Hsd11b2

UniProt ID: P50233
Organism: Rattus norvegicus
Review Status: COMPLETE
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Gene Description

Hsd11b2 encodes NAD-dependent 11beta-hydroxysteroid dehydrogenase type 2, an endoplasmic-reticulum enzyme that oxidizes active 11beta-hydroxyglucocorticoids such as corticosterone to inactive 11-keto forms. Its core pre-receptor role is to confer aldosterone specificity on the otherwise non-selective mineralocorticoid receptor in aldosterone-sensitive epithelia (distal nephron, colon), and to act as a placental/fetal barrier limiting fetal glucocorticoid exposure; this is the inactivating dehydrogenase, distinct from the reductive Hsd11b1. The review accepts glucocorticoid metabolism and NAD-dependent dehydrogenase activity, keeps steroid/NAD binding and renal/placental physiological contexts as non-core, and marks stimulus-response expression annotations and Smoothened signaling as over-extensions. Falcon (Edison Scientific) deep research corroborates the inactivating NAD-dependent dehydrogenase activity and the mineralocorticoid-receptor-protection role.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0070523 11-beta-hydroxysteroid dehydrogenase (NAD+) activity
IBA
GO_REF:0000033 		ACCEPT
Summary: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity is retained for Hsd11b2 because it matches the documented core enzymatic role or its direct pathway consequence (IBA, GO_REF:0000033).
Reason: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity is directly supported by the curated function of Hsd11b2 and is not merely a downstream phenotype or expression response.
Supporting Evidence:
UniProtKB:P50233
FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone, in the presence of NAD(+).
file:rat/Hsd11b2/Hsd11b2-deep-research-falcon.md
11β‑HSD2 is described as **NAD-dependent/NAD+-dependent**, consistent with SDR-family dehydrogenase directionality in epithelia.
GO:0008211 glucocorticoid metabolic process
IBA
GO_REF:0000033 		ACCEPT
Summary: glucocorticoid metabolic process is retained for Hsd11b2 because it matches the documented core enzymatic role or its direct pathway consequence (IBA, GO_REF:0000033).
Reason: glucocorticoid metabolic process is directly supported by the curated function of Hsd11b2 and is not merely a downstream phenotype or expression response.
Supporting Evidence:
UniProtKB:P50233
FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone, in the presence of NAD(+).
file:rat/Hsd11b2/Hsd11b2-deep-research-falcon.md
11β‑HSD2 catalyzes oxidation/inactivation of glucocorticoids: **cortisol→cortisone** and **corticosterone→11‑dehydrocorticosterone**.
GO:0005783 endoplasmic reticulum
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: endoplasmic reticulum is retained as contextual support for Hsd11b2, but it is not the core function (IEA, GO_REF:0000044).
Reason: endoplasmic reticulum records localization, cofactor/substrate binding, oligomeric state, or physiological context rather than the defining molecular activity of Hsd11b2.
Supporting Evidence:
UniProtKB:P50233
FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone, in the presence of NAD(+).
GO:0034650 cortisol metabolic process
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: cortisol metabolic process is an over-annotation for the rat enzyme; it is an electronic ortholog transfer from human, where cortisol is the primary substrate (IEA, GO_REF:0000107).
Reason: Rats are a corticosterone-dominated glucocorticoid species, and rat 11beta-HSD2 acts principally on corticosterone, not cortisol. GO:0034650 is specific to cortisol (11-beta-17,21-trihydroxypregn-4-ene-3,20-dione). This electronic annotation derives from ortholog transfer out of the human context, where cortisol is the primary substrate; in the rat the relevant glucocorticoid metabolic process is the corticosterone-directed activity captured by GO:0008211, so the cortisol-specific term over-annotates the rat gene.
Supporting Evidence:
UniProtKB:P50233
FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone, in the presence of NAD(+).
GO:0045880 positive regulation of smoothened signaling pathway
IEA
GO_REF:0000107 		REMOVE
Summary: positive regulation of smoothened signaling pathway should not be retained for Hsd11b2 based on the combined gene function and cited/source evidence (IEA, GO_REF:0000107).
Reason: The available evidence supports Hsd11b2's curated activity rather than positive regulation of smoothened signaling pathway; this annotation is unsupported, assigned to the wrong biological context, or too misleading to keep as non-core.
Supporting Evidence:
UniProtKB:P50233
FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone, in the presence of NAD(+).
GO:0047022 7-beta-hydroxysteroid dehydrogenase (NADP+) activity
IEA
GO_REF:0000120 		MARK AS OVER ANNOTATED
Summary: 7-beta-hydroxysteroid dehydrogenase (NADP+) activity is an over-annotation for Hsd11b2; Hsd11b2 is an NAD(+)-dependent 11beta-hydroxysteroid oxidase, not a documented NADP(+)-dependent 7-beta dehydrogenase.
Reason: This activity appears to be an electronic or family-level transfer from related SDR enzymes. UniProtKB:P50233 supports NAD(+)-dependent oxidation of 11beta-hydroxyglucocorticoids such as corticosterone; it does not support NADP(+)-dependent 7-beta-hydroxysteroid dehydrogenase activity as a genuine secondary function.
Supporting Evidence:
UniProtKB:P50233
FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone, in the presence of NAD(+).
GO:0070523 11-beta-hydroxysteroid dehydrogenase (NAD+) activity
IEA
GO_REF:0000120 		ACCEPT
Summary: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity is retained for Hsd11b2 because it matches the documented core enzymatic role or its direct pathway consequence (IEA, GO_REF:0000120).
Reason: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity is directly supported by the curated function of Hsd11b2 and is not merely a downstream phenotype or expression response.
Supporting Evidence:
UniProtKB:P50233
FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone, in the presence of NAD(+).
GO:0045880 positive regulation of smoothened signaling pathway
ISO
GO_REF:0000121 		REMOVE
Summary: positive regulation of smoothened signaling pathway should not be retained for Hsd11b2 based on the combined gene function and cited/source evidence (ISO, GO_REF:0000121).
Reason: The available evidence supports Hsd11b2's curated activity rather than positive regulation of smoothened signaling pathway; this annotation is unsupported, assigned to the wrong biological context, or too misleading to keep as non-core.
Supporting Evidence:
UniProtKB:P50233
FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone, in the presence of NAD(+).
GO:0047022 7-beta-hydroxysteroid dehydrogenase (NADP+) activity
ISS
GO_REF:0000024 		MARK AS OVER ANNOTATED
Summary: 7-beta-hydroxysteroid dehydrogenase (NADP+) activity is an over-annotation for Hsd11b2; Hsd11b2 is an NAD(+)-dependent 11beta-hydroxysteroid oxidase, not a documented NADP(+)-dependent 7-beta dehydrogenase.
Reason: This activity appears to be an electronic or family-level transfer from related SDR enzymes. UniProtKB:P50233 supports NAD(+)-dependent oxidation of 11beta-hydroxyglucocorticoids such as corticosterone; it does not support NADP(+)-dependent 7-beta-hydroxysteroid dehydrogenase activity as a genuine secondary function.
Supporting Evidence:
UniProtKB:P50233
FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone, in the presence of NAD(+).
GO:0047022 7-beta-hydroxysteroid dehydrogenase (NADP+) activity
ISO
GO_REF:0000121 		MARK AS OVER ANNOTATED
Summary: 7-beta-hydroxysteroid dehydrogenase (NADP+) activity is an over-annotation for Hsd11b2; Hsd11b2 is an NAD(+)-dependent 11beta-hydroxysteroid oxidase, not a documented NADP(+)-dependent 7-beta dehydrogenase.
Reason: This activity appears to be an electronic or family-level transfer from related SDR enzymes. UniProtKB:P50233 supports NAD(+)-dependent oxidation of 11beta-hydroxyglucocorticoids such as corticosterone; it does not support NADP(+)-dependent 7-beta-hydroxysteroid dehydrogenase activity as a genuine secondary function.
Supporting Evidence:
UniProtKB:P50233
FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone, in the presence of NAD(+).
GO:0034650 cortisol metabolic process
ISO
GO_REF:0000121 		MARK AS OVER ANNOTATED
Summary: cortisol metabolic process is an over-annotation for the rat enzyme; it is an ortholog (ISO) transfer from human, where cortisol is the primary substrate (ISO, GO_REF:0000121).
Reason: Rats are a corticosterone-dominated glucocorticoid species, and rat 11beta-HSD2 acts principally on corticosterone, not cortisol. GO:0034650 is specific to cortisol (11-beta-17,21-trihydroxypregn-4-ene-3,20-dione). This ISO annotation derives from ortholog transfer out of the human context, where cortisol is the primary substrate; in the rat the relevant glucocorticoid metabolic process is the corticosterone-directed activity captured by GO:0008211, so the cortisol-specific term over-annotates the rat gene.
Supporting Evidence:
UniProtKB:P50233
FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone, in the presence of NAD(+).
GO:0070523 11-beta-hydroxysteroid dehydrogenase (NAD+) activity
ISO
GO_REF:0000121 		ACCEPT
