hsd17b3

UniProt ID: Q6QA32
Organism: Danio rerio
Review Status: COMPLETE
📝 Provide Detailed Feedback

Gene Description

hsd17b3 encodes zebrafish 17beta-hydroxysteroid dehydrogenase type 3 (Hsd17b3), a short-chain dehydrogenase/reductase (SDR) family oxidoreductase with an N-terminal transmembrane helix that anchors it in the endoplasmic reticulum. The enzyme uses NADPH to reduce 17-oxosteroids to 17beta-hydroxysteroids, and its preferred reaction is the reduction of androstenedione to testosterone, the terminal step of testosterone biosynthesis. Recombinant zebrafish Hsd17b3 also reduces dehydroepiandrosterone and epiandrosterone at C-17, and reduces 11-ketoandrostenedione and 11beta-hydroxyandrostenedione to 11-ketotestosterone and 11beta-hydroxytestosterone, placing it on the route to 11-ketotestosterone, the principal teleost androgen; unlike the human enzyme it does not accept androsterone or androstanedione. Unlike testis-restricted mammalian HSD17B3, the zebrafish gene is expressed from sphere stage through embryogenesis and in many adult tissues with strong sexual dimorphism (highest in male liver and in ovary), suggesting a broader, partly extragonadal role in androgen metabolism.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005783 endoplasmic reticulum
IBA
GO_REF:0000033 		ACCEPT
Summary: PAINT-propagated assertion that Hsd17b3 is active in the endoplasmic reticulum (qualifier is_active_in). The ancestral node PTN000671707 covers the HSD17B3/HSD17B12-like ER-anchored SDR clade (human HSD17B3, mouse Hsd17b3/Hsd17b12, fly, and both zebrafish genes are listed among the donors). The zebrafish protein itself has direct experimental ER localization from PMID:16216911, which is why ZDB-GENE-040426-1339 appears in the WITH/FROM list.
Reason: Node placement is sound: the 17beta-HSD3/12 clade members are all ER-resident single-pass membrane enzymes, and the zebrafish protein was shown by the primary paper to localize to the ER together with the human enzyme [PMID:16216911 "both human and zebrafish 17beta-HSD type 3 localize to the endoplasmic reticulum"]. UniProt records this as the curated subcellular location and predicts the N-terminal transmembrane helix (residues 6-26) that anchors the enzyme. The gene appearing in its own WITH/FROM reflects that its IDA fed the IBD and is expected, not circular.
Supporting Evidence:
PMID:16216911
At the subcellular level, both human and zebrafish 17beta-HSD type 3 localize to the endoplasmic reticulum.
file:DANRE/hsd17b3/hsd17b3-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum {ECO:0000269|PubMed:16216911}. Membrane {ECO:0000255}; Single-pass membrane protein {ECO:0000255}.
GO:0047045 testosterone dehydrogenase (NADP+) activity
IBA
GO_REF:0000033 		ACCEPT
Summary: PAINT-propagated assertion of testosterone 17beta-dehydrogenase (NADP+) activity (EC 1.1.1.64; androstenedione + NADPH <-> testosterone + NADP+). The IBD node PTN002387784 is seeded by the zebrafish gene's own experimental annotation from PMID:16216911, i.e. the function is placed at a node that includes the zebrafish ortholog and the target is in its own WITH/FROM.
Reason: This is the defining reaction of the enzyme and is directly demonstrated for the zebrafish protein: recombinant zebrafish Hsd17b3 converts androstenedione to testosterone with NADPH as cofactor [PMID:16216911 "The zebrafish enzyme in vitro effectively catalyzed the conversion of androstenedione to testosterone by use of NADPH as cofactor"], and UniProt curates the Rhea:14981 reaction (EC 1.1.1.64) with physiological direction toward testosterone from both PMID:16216911 and PMID:27927697. The IBA adds that the activity is inherited within the HSD17B3 clade rather than lineage-specific.
Supporting Evidence:
PMID:16216911
The zebrafish enzyme in vitro effectively catalyzed the conversion of androstenedione to testosterone by use of NADPH as cofactor.
file:DANRE/hsd17b3/hsd17b3-uniprot.txt
