Crystal Structure of Codeinone Reductase Reveals Novel Features Responsible for Defining Benzylisoquinoline Alkaloid Substrate Specificity
Bibliographic record
Abstract
The pharmaceutical properties of plant‐derived compounds are widely used in medicine. Benzylisoquinoline alkaloids (BIAs) are a class of specialized metabolites with a diverse range of chemical structures and physiological effects. Codeine and morphine are closely related BIAs with particularly useful analgesic properties. The aldo‐keto reductase (AKR) codeinone reductase (COR) catalyzes the final step and the penultimate step in biosynthesis of codeine and morphine, respectively, in opium poppy ( Papaver somniferum). Using X‐ray crystallography, we have determined the structure of apo‐COR (2.4 Å resolution) for the first time, using the structure of chalcone reductase as a search model. The structure of apo‐COR reveals a three‐dimensional framework for understanding BIA substrate recognition and catalysis. Structural comparisons of COR to closely related plant AKR's and more distantly related homologues reveal a novel conformation in the β1α1 loop adjacent to the BIA binding pocket. The proximity of this loop several highly conserved active site residues and the expected location of the nicotinamide ring of the NADPH cofactor suggest the importance of several key residues in BIA substrate recognition. The effects of mutations in residues in this loop and at other nearby positions help to define specific roles in substrate recognition and catalysis. Combined with the structure of COR, these findings from mutagenesis also help to suggest structure‐function relationships in a second AKR critical to BIA biosynthesis, the 1,2 dehydroreticuline reductase domain in the critical enzyme reticuline epimerase.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".