Summary: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity is retained for Hsd11b2 because it matches the documented core enzymatic role or its direct pathway consequence (ISO, GO_REF:0000121).
Reason: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity is directly supported by the curated function of Hsd11b2 and is not merely a downstream phenotype or expression response.
Supporting Evidence:
UniProtKB:P50233
FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone, in the presence of NAD(+).
GO:0008211 glucocorticoid metabolic process
IDA
PMID:11755176
Effect of cellular differentiation on 11beta-hydroxysteroid ... 		ACCEPT
Summary: glucocorticoid metabolic process is retained for Hsd11b2 because it matches the documented core enzymatic role or its direct pathway consequence (IDA, PMID:11755176).
Reason: glucocorticoid metabolic process is directly supported by the curated function of Hsd11b2 and is not merely a downstream phenotype or expression response.
Supporting Evidence:
PMID:11755176
Type 2 11betaHSD has only oxidase activity converting corticosterone to 11-dehydrocorticosterone.
file:rat/Hsd11b2/Hsd11b2-deep-research-falcon.md
11β‑HSD2 is the inactivating dehydrogenase
GO:0007565 female pregnancy
ISO
GO_REF:0000121 		KEEP AS NON CORE
Summary: female pregnancy is retained as contextual support for Hsd11b2, but it is not the core function (ISO, GO_REF:0000121).
Reason: female pregnancy records localization, cofactor/substrate binding, oligomeric state, or physiological context rather than the defining molecular activity of Hsd11b2.
Supporting Evidence:
UniProtKB:P50233
FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone, in the presence of NAD(+).
GO:0001666 response to hypoxia
IEP
PMID:19470702
Chronic intermittent hypoxia induces 11beta-hydroxysteroid d... 		MARK AS OVER ANNOTATED
Summary: response to hypoxia reflects an expression, phenotype, or systemic context for Hsd11b2, not a direct core gene-product function (IEP, PMID:19470702).
Reason: The cited/source evidence links Hsd11b2 to changes in expression or a downstream physiological state; it does not establish Hsd11b2 as an effector of response to hypoxia.
Supporting Evidence:
PMID:19470702
We first demonstrated that adaptation to CIH led to a significant increase in 11HSD2 transcript levels and activity in the myocardium.
GO:0007565 female pregnancy
IEP
PMID:19050325
Reciprocal changes in maternal and fetal metabolism of corti... 		KEEP AS NON CORE
Summary: female pregnancy is retained as contextual support for Hsd11b2, but it is not the core function (IEP, PMID:19050325).
Reason: female pregnancy records localization, cofactor/substrate binding, oligomeric state, or physiological context rather than the defining molecular activity of Hsd11b2.
Supporting Evidence:
PMID:19050325
The final third of gestation is accompanied by reciprocal changes in placental and fetal metabolism of corticosterone due to changes in 11HSD1 and 11HSD2.
file:rat/Hsd11b2/Hsd11b2-deep-research-falcon.md
11β‑HSD2 is highly expressed in **placenta and fetal tissues** where it **minimizes fetal exposure to maternal glucocorticoids**
GO:0009410 response to xenobiotic stimulus
IEP
PMID:10792625
Effects of spironolactone on systolic blood pressure in expe... 		MARK AS OVER ANNOTATED
Summary: response to xenobiotic stimulus reflects an expression, phenotype, or systemic context for Hsd11b2, not a direct core gene-product function (IEP, PMID:10792625).
Reason: The cited/source evidence links Hsd11b2 to changes in expression or a downstream physiological state; it does not establish Hsd11b2 as an effector of response to xenobiotic stimulus.
Supporting Evidence:
PMID:10792625
Four weeks after an injection of STZ, the renal 11beta-HSD2 and mRNA levels were significantly lower in diabetic rats than in control rats, and the mean systolic blood pressure was 14.8% higher in diabetic rats than in controls.
GO:0032094 response to food
IEP
PMID:18548384
Tissue-specific programming expression of glucocorticoid rec... 		MARK AS OVER ANNOTATED
Summary: response to food reflects an expression, phenotype, or systemic context for Hsd11b2, not a direct core gene-product function (IEP, PMID:18548384).
Reason: The cited/source evidence links Hsd11b2 to changes in expression or a downstream physiological state; it does not establish Hsd11b2 as an effector of response to food.
Supporting Evidence:
PMID:18548384
This study demonstrated that maternal food restriction has both long-term and tissue-specific effects on gene expression of factors involved in glucocorticoid sensitivity.
GO:0032868 response to insulin
IEP
PMID:9495277
Gene expression of 11beta-hydroxysteroid dehydrogenase type ... 		MARK AS OVER ANNOTATED
