DUOX1 notes

2026-09-08 paired human–horse review

DUOX1 is a membrane NADPH oxidase that assembles with DUOXA1 and generates extracellular hydrogen peroxide. Its transmembrane hemes and cytosolic FAD/NADPH-binding machinery conduct electron transfer, while intracellular EF-hand elements mediate calcium regulation. The extracellular N-terminal region has a peroxidase-like fold but lacks the intrinsic peroxidase activity of a conventional mammalian peroxidase. DUOX1-derived peroxide contributes to epithelial defense and redox signaling.

Two domains with very different catalytic implications

The heme-containing membrane oxidase/dehydrogenase machinery transfers reducing equivalents from NADPH through FAD and hemes to oxygen. The extracellular peroxidase-like domain is a different structural region. Direct biochemical work finds that the isolated human peroxidase-like domain lacks heme binding and intrinsic peroxidase activity; the C. elegans homolog behaves differently. The human NOT-peroxidase annotation is therefore supported, without negating the heme required by the membrane oxidase. High- and low-calcium structures of DUOX1–DUOXA1 establish EF-hand-dependent conformational regulation. The selected horse deletion removes major elements of that regulatory region, making exact-sequence transfer much less secure than ordinary family identification. Hormone synthesis requires coupling peroxide production to separate peroxidases and the appropriate tissue context.

Decisive inspected evidence

From PMID:33420071(https://pubmed.ncbi.nlm.nih.gov/33420071/):

Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. They are involved in many crucial biological processes and human diseases, especially in thyroid diseases. DUOXs are protein complexes co-assembled from the catalytic DUOX subunits and the auxiliary DUOXA subunits and their activities are regulated by intracellular calcium concentrations.

Evidence inventory

Transfer to the selected horse protein

The exact target is A0A9L0SQG9, not an arbitrary horse record with a matching name. The reproducible paired-sequence analysis records identity, coverage and internal gaps. It supports homology but is not a reciprocal orthology test. Molecular properties are transferred only with the relevant domain, targeting and paralog constraints. The prediction-time sequence is not independently verified.

Open evidence questions

The following annotation scopes need source-specific follow-up: cell leading edge, cellular response to cytokine stimulus, cuticle development, protein binding, protein heterodimerization activity, regulation of thyroid hormone generation, response to cAMP, response to virus, superoxide anion generation, superoxide-generating NAD(P)H oxidase activity, thyroid hormone generation. Experimental annotations are not removed merely because a cached abstract omits the gene or a specific assay. High-throughput protein-binding rows require their actual partner or complex context before replacement with an informative molecular function.

Research provenance: external Falcon/Edison was attempted with Perplexity fallback. Some requests returned HTTP 429 and fallback returned insufficient-quota HTTP 401; successful external reports are preserved separately. Primary-source manual synthesis is explicitly labeled manual where no external report was available.

2026-10-20 — Full re-review, independent of the ProtNLM2 predictions

Re-reviewed all 75 existing annotations from scratch against the literature and the
PANTHER/PAINT evidence. No ProtNLM2 output was opened or used.

Identity of the benchmark accession

Q9NRD9 is the canonical, reviewed UniProt entry for human DUOX1 (DUOX1_HUMAN, 1551 aa,
Flags: Precursor), the same product this folder is keyed to. It is not a fragment, an
isoform or an alternative gene model: the length matches the 1551-residue ThOX1 ORF
reported at cloning PMID:10806195, and all catalytic machinery is present — three EF-hand domains
(815-850, 851-886, 895-930), the ferric-oxidoreductase domain (1096-1236), the FAD-binding
FR-type domain (1270-1376), seven transmembrane segments in the record's feature table,
and heme, FAD, NADPH and Ca(2+) ligand sites. A second splice isoform (Q9NRD9-2,
VSP_017262/VSP_017263) exists and is recorded in alternative_products; no annotation in
GOA is isoform-scoped.

Evolutionary grounding

Q9NRD9 is in PANTHER subfamily PTHR11972:SF75 (DUAL OXIDASE 1), with rat Q8CIY2, pig
Q8HZK3, dog Q9MZF4 and mouse A2AQ92. DUOX2 (Q9NRD8) is the sister subfamily SF67; the
C. elegans Duox bli-3 (O61213) is SF175, a different subfamily again.

The PAINT record (interpro/panther/PTHR11972/PTHR11972-paint.tsv) separates two activities
that the GOA rows conflate:

That is a deliberate curatorial split, and it matches the biochemistry: the mature thyroid
oxidase releases H2O2 rather than superoxide, and superoxide is seen only from the immature
ER form or when the DUOXA N-terminus is altered [PMID:15972824 "it was shown that mature
thyroid NADPH oxidase does not release O2*- but H2O2"; "the partially glycosylated form of
Duox2, located in the endoplasmic reticulum, generates superoxide in a calcium-dependent
manner"], with the DUOXA1 C-terminus directing DUOX1 output to H2O2 PMID:22814254.
Both superoxide rows were therefore MODIFYed to their H2O2 counterparts, with a
propagation_review recording the node inspection, rather than removed.

Changes made (75 rows, all re-decided)

Ontology gap recorded

UniProt gives DUOX1 a third curated catalytic activity, NAADPH + O2 + H(+) = NAADP(+) +
H2O2 (Rhea:86235, ECO:0000269|PubMed:34784249), and GO has no molecular function for it
(GO:0016174 is defined on NAD(P)H). Recorded as a proposed_new_terms entry only; no
annotation is proposed, and the T-cell calcium phenotype in that paper was DUOX2-specific
for the early microdomains.

Family review

interpro/panther/PTHR11972/PTHR11972-review.yaml places Q9NRD9 in SF75 and treats
GO:0004601 as UNRESOLVED at family level because of the PMID:11514595 / PMID:19460756
conflict. No disagreement with the subfamily placement used here. The family review's
caution that "ferric reduction, superoxide production and hydrogen-peroxide production must
be assigned to the appropriate branch" is exactly what the two MODIFYs implement; a note
for whoever next edits that file is that the branch assignment is now resolvable from the
PAINT node split described above.

Deep research

just deep-research-falcon human DUOX1 --fallback perplexity-lite failed: the falcon
provider errored and the perplexity-lite fallback timed out at 600 s. No new
deep-research file was produced, and none was fabricated. The review was written from the
15 cached publications (two with full text: PMID:33420071 and PMID:39126279, plus
PMID:11514595), the UniProt record and the PANTHER/PAINT files.

Modules

No module under modules/ references DUOX1 or Q9NRD9, and gocams/index.tsv has no entry
for it. None created.

Relative to review next

Mouse Duox1 (UniProtKB:A2AQ92, MGI:2139422, 1551 aa, PTHR11972:SF75 — the same subfamily),
the true ortholog and the donor of the ISS (GO_REF:0000024) and Ensembl Compara
(GO_REF:0000107) rows on this gene, and the organism in which the in vivo antiviral
phenotype was established PMID:34168077. There is no
genes/mouse/Duox1/ folder, so it needs a review.

2026-10-27 — Mouse ortholog (genes/mouse/Duox1/), PTHR11972 family update, and mucosal DUOX1–LPO module