductase isoform 1.3 Apo form
Structural highlights
Function[COR13_PAPSO] Reduces codeinone to codeine in the penultimate step in morphine biosynthesis. Can use morphinone, hydrocodone and hydromorphone as substrate during reductive reaction with NADPH as cofactor, and morphine and dihydrocodeine as substrate during oxidative reaction with NADP as cofactor.[1] Publication Abstract from PubMedBenzylisoquinoline alkaloids (BIAs) are a class of specialized metabolites with a diverse range of chemical structures and physiological effects. Codeine and morphine are two closely related BIAs with particularly useful analgesic properties. The aldo-keto reductase (AKR) codeinone reductase (COR) catalyzes the final and penultimate steps in the biosynthesis of codeine and morphine, respectively, in opium poppy (Papaver somniferum). However, the structural determinants that mediate substrate recognition and catalysis are not well defined. Here, we describe the crystal structure of apo-COR determined to a resolution of 2.4 A by molecular replacement using chalcone reductase as a search model. Structural comparisons of COR to closely related plant AKRs and more distantly related homologues reveal a novel conformation in the beta1alpha1 loop adjacent to the BIA binding pocket. The proximity of this loop to several highly conserved active-site residues and the expected location of the nicotinamide ring of the NADP(H) cofactor suggest a model for BIA recognition that implies roles for several key residues. Using site-directed mutagenesis, we show that substitutions at Met-28 and His-120 of COR lead to changes in AKR activity for the major and minor substrates codeinone and neopinone, respectively. Our findings provide a framework for understanding the molecular basis of substrate recognition in COR and the closely related 1,2-dehydroreticuline reductase responsible for the second half of a stereochemical inversion that initiates the morphine biosynthesis pathway. Structural studies of codeinone reductase reveal novel insights into aldo-keto reductase function in benzylisoquinoline alkaloid biosynthesis.,Carr SC, Torres MA, Morris JS, Facchini PJ, Ng KKS J Biol Chem. 2021 Sep 18:101211. doi: 10.1016/j.jbc.2021.101211. PMID:34547292[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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