Summary: response to insulin reflects an expression, phenotype, or systemic context for Hsd11b2, not a direct core gene-product function (IEP, PMID:9495277).
Reason: The cited/source evidence links Hsd11b2 to changes in expression or a downstream physiological state; it does not establish Hsd11b2 as an effector of response to insulin.
Supporting Evidence:
PMID:9495277
The renal 11beta-HSD2 activity and level of mRNA expression were significantly decreased in diabetic rats.
GO:0048545 response to steroid hormone
IEP
PMID:18032797
DHEA induces 11 -HSD2 by acting on CCAAT/enhancer-binding pr... 		MARK AS OVER ANNOTATED
Summary: response to steroid hormone reflects an expression, phenotype, or systemic context for Hsd11b2, not a direct core gene-product function (IEP, PMID:18032797).
Reason: The cited/source evidence links Hsd11b2 to changes in expression or a downstream physiological state; it does not establish Hsd11b2 as an effector of response to steroid hormone.
Supporting Evidence:
PMID:18032797
DHEA treatment markedly increased mRNA expression and activity of 11beta-HSD2 in a rat cortical collecting duct cell line and in kidneys of C57BL/6J mice and Sprague-Dawley rats.
GO:0051384 response to glucocorticoid
IEP
PMID:19490994
Dexamethasone and betamethasone administration during pregna... 		MARK AS OVER ANNOTATED
Summary: response to glucocorticoid reflects an expression, phenotype, or systemic context for Hsd11b2, not a direct core gene-product function (IEP, PMID:19490994).
Reason: The cited/source evidence links Hsd11b2 to changes in expression or a downstream physiological state; it does not establish Hsd11b2 as an effector of response to glucocorticoid.
Supporting Evidence:
PMID:19490994
Placental 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) is the key enzyme which protects the fetus from overexposure to glucocorticoids (GCs) by their oxidation into inactive derivates.
GO:0002017 regulation of blood volume by renal aldosterone
IMP
PMID:15718388
Interactions between 11beta-hydroxysteroid dehydrogenase and... 		KEEP AS NON CORE
Summary: regulation of blood volume by renal aldosterone is retained as contextual support for Hsd11b2, but it is not the core function (IMP, PMID:15718388).
Reason: regulation of blood volume by renal aldosterone records localization, cofactor/substrate binding, oligomeric state, or physiological context rather than the defining molecular activity of Hsd11b2.
Supporting Evidence:
PMID:15718388
These data indicate that COX-2 plays a modulating role in the development of hypertension due to 11betaHSD2 deficiency and that 11betaHSD2 regulates renal COX-2 expression by preventing glucocorticoid access to MRs during postnatal development.
file:rat/Hsd11b2/Hsd11b2-deep-research-falcon.md
11β‑HSD2 enables aldosterone-specific MR signaling** in target cells by locally removing active glucocorticoids.
GO:0005496 steroid binding
IPI
PMID:15761036
11{beta}-Hydroxysteroid dehydrogenase 2 in rat leydig cells:... 		KEEP AS NON CORE
Summary: steroid binding is retained as contextual support for Hsd11b2, but it is not the core function (IPI, PMID:15761036).
Reason: steroid binding records localization, cofactor/substrate binding, oligomeric state, or physiological context rather than the defining molecular activity of Hsd11b2.
Supporting Evidence:
PMID:15761036
the high-affinity, low-capacity 11beta HSD2 isoform, present at only one thousandth the level of the low-affinity isoform may significantly affect the level of CORT
GO:0051287 NAD binding
IDA
PMID:15761036
11{beta}-Hydroxysteroid dehydrogenase 2 in rat leydig cells:... 		KEEP AS NON CORE
Summary: NAD binding is retained as contextual support for Hsd11b2, but it is not the core function (IDA, PMID:15761036).
Reason: NAD binding records localization, cofactor/substrate binding, oligomeric state, or physiological context rather than the defining molecular activity of Hsd11b2.
Supporting Evidence:
PMID:15761036
the nicotinamide adenine dinucleotide-dependent 11beta HSD2 high-affinity unidirectional oxidase
GO:0008211 glucocorticoid metabolic process
IDA
PMID:16763064
Expression and functional state of the corticosteroid recept... 		ACCEPT
Summary: glucocorticoid metabolic process is retained for Hsd11b2 because it matches the documented core enzymatic role or its direct pathway consequence (IDA, PMID:16763064).
Reason: glucocorticoid metabolic process is directly supported by the curated function of Hsd11b2 and is not merely a downstream phenotype or expression response.
Supporting Evidence:
PMID:16763064
11 beta-Hydroxysteroid-dehydrogenase type 2 (HSD2), an enzyme that inactivates glucocorticoids, was strongly expressed and active in quiescent SC.

