IRC24

UniProt ID: P40580
Organism: Saccharomyces cerevisiae S288C
Review Status: COMPLETE
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Gene Description

IRC24 (YIR036C) encodes a cytoplasmic classical short-chain dehydrogenase/reductase (SDR) of about 263 residues. Purified recombinant Irc24 reduces aromatic alpha-diketones stereoselectively with NADPH (NADH is used about half as well), converting benzil to (S)-benzoin and 1-phenyl-1,2-propanedione to 2-hydroxy-1-phenyl-1-propanone. These substrates are xenobiotic, and the physiological substrate and pathway are unknown. IRC24 is a paralog of the adjacent gene NRE1 (52% identity), and its deletion raises spontaneous Rad52 focus levels, although no mechanism links the reductase to genome maintenance.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0004090 carbonyl reductase (NADPH) activity
IEA
GO_REF:0000116
ACCEPT
Summary: Rhea-mapping IEA from RHEA:31891 (1-phenyl-1,2-propanedione reduction); the most informative existing MF term for this broad-specificity NADPH carbonyl reductase.
Reason: The protein reduces aryl alpha-diketones (benzil, 1-phenyl-1,2-propanedione) to secondary alcohols with NADPH. That is the reaction class of GO:0004090 (EC 1.1.1.184). The physiological substrate is unknown, which is consistent with this broad term rather than a substrate-specific one.
Supporting Evidence:
PMID:11796169
both recombinant proteins also reduced benzil to (S)-benzoin in
GO:0005737 cytoplasm
HDA
PMID:14562095
Global analysis of protein localization in budding yeast.
ACCEPT
Summary: Genome-wide GFP localization places Irc24 in the cytoplasm.
Reason: Consistent with a soluble SDR without targeting signals; supported for the paralog Nre1 by the same high-throughput datasets.
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: The only process-level data are an increased-Rad52-foci deletion phenotype (a screen hit with no mechanism) and benzil reduction, a non-physiological reaction. ND is the honest statement. IRC24-notes.md weighs the two process-level hints in this species (Rad52 foci on deletion, PMID:18085829; induction by DNA damage, PMID:17163986) and finds that neither identifies a biological process.
Supporting Evidence:
file:yeast/IRC24/IRC24-notes.md
Neither connects the reductase chemistry to genome maintenance
GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor
EXP
PMID:11796169
The enzymes with benzil reductase activity conserved from ba...
MODIFY
Summary: In vitro NADPH-dependent reduction of benzil to (S)-benzoin by recombinant YIR036C.
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.
Supporting Evidence:
PMID:11796169
both recombinant proteins also reduced benzil to (S)-benzoin in
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 Irc24 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.
Supporting Evidence:
PMID:37602278
Both enzymes were active with both coenzymes but showed a two-fold preference for NADPH
PMID:37602278
a decrease in absorbance was followed at 340 nm
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).
Supporting Evidence:
PMID:11796169
both recombinant proteins also reduced benzil to (S)-benzoin in
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 IRC24's own 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 Β· 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.
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
IDA
PMID:11796169
The enzymes with benzil reductase activity conserved from ba...
MODIFY
Summary: Benzil reductase assay annotated to an NAD(P)H:O2 oxidoreductase term.
Reason: GO:0050664 (EC 1.6.3.-) describes NAD(P)H oxidation with molecular oxygen as the electron acceptor (NAD(P)H oxidases). The benzil reductase assay measures NADPH consumption coupled to reduction of an organic diketone; O2 is not the acceptor. The experimental observation is correct, but the term does not describe it. The correct term is GO:0004090 carbonyl reductase (NADPH) activity.
Supporting Evidence:
PMID:11796169
both recombinant proteins also reduced benzil to (S)-benzoin in

Core Functions

Irc24 is a cytoplasmic NADPH-preferring SDR carbonyl reductase that reduces aromatic alpha-diketones to (S)-hydroxyketones in vitro; physiological substrate unknown.

Cellular Locations:
Supporting Evidence:
  • PMID:11796169
    both recombinant proteins also reduced benzil to (S)-benzoin in
  • PMID:37602278
    Both enzymes were active with both coenzymes but showed a two-fold preference for NADPH

References

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Suggested Questions for Experts

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?

Suggested Experiments

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

Deep Research

SGD

(IRC24-deep-research-sgd.md)
SGD gene description for IRC24 (yeast) SGD

SGD gene description for IRC24 (yeast)

Benzil oxidoreductase with preference for NADPH; localizes to the cytoplasm; induced by the DNA-damaging agent MMS; null mutant has elevated levels of spontaneous Rad52p foci; sequence similarity with short-chain dehydrogenase/reductases; putative paralog of IRC24

OpenScientist

(IRC24-hypotheses/paralog-pocket-specificity-alphafold/openscientist.md)

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πŸ“š Additional Documentation

Notes

(IRC24-notes.md)

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