NRE1 (YIR035C) encodes a cytoplasmic classical short-chain dehydrogenase/reductase (SDR) of 254 residues, the paralog of the adjacent gene IRC24 (52% identity). Crystal structures (PDB 3KZV, 6UHX) show a Rossmann-fold SDR with the conserved Ser-Tyr-Lys catalytic triad. Purified Nre1 reduces the xenobiotic diketone benzil with NADPH, and NADH about half as well, with kinetics similar to Irc24. Its physiological substrate and biological role are unknown.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | HDA PMID:11914276 Subcellular localization of the yeast proteome. | ACCEPT | Summary: High-throughput localization: cytoplasm. Reason: Consistent with a soluble SDR; corroborated by a second independent dataset. Supporting Evidence: PMID:37602278 High-throughput protein expression data confirm that Nre1p is cytoplasmic |
| GO:0005737 cytoplasm | HDA PMID:14562095 Global analysis of protein localization in budding yeast. | ACCEPT | Summary: Genome-wide GFP localization: cytoplasm. Reason: Consistent with a soluble SDR without targeting signals. Supporting Evidence: PMID:37602278 High-throughput protein expression data confirm that Nre1p is cytoplasmic |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Keyword-mapped cytoplasm location; consistent with a soluble SDR lacking targeting signals. Reason: Soluble SDR-family reductase with no signal peptide or transmembrane segment, and Nre1 is independently placed in the cytoplasm by two high-throughput datasets, which this review accepts as separate HDA rows. Supporting Evidence: PMID:37602278 High-throughput protein expression data confirm that Nre1p is cytoplasmic |
| GO:0008150 biological_process | ND GO_REF:0000015 | ACCEPT | Summary: No biological process is established. Reason: Benzil reduction is a non-physiological in vitro activity; no process data exist. |
| GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor | IDA PMID:37602278 Saccharomyces cerevisiae NRE1 and IRC24 Encode Paralogous Be... | MODIFY | Summary: Purified His-tagged Nre1 reduces benzil with NADPH (preferred) or NADH. Reason: The assay (NADPH-dependent reduction of the diketone benzil to the secondary alcohol (S)-benzoin) is sound, but GO:0016616 is the EC 1.1.1.- grouping class and says only that some CH-OH/NAD(P) oxidoreduction occurs. The specific term GO:0102306 benzil reductase [(S)-benzoin-forming] activity was obsoleted (go-ontology#30498) because benzil is not a physiological substrate, and annotations were moved up to this grouping term. The reaction is, however, an instance of GO:0004090 carbonyl reductase (NADPH) activity (a secondary alcohol + NADP+ = a ketone + NADPH + H+; EC 1.1.1.184, whose synonyms explicitly include xenobiotic ketone reductase). GO already maps the sister EC 1.1.1.320 reaction RHEA:31891 (1-phenyl-1,2-propanedione) to GO:0004090. GO:0004090 is the informative term that respects the obsoletion decision; no new benzil-specific term is warranted. Proposed replacements: carbonyl reductase (NADPH) activity Supporting Evidence: PMID:37602278 Thus, Nre1p is a benzil reductase in vitro and likely paralog of Irc24p. PMID:37602278 Both enzymes were active with both coenzymes but showed a two-fold preference for NADPH |
| GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor | IEA GO_REF:0000120 | MODIFY | Summary: Combined IEA driven by RHEA:25968 mapped to the EC 1.1.1.- grouping class. Reason: This IEA is generated from the RHEA:25968 narrowMatch xref on the grouping class GO:0016616, which was added when GO:0102306 was obsoleted. It is not wrong, but it is uninformative; a RHEA reaction mapped to an EC-incomplete grouping class yields annotations that say nothing about substrate class. Replace with GO:0004090 (and fix the xref upstream: RHEA:25968 should be a narrowMatch of GO:0004090, as its sister reaction RHEA:31891 already is). Proposed replacements: carbonyl reductase (NADPH) activity Supporting Evidence: PMID:37602278 Both enzymes were active with both coenzymes but showed a two-fold preference for NADPH |
| GO:0050664 oxidoreductase activity, acting on NAD(P)H, oxygen as acceptor | IBA GO_REF:0000033 | MODIFY | Summary: IBA to an NAD(P)H oxidase (O2 acceptor) class, seeded by the IRC24 IDA. Reason: This IBA inherits from PTN002453021, which is seeded by the IRC24 IDA (SGD:S000001475) to GO:0050664. That seed annotation used a term whose acceptor (O2) does not match the benzil reductase assay, so the propagated term is wrong for the same reason. The underlying inherited function (an NADPH-dependent carbonyl reductase shared by the IRC24/NRE1 paralogs) is sound and is better expressed as GO:0004090. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN002453021 · PTN002453021 SOURCE BAD The node is seeded by the IRC24 IDA (SGD:S000001475) to GO:0050664. The citation is correct in every respect: right gene, right organism, right paper, and a real experiment. What is wrong is only the term, whose EC 1.6.3.- acceptor is molecular oxygen while the assayed acceptor is benzil. No failure_modes value describes a wrong-acceptor term, so none is asserted rather than naming one that would misstate the problem. source_status is SOURCE_BAD in the narrow sense its definition allows, that the source annotation itself carries the wrong term; it is not a claim about the citation. The underlying carbonyl reductase function is inherited correctly. Proposed replacements: carbonyl reductase (NADPH) activity Supporting Evidence: PMID:37602278 Thus, Nre1p is a benzil reductase in vitro and likely paralog of Irc24p. |
Loading supporting content…
Download this section (compressed HTML)Q: What is the physiological substrate of this SDR? Benzil is a synthetic diketone (GO:0102306 was obsoleted for that reason), so the native carbonyl substrate(s) remain to be found.
Q: Should RHEA:25968 ((S)-benzoin + NADP+ = benzil + NADPH) be re-pointed from the EC 1.1.1.- grouping class GO:0016616 to GO:0004090 carbonyl reductase (NADPH) activity as a narrowMatch, matching the sister EC 1.1.1.320 reaction RHEA:31891?
Experiment: Untargeted substrate screen (metabolite library or activity-based metabolomics of deletion vs. wild-type extracts) to identify native carbonyl substrates of the benzil reductase clade.
Hypothesis: The enzyme reduces an endogenous aromatic or quinone carbonyl compound; benzil is a surrogate substrate.
Type: biochemical substrate profiling
Benzil oxidoreductase with preference for NADPH; localizes to the cytoplasm; sequence similarity with short-chain dehydrogenase/reductases; putative paralog of IRC24
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)