Core Functions

Hsd11b2 inactivates active glucocorticoids through NAD-dependent 11beta-hydroxysteroid dehydrogenase activity, oxidizing corticosterone (and cortisol in species that produce it) to inactive 11-keto forms and thereby conferring aldosterone specificity on the mineralocorticoid receptor.

Molecular Function:
11-beta-hydroxysteroid dehydrogenase (NAD+) activity
Directly Involved In:
glucocorticoid metabolic process
Supporting Evidence:
  • UniProtKB:P50233
    FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone, in the presence of NAD(+).
  • file:rat/Hsd11b2/Hsd11b2-deep-research-falcon.md
    11β‑HSD2 catalyzes oxidation/inactivation of glucocorticoids: **cortisol→cortisone** and **corticosterone→11‑dehydrocorticosterone**.
  • file:rat/Hsd11b2/Hsd11b2-deep-research-falcon.md
    11β‑HSD2 enables aldosterone-specific MR signaling** in target cells by locally removing active glucocorticoids.

References

GO_REF:0000024
GO reference used by source annotation pipeline
  • Source annotation pipeline provenance for Hsd11b2 annotations including 7-beta-hydroxysteroid dehydrogenase (NADP+) activity.
    "GO_REF entry used only to trace source annotation method; biological support was assessed from UniProt and cached literature where available."
GO_REF:0000033
GO reference used by source annotation pipeline
  • Source annotation pipeline provenance for Hsd11b2 annotations including 11-beta-hydroxysteroid dehydrogenase (NAD+) activity; glucocorticoid metabolic process.
    "GO_REF entry used only to trace source annotation method; biological support was assessed from UniProt and cached literature where available."
GO_REF:0000044
GO reference used by source annotation pipeline
  • Source annotation pipeline provenance for Hsd11b2 annotations including endoplasmic reticulum.
    "GO_REF entry used only to trace source annotation method; biological support was assessed from UniProt and cached literature where available."
GO_REF:0000107
GO reference used by source annotation pipeline
  • Source annotation pipeline provenance for Hsd11b2 annotations including cortisol metabolic process; positive regulation of smoothened signaling pathway.
    "GO_REF entry used only to trace source annotation method; biological support was assessed from UniProt and cached literature where available."
GO_REF:0000120
GO reference used by source annotation pipeline
  • Source annotation pipeline provenance for Hsd11b2 annotations including 11-beta-hydroxysteroid dehydrogenase (NAD+) activity; 7-beta-hydroxysteroid dehydrogenase (NADP+) activity.
    "GO_REF entry used only to trace source annotation method; biological support was assessed from UniProt and cached literature where available."
GO_REF:0000121
GO reference used by source annotation pipeline
  • Source annotation pipeline provenance for Hsd11b2 annotations including 11-beta-hydroxysteroid dehydrogenase (NAD+) activity; 7-beta-hydroxysteroid dehydrogenase (NADP+) activity; cortisol metabolic process; female pregnancy; positive regulation of smoothened signaling pathway.
    "GO_REF entry used only to trace source annotation method; biological support was assessed from UniProt and cached literature where available."
PMID:9495277
Gene expression of 11beta-hydroxysteroid dehydrogenase type 1 and type 2 in the kidneys of insulin-dependent diabetic rats.
  • For Hsd11b2, this publication was assessed for annotations including response to insulin.
    "The renal 11beta-HSD2 activity and level of mRNA expression were significantly decreased in diabetic rats."
PMID:10792625
Effects of spironolactone on systolic blood pressure in experimental diabetic rats.
  • For Hsd11b2, this publication was assessed for annotations including response to xenobiotic stimulus.
    "Four weeks after an injection of STZ, the renal 11beta-HSD2 and mRNA levels were significantly lower in diabetic rats than in control rats, and the mean systolic blood pressure was 14.8% higher in diabetic rats than in controls."
PMID:11755176
Effect of cellular differentiation on 11beta-hydroxysteroid dehydrogenase activity in the intestine.
  • For Hsd11b2, this publication was assessed for annotations including glucocorticoid metabolic process.
    "Type 2 11betaHSD has only oxidase activity converting corticosterone to 11-dehydrocorticosterone."
PMID:15718388
Interactions between 11beta-hydroxysteroid dehydrogenase and COX-2 in kidney.
  • For Hsd11b2, this publication was assessed for annotations including regulation of blood volume by renal aldosterone.
    "These data indicate that COX-2 plays a modulating role in the development of hypertension due to 11betaHSD2 deficiency and that 11betaHSD2 regulates renal COX-2 expression by preventing glucocorticoid access to MRs during postnatal development."
PMID:15761036
11{beta}-Hydroxysteroid dehydrogenase 2 in rat leydig cells: its role in blunting glucocorticoid action at physiological levels of substrate.