Reaction=testosterone + NADP(+) = androst-4-ene-3,17-dione + NADPH + H(+); Xref=Rhea:RHEA:14981, ChEBI:CHEBI:15378, ChEBI:CHEBI:16422, ChEBI:CHEBI:17347, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.64; Evidence={ECO:0000269|PubMed:16216911, ECO:0000269|PubMed:27927697};
GO:0016020 membrane
IEA
GO_REF:0000044 		MODIFY
Summary: UniProt subcellular-location keyword mapping (SL-0162 Membrane) derived from the ECO:0000255-predicted single-pass membrane topology. Hsd17b3 has a predicted N-terminal transmembrane helix (residues 6-26) and experimentally localizes to the ER, so it is an ER membrane protein.
Reason: The term is correct but uninformative: the protein is a membrane protein because it is anchored in the endoplasmic reticulum, which was shown directly [PMID:16216911 "both human and zebrafish 17beta-HSD type 3 localize to the endoplasmic reticulum"], and UniProt annotates a helical TRANSMEM segment at residues 6-26. The combination of experimental ER localization and predicted single-pass topology supports the more specific child term endoplasmic reticulum membrane (GO:0005789), which is how mammalian HSD17B3 is annotated. The topology itself is sequence-predicted rather than demonstrated, so this is a MODIFY rather than a NEW experimental claim.
Proposed replacements: endoplasmic reticulum membrane
Supporting Evidence:
file:DANRE/hsd17b3/hsd17b3-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum {ECO:0000269|PubMed:16216911}. Membrane {ECO:0000255}; Single-pass membrane protein {ECO:0000255}.
PMID:16216911
At the subcellular level, both human and zebrafish 17beta-HSD type 3 localize to the endoplasmic reticulum.
GO:0047045 testosterone dehydrogenase (NADP+) activity
IEA
GO_REF:0000003 		ACCEPT
Summary: EC 1.1.1.64 (testosterone 17beta-dehydrogenase (NADP+)) to GO mapping. UniProt assigns EC 1.1.1.64 to zebrafish Hsd17b3 on experimental evidence from PMID:16216911 and PMID:27927697.
Reason: The EC number is experimentally assigned, not inherited by similarity: the recombinant zebrafish enzyme reduces androstenedione to testosterone with NADPH [PMID:16216911 "The zebrafish enzyme in vitro effectively catalyzed the conversion of androstenedione to testosterone by use of NADPH as cofactor"]. The mapping therefore reproduces the core, directly demonstrated activity and is consistent with the IDA and IBA rows for the same term.
Supporting Evidence:
file:DANRE/hsd17b3/hsd17b3-uniprot.txt
Reaction=testosterone + NADP(+) = androst-4-ene-3,17-dione + NADPH + H(+); Xref=Rhea:RHEA:14981, ChEBI:CHEBI:15378, ChEBI:CHEBI:16422, ChEBI:CHEBI:17347, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.64; Evidence={ECO:0000269|PubMed:16216911, ECO:0000269|PubMed:27927697};
PMID:16216911
The zebrafish enzyme in vitro effectively catalyzed the conversion of androstenedione to testosterone by use of NADPH as cofactor.
GO:0061370 testosterone biosynthetic process
IEA
GO_REF:0000041 		ACCEPT
Summary: UniPathway UPA00367 (testosterone biosynthesis) mapping. Hsd17b3 catalyzes the final step of this pathway, the 17beta-reduction of androstenedione to testosterone.
Reason: Participation is direct: the enzyme itself performs the terminal reaction of testosterone synthesis [PMID:16216911 "The main player in testosterone formation is considered to be 17beta-HSD type 3, which catalyzes the reduction of androstenedione to testosterone"; "The zebrafish enzyme in vitro effectively catalyzed the conversion of androstenedione to testosterone"], and UniProt curates the pathway "Hormone biosynthesis; testosterone biosynthesis". The evidence is in vitro enzymology plus expression; a caveat noted in the deep-research summary is that hsd17b3 transcripts are low or undetected in juvenile (19-30 dpf) gonads, so its in vivo contribution may be stage- and tissue-dependent, but this does not undermine the biosynthetic role of the enzyme.
Supporting Evidence:
PMID:16216911
The zebrafish enzyme in vitro effectively catalyzed the conversion of androstenedione to testosterone by use of NADPH as cofactor.
file:DANRE/hsd17b3/hsd17b3-uniprot.txt
PATHWAY: Hormone biosynthesis; testosterone biosynthesis.
file:DANRE/hsd17b3/hsd17b3-deep-research-falcon.md
