Evolutionary analysis of Quinone Reductases 1 and 2 suggest that NQO2 evolved to function as a pseudoenzyme
Bibliographic record
Abstract
Abstract Quinone reductases 1 and 2 (NQO1 and NQO2) are paralogous FAD-linked enzymes found in all amniotes. NQO1 and NQO2 have similar structures and can both catalyze reduction of quinones and other electrophiles. The two enzymes differ in their cosubstrate specificity, with NQO1 using cellular redox couples NAD(H) and NADP(H), while NQO2 is almost completely inactive with these cosubstrates, and instead uses dihydronicotinamide riboside (NRH) and small synthetic cosubstrates such as N- benzyl-dihydronicotinamide (BNAH). We used ancestral sequence reconstruction to investigate the catalytic properties of a predicted common ancestor and 2 additional ancestors from each of the evolutionary pathways to extant NQO1 and NQO2. In all cases, the small nicotinamide cosubstrates NRH and BNAH were good cosubstrates for the common ancestor and the enzymes along the NQO1 and NQO2 lineages. In the case of NADH, however, extant NQO1 evolved to a catalytic efficiency 100x higher than the common ancestor, while NQO2 has evolved to a catalytic efficiency 1000x lower than the common ancestor. In addition, 13 chimeric enzymes were created to investigate the molecular basis of cosubstrate specificity, which was further elaborated by site-directed mutagenesis of the ancestral NQO2. Overall, the results suggest a selective pressure for evolution of NQO1 towards greater efficiency with NADH, and for NQO2 towards extremely low efficiency with NADH. These divergent trajectories have implications for the cellular functions of both enzymes, but particularly for NQO2 whose cellular functions are only beginning to be uncovered.
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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 | 0.000 | 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".