  • For Hsd11b2, this publication was assessed for annotations including NAD binding; steroid binding.
    "We showed that 11beta HSD2 is present in rat Leydig cells by PCR amplification, immunohistochemical staining, enzyme histochemistry, immunoprecipitation, and Western blotting."
PMID:16763064
Expression and functional state of the corticosteroid receptors and 11 beta-hydroxysteroid dehydrogenase type 2 in Schwann cells.
  • For Hsd11b2, this publication was assessed for annotations including glucocorticoid metabolic process.
    "11 beta-Hydroxysteroid-dehydrogenase type 2 (HSD2), an enzyme that inactivates glucocorticoids, was strongly expressed and active in quiescent SC."
PMID:18032797
DHEA induces 11 -HSD2 by acting on CCAAT/enhancer-binding proteins.
  • For Hsd11b2, this publication was assessed for annotations including response to steroid hormone.
    "DHEA treatment markedly increased mRNA expression and activity of 11beta-HSD2 in a rat cortical collecting duct cell line and in kidneys of C57BL/6J mice and Sprague-Dawley rats."
PMID:18548384
Tissue-specific programming expression of glucocorticoid receptors and 11 beta-HSDs by maternal perinatal undernutrition in the HPA axis of adult male rats.
  • For Hsd11b2, this publication was assessed for annotations including response to food.
    "This study demonstrated that maternal food restriction has both long-term and tissue-specific effects on gene expression of factors involved in glucocorticoid sensitivity."
PMID:19050325
Reciprocal changes in maternal and fetal metabolism of corticosterone in rat during gestation.
  • For Hsd11b2, this publication was assessed for annotations including female pregnancy.
    "The final third of gestation is accompanied by reciprocal changes in placental and fetal metabolism of corticosterone due to changes in 11HSD1 and 11HSD2."
PMID:19470702
Chronic intermittent hypoxia induces 11beta-hydroxysteroid dehydrogenase in rat heart.
  • For Hsd11b2, this publication was assessed for annotations including response to hypoxia.
    "We first demonstrated that adaptation to CIH led to a significant increase in 11HSD2 transcript levels and activity in the myocardium."
PMID:19490994
Dexamethasone and betamethasone administration during pregnancy affects expression and function of 11 beta-hydroxysteroid dehydrogenase type 2 in the rat placenta.
  • For Hsd11b2, this publication was assessed for annotations including response to glucocorticoid.
    "Placental 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) is the key enzyme which protects the fetus from overexposure to glucocorticoids (GCs) by their oxidation into inactive derivates."
file:rat/Hsd11b2/Hsd11b2-deep-research-falcon.md
Falcon (Edison Scientific) deep research report: rat Hsd11b2 (11-beta-hydroxysteroid dehydrogenase type 2, UniProt P50233)
  • 11beta-HSD2 is the inactivating (oxidative) member of the 11beta-HSD pair, distinct from the reductive 11beta-HSD1.
    "11β‑HSD2 is the inactivating dehydrogenase"
  • The catalyzed reaction is the oxidation/inactivation of active glucocorticoids to their inert 11-keto forms.
    "11β‑HSD2 catalyzes oxidation/inactivation of glucocorticoids: **cortisol→cortisone** and **corticosterone→11‑dehydrocorticosterone**."
  • The enzyme uses NAD(+) as cofactor, consistent with SDR-family oxidative directionality in epithelia.
    "11β‑HSD2 is described as **NAD-dependent/NAD+-dependent**, consistent with SDR-family dehydrogenase directionality in epithelia."
  • By locally removing active glucocorticoids the enzyme confers aldosterone specificity on the otherwise non-selective mineralocorticoid receptor.
    "11β‑HSD2 enables aldosterone-specific MR signaling** in target cells by locally removing active glucocorticoids."
  • Glucocorticoids circulate far in excess of aldosterone; the enzyme prevents them occupying MR while aldosterone, not a substrate, signals through MR.
    "aldosterone is not a substrate and can therefore signal through MR."
  • Canonical sites of action are the classic aldosterone-sensitive epithelia.
    "Canonical sites include **distal nephron/kidney**, **colon**, **salivary glands**, and **sweat glands**"
  • The enzyme acts as a placental/fetal barrier limiting fetal exposure to maternal glucocorticoids.
    "11β‑HSD2 is highly expressed in **placenta and fetal tissues** where it **minimizes fetal exposure to maternal glucocorticoids**"
  • In adult rodent CNS the enzyme is restricted to discrete hindbrain regions supporting aldosterone-specific control of salt appetite and blood pressure.
    "nucleus of the solitary tract** and **subcommissural organ**, where 11β-HSD2 supports aldosterone-specific control of **salt appetite** and influences **blood pressure**."
  • Loss of enzyme function causes apparent mineralocorticoid excess (AME), underscoring its physiological role.
    "Loss of 11β‑HSD2 function causes **AME**"