They report that **hsd17b3 expression is low** at both 19 and 30 dpf and that they **did not detect hsd17b3** in ZZ NA gonads at 30 dpf.
GO:0005783 endoplasmic reticulum
IDA
PMID:16216911
Androgen metabolism via 17beta-hydroxysteroid dehydrogenase ... 		ACCEPT
Summary: ZFIN experimental annotation from the primary characterization paper, which examined the subcellular localization of the zebrafish enzyme alongside the human one. Note: current GOA attaches ZFIN's experimental rows for this gene to a newer TrEMBL accession of the same gene; the row is retained here and reviewed on its merits.
Reason: The abstract states the result directly for the zebrafish protein [PMID:16216911 "At the subcellular level, both human and zebrafish 17beta-HSD type 3 localize to the endoplasmic reticulum"], and UniProt adopts this as the curated SUBCELLULAR LOCATION with the same citation. The cache is abstract-only, but the claim is explicit in the abstract and concordant with the predicted N-terminal transmembrane anchor and with the ER residence of all HSD17B3 orthologs, so the curator's call is accepted.
Supporting Evidence:
PMID:16216911
At the subcellular level, both human and zebrafish 17beta-HSD type 3 localize to the endoplasmic reticulum.
file:DANRE/hsd17b3/hsd17b3-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum {ECO:0000269|PubMed:16216911}.
GO:0006702 androgen biosynthetic process
IDA
PMID:16216911
Androgen metabolism via 17beta-hydroxysteroid dehydrogenase ... 		ACCEPT
Summary: ZFIN experimental annotation (qualifier acts_upstream_of_or_within) based on the in vitro demonstration that zebrafish Hsd17b3 makes testosterone from androstenedione and 11-oxygenated testosterones from their 17-keto precursors. Retained from the remapped ZFIN record and reviewed on its merits.
Reason: Passes the participation test: the gene product itself catalyzes a step of androgen biosynthesis rather than being merely required for it. The zebrafish enzyme reduces androstenedione to testosterone and also reduces DHEA and epiandrosterone at C-17, and converts 11-ketoandrostenedione and 11beta-hydroxyandrostenedione to their testosterone forms, i.e. toward 11-ketotestosterone, the main fish androgen [PMID:16216911 "both enzymes can reduce 11-ketoandrostenedione as well as 11beta-hydroxyandrostenedione at C-17 to the respective testosterone forms"]. The evidence is recombinant-enzyme biochemistry rather than in vivo loss of function, which is appropriate for a process annotation on a biosynthetic enzyme. The term is a suitable parent that captures both the testosterone and the 11-oxygenated-androgen branches.
Supporting Evidence:
PMID:16216911
The zebrafish enzyme in vitro effectively catalyzed the conversion of androstenedione to testosterone by use of NADPH as cofactor. Among further tested androgens epiandrosterone and dehydroepiandrosterone were accepted as substrates and reduced at C-17 by the human and the zebrafish enzyme.
PMID:16216911
we found that both enzymes can reduce 11-ketoandrostenedione as well as 11beta-hydroxyandrostenedione at C-17 to the respective testosterone forms.
file:DANRE/hsd17b3/hsd17b3-uniprot.txt
Favors the reduction of androstenedione to testosterone (PubMed:16216911, PubMed:27927697).
GO:0047045 testosterone dehydrogenase (NADP+) activity
IDA
PMID:16216911
Androgen metabolism via 17beta-hydroxysteroid dehydrogenase ... 		ACCEPT
Summary: ZFIN experimental annotation of the core catalytic activity, based on enzyme assays with the recombinant zebrafish protein. Retained from the remapped ZFIN record and reviewed on its merits.
Reason: Direct biochemical evidence for exactly this reaction in the physiological (reductive) direction with the cofactor named in the term [PMID:16216911 "The zebrafish enzyme in vitro effectively catalyzed the conversion of androstenedione to testosterone by use of NADPH as cofactor"]. UniProt independently curates the Rhea:14981 reaction with EC 1.1.1.64 from this paper and from PMID:27927697, which re-examined zebrafish androgen metabolism with recombinant enzymes. This is the core molecular function of the gene product.
Supporting Evidence:
PMID:16216911
The zebrafish enzyme in vitro effectively catalyzed the conversion of androstenedione to testosterone by use of NADPH as cofactor.
file:DANRE/hsd17b3/hsd17b3-uniprot.txt
Reaction=testosterone + NADP(+) = androst-4-ene-3,17-dione + NADPH + H(+); Xref=Rhea:RHEA:14981, ChEBI:CHEBI:15378, ChEBI:CHEBI:16422, ChEBI:CHEBI:17347, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.64; Evidence={ECO:0000269|PubMed:16216911, ECO:0000269|PubMed:27927697};
GO:0005783 endoplasmic reticulum
IEA
GO_REF:0000120 		ACCEPT
Summary: Combined automated (ARBA rule plus UniProt SubCell SL-0095 Endoplasmic reticulum) localization annotation. It reproduces the experimentally established ER localization of the zebrafish protein.
Reason: The electronic call is correct and independently confirmed by the primary paper [PMID:16216911 "both human and zebrafish 17beta-HSD type 3 localize to the endoplasmic reticulum"] and by the IDA and IBA rows for the same term; it adds no new claim and is consistent with them.
Supporting Evidence:
file:DANRE/hsd17b3/hsd17b3-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum {ECO:0000269|PubMed:16216911}.
PMID:16216911
At the subcellular level, both human and zebrafish 17beta-HSD type 3 localize to the endoplasmic reticulum.
GO:0008610 lipid biosynthetic process
IEA
GO_REF:0000117 		MODIFY
Summary: ARBA machine-learning rule assigning the broad parent term lipid biosynthetic process. Steroid hormones are lipids, so the term is a true but very distant ancestor of the enzyme's actual role.
Reason: Not wrong, but far too general to convey what Hsd17b3 does: the enzyme catalyzes a single 17beta-reduction that forms testosterone and 11-oxygenated testosterones from their 17-keto precursors [PMID:16216911 "The zebrafish enzyme in vitro effectively catalyzed the conversion of androstenedione to testosterone"]. The specific descendants androgen biosynthetic process (GO:0006702, IDA) and testosterone biosynthetic process (GO:0061370) are already annotated and fully subsume this term; the ARBA row should be replaced by (or collapsed into) the androgen-biosynthesis annotation rather than kept as an uninformative parent.
Proposed replacements: androgen biosynthetic process
Supporting Evidence:
PMID:16216911
The zebrafish enzyme in vitro effectively catalyzed the conversion of androstenedione to testosterone by use of NADPH as cofactor.
file:DANRE/hsd17b3/hsd17b3-uniprot.txt
PATHWAY: Hormone biosynthesis; testosterone biosynthesis.
GO:0033764 steroid dehydrogenase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor
IEA
GO_REF:0000117 		MODIFY
Summary: ARBA rule assigning the generic steroid dehydrogenase (NAD/NADP) activity term, the grouping parent of the specific 17beta-HSD reactions.
Reason: Biochemically true (the enzyme is an NADP(H)-dependent steroid 17beta-dehydrogenase/reductase), but the exact reaction is experimentally established for the zebrafish protein and already annotated as testosterone dehydrogenase (NADP+) activity (GO:0047045) by IDA, IBA and EC mapping [PMID:16216911 "The zebrafish enzyme in vitro effectively catalyzed the conversion of androstenedione to testosterone by use of NADPH as cofactor"]. The generic parent should be replaced by the specific child; retaining both adds no information. The enzyme's additional substrates (DHEA, epiandrosterone, 11-ketoandrostenedione, 11beta-hydroxyandrostenedione) are all 17beta-reductions of the same chemical class and are captured by UniProt's Rhea reactions rather than by this broad term.
Supporting Evidence:
PMID:16216911
The zebrafish enzyme in vitro effectively catalyzed the conversion of androstenedione to testosterone by use of NADPH as cofactor.
file:DANRE/hsd17b3/hsd17b3-uniprot.txt
Reaction=a 17beta-hydroxy steroid + NADP(+) = a 17-oxo steroid + NADPH + H(+); Xref=Rhea:RHEA:69284, ChEBI:CHEBI:15378, ChEBI:CHEBI:19168, ChEBI:CHEBI:35343, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; Evidence={ECO:0000269|PubMed:16216911, ECO:0000269|PubMed:27927697};