Deep Research

Falcon

(Hsd11b2-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 36 citations 2 artifacts 2026-06-01T00:21:23.171698
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000032 The document contains the following relevant data for HSD11B2 (11β-HSD2): 1. **Precursor-to-product ratios**: Table 2 (page 6) repo (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Rat Hsd11b2 (UniProt P50233) — Functional Annotation of 11β-Hydroxysteroid Dehydrogenase Type 2 (11β-HSD2)

Executive summary

The rat gene Hsd11b2 encodes 11β-hydroxysteroid dehydrogenase type 2 (11β‑HSD2), an NAD-dependent short-chain dehydrogenase/reductase (SDR) enzyme that inactivates glucocorticoids by oxidizing cortisol→cortisone and corticosterone→11‑dehydrocorticosterone. Its primary physiological role is pre-receptor control of mineralocorticoid receptor (MR) signaling, most prominently in aldosterone-sensitive epithelia (distal nephron), by preventing abundant glucocorticoids from occupying and activating the MR. In placenta/fetus, 11β‑HSD2 functions as a barrier limiting fetal exposure to maternal glucocorticoids. Recent (2023–2024) work emphasizes that epigenetic and microRNA regulation of HSD11B2 is mechanistically linked to salt-sensitive hypertension and that altered glucocorticoid metabolite ratios are detectable in pregnancy complications such as preeclampsia. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2, seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2, takeda2024epigeneticregulationof pages 9-11)

Identity verification and gene/protein disambiguation

The requested target identity (UniProt P50233, Rattus norvegicus, gene Hsd11b2/Hsd11k, protein “11‑beta‑hydroxysteroid dehydrogenase type 2”) aligns with authoritative literature definitions of HSD11B2/11β‑HSD2 as the glucocorticoid-inactivating (dehydrogenase) isoenzyme, explicitly contrasted with HSD11B1/11β‑HSD1 as the glucocorticoid-regenerating (reductase) isoenzyme. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2)

Note on UniProt mapping: the retrieved peer-reviewed papers did not explicitly list the UniProt accession P50233, so this report uses the user-provided UniProt identity and ensures all cited biology refers specifically to HSD11B2/11β‑HSD2 (not HSD11B1). (seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2)

1) Key concepts and definitions (current understanding)

1.1 Pre-receptor steroid metabolism (“glucocorticoid gatekeeping”)

11β‑HSD enzymes control local steroid action by interconverting active 11‑hydroxy glucocorticoids and inert 11‑keto forms. In this system, 11β‑HSD2 is the inactivating dehydrogenase, while 11β‑HSD1 is predominantly the activating reductase in metabolic tissues and many CNS regions. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 3-3, seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2)

1.2 Enzymatic function: reaction and cofactor

Reaction: 11β‑HSD2 catalyzes oxidation/inactivation of glucocorticoids: cortisol→cortisone and corticosterone→11‑dehydrocorticosterone. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2, seckl202411β‐hydroxysteroiddehydrogenaseand pages 3-3)

Cofactor: 11β‑HSD2 is described as NAD-dependent/NAD+-dependent, consistent with SDR-family dehydrogenase directionality in epithelia. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2, sagmeister2024evaluationof11βhydroxysteroid pages 52-57)

1.3 Substrate specificity and physiological selectivity

A central concept is that the MR is intrinsically non-selective, and glucocorticoids are present in circulation at large excess over aldosterone; therefore, 11β‑HSD2 enables aldosterone-specific MR signaling in target cells by locally removing active glucocorticoids. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2, seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2)

2) Biological function, pathways, and localization

2.1 Mineralocorticoid receptor specificity in aldosterone-sensitive epithelia

Mechanism: In aldosterone-sensitive tissues (especially distal nephron), 11β‑HSD2 rapidly inactivates cortisol so it cannot occupy MR; aldosterone is not a substrate and can therefore signal through MR. This provides aldosterone specificity despite ~100–1000× higher circulating glucocorticoid concentrations. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2, seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2)

Canonical tissues: distal nephron/kidney, colon, salivary and sweat glands. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2, seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2)

2.2 Placenta/fetal barrier function

11β‑HSD2 is highly expressed in placenta and fetal tissues where it minimizes fetal exposure to maternal glucocorticoids, helping maintain a low-glucocorticoid fetal environment. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2, cao2023expressionofkey pages 6-7)

Recent human placental data show HSD11B2 protein localization mainly in fetal syncytiotrophoblast, consistent with a fetal-side barrier. (trummer2024steroidprofilesand media 87cb528a)

2.3 CNS localization and function (rodent-relevant)

In adult rodents, 11β‑HSD2 is restricted to discrete hindbrain regions, including the nucleus tractus solitarius (NTS) and subcommissural organ (SCO), where it supports aldosterone-specific MR signaling to regulate salt appetite and potentially blood pressure. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 4-5, seckl202411β‐hydroxysteroiddehydrogenaseand pages 5-5)

3) Recent developments and latest research (prioritizing 2023–2024)

3.1 2024 expert synthesis: 11β‑HSD2 and aldosterone specificity

A 2024 authoritative review (Seckl, Journal of Internal Medicine, Nov 2024) synthesizes decades of work and reiterates 11β‑HSD2 as a potent glucocorticoid-inactivating dehydrogenase essential for MR specificity in kidney epithelia, and highlights its restricted CNS distribution and developmental barrier roles. URL: https://doi.org/10.1111/joim.13741 (seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2, seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2)