Core Functions

NADPH-dependent 17beta-reduction of androstenedione to testosterone (and of 11-ketoandrostenedione and 11beta-hydroxyandrostenedione to their testosterone forms) as the terminal enzyme of testosterone/androgen biosynthesis, anchored in the endoplasmic reticulum membrane by an N-terminal transmembrane helix.

Molecular Function:
testosterone dehydrogenase (NADP+) activity
Directly Involved In:
testosterone biosynthetic process androgen biosynthetic process
Cellular Locations:
endoplasmic reticulum
Supporting Evidence:
  • PMID:16216911
    The zebrafish enzyme in vitro effectively catalyzed the conversion of androstenedione to testosterone by use of NADPH as cofactor.
  • PMID:16216911
    At the subcellular level, both human and zebrafish 17beta-HSD type 3 localize to the endoplasmic reticulum.
  • file:DANRE/hsd17b3/hsd17b3-uniprot.txt
    FUNCTION: Catalyzes the conversion of 17-oxosteroids to 17beta-hydroxysteroids in the presence of NADPH (PubMed:16216911, PubMed:27927697). Favors the reduction of androstenedione to testosterone (PubMed:16216911, PubMed:27927697).

References

Loading supporting content…

Download this section (compressed HTML)

Suggested Questions for Experts

Q: Which 17beta-HSD supplies testosterone/11-ketotestosterone synthesis in juvenile zebrafish gonads, given that hsd17b3 transcripts are low or undetected at 19-30 dpf while the recombinant enzyme clearly performs the reaction in vitro?

Q: Does the strong hepatic and ovarian expression of hsd17b3 in adults reflect an extragonadal androgen-activation (or 11-oxygenated androgen) role that differs from the testis-restricted function of mammalian HSD17B3?

Suggested Experiments

Experiment: Generate an hsd17b3 knockout line and profile plasma and gonadal testosterone and 11-ketotestosterone by LC-MS/MS in adults of both sexes, to test whether Hsd17b3 is the physiologically dominant androstenedione 17beta-reductase in vivo.

Type: genetic knockout with steroid profiling

Experiment: Determine kinetic constants (Km, kcat) of purified zebrafish Hsd17b3 for androstenedione versus 11-ketoandrostenedione and 11beta-hydroxyandrostenedione, to establish whether the enzyme is tuned toward the 11-oxygenated androgen branch characteristic of teleosts.

Type: enzyme kinetics

Deep Research

Falcon

(hsd17b3-deep-research-falcon.md)

Loading supporting content…

Download this section (compressed HTML)

📚 Additional Documentation

Notes

(hsd17b3-notes.md)

Loading supporting content…

Download this section (compressed HTML)

📄 View Raw YAML

Loading supporting content…

Download this section (compressed HTML)