3.2 2024 epigenetic/miRNA regulation linked to hypertension

A 2024 review on RAAS epigenetics (Takeda et al., IJMS, Jul 2024) highlights HSD11B2 as a key salt-sensitive hypertension gene under DNA methylation and microRNA control in renal and vascular tissues; it summarizes evidence that miRNAs (e.g., miR‑20a) can reduce 11β‑HSD2 activity and that dietary exposures can alter offspring Hsd11b2 expression/activity via miRNA pathways. URL: https://doi.org/10.3390/ijms25158099 (takeda2024epigeneticregulationof pages 9-11, takeda2024epigeneticregulationof pages 15-16)

3.3 2024 pregnancy steroid profiling: metabolite ratios implicating 11β‑HSD2

A 2024 primary study (Trummer et al., IJMS, Nov 2024) measured 14 steroids longitudinally and inferred enzyme activities from precursor-to-product ratios, reporting that ratios consistent with 11β‑HSD2 activity were decreased in preeclampsia (with broader steroid imbalance). The study also reports compartmentalized placental localization, with HSD11B2 predominantly in syncytiotrophoblast. URL: https://doi.org/10.3390/ijms252312704 (trummer2024steroidprofilesand pages 1-2, trummer2024steroidprofilesand media 87cb528a)

4) Current applications and real-world implementations

4.1 Apparent mineralocorticoid excess (AME): diagnosis and treatment logic

Loss of 11β‑HSD2 function causes AME, in which suppressed aldosterone is accompanied by MR activation driven by glucocorticoids; a hallmark is elevated urinary cortisol:cortisone metabolites indicating deficient 11β‑dehydrogenase activity. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2)

A 2025 clinical case series (Ding et al., Frontiers in Endocrinology, Jan 2025) reports three genetically confirmed pediatric AME cases managed with spironolactone plus potassium chloride, which normalized blood pressure and potassium; the paper also emphasizes genetic testing as a practical diagnostic implementation for suspected AME. URL: https://doi.org/10.3389/fendo.2024.1491825 (ding2025casereportclinical pages 1-2)

4.2 Drug/herbal inhibition: licorice/glycyrrhizin pseudoaldosteronism

A widely implemented real-world scenario is 11β‑HSD2 inhibition by licorice constituents, producing an AME-like phenotype (“pseudoaldosteronism”); review evidence describes potent inhibition with low-nanomolar Ki for licorice-derived inhibitors. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2)

A 2024 pharmacovigilance analysis (Uneda et al., PLOS ONE, Jan 2024) used a national adverse event database (Japan) to identify pseudoaldosteronism associated with glycyrrhiza-containing Kampo formulas and quantified risk factors (see statistics below). URL: https://doi.org/10.1371/journal.pone.0296450 (uneda2024analysisofclinical pages 1-2)

5) Expert opinions and analysis (authoritative sources)

Consensus mechanism (expert synthesis): The central expert view is that 11β‑HSD2 is a “pre-receptor” determinant of steroid signaling specificity, and in kidney it is the mechanistic reason MR can function as an aldosterone receptor despite glucocorticoid excess. This conceptualization is explicitly emphasized in the 2024 Seckl review and used to interpret AME and licorice effects. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2, seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2)

Emerging emphasis (2024): Contemporary reviews increasingly frame HSD11B2 as a regulatable node (via methylation/miRNAs and environmental inputs) within salt-sensitive hypertension mechanisms, broadening its role from a “fixed barrier enzyme” to a dynamically regulated determinant of cardio-renal phenotype. (takeda2024epigeneticregulationof pages 9-11, takeda2024epigeneticregulationof pages 1-2)

6) Relevant statistics and quantitative data (recent studies)

6.1 Real-world adverse event statistics (2024)

In the 2024 JADER database study (Apr 2004–Nov 2022):
- 6334 Kampo-related adverse events were reported; 2471 had complete clinical data; 210 involved pseudoaldosteronism. (uneda2024analysisofclinical pages 1-2)
- Strong associations were observed for specific formulas: Shakuyaku-kanzoto ROR 18.3 [13.0–25.9], Yokukansan ROR 8.1 [5.4–12.0], Ryokeijutsukanto ROR 5.5 [1.4–21.9]. (uneda2024analysisofclinical pages 1-2)
- Logistic regression risk factors included female sex (OR 1.7 [1.2–2.6]), age ≥70 (OR 5.0 [3.2–7.8]), low body weight <50 kg (OR 2.2 [1.5–3.2]), diuretics (OR 2.1 [1.3–4.8]), hypertension (OR 1.6 [1.1–2.4]), dementia (OR 7.0 [4.2–11.6]), higher glycyrrhiza dose (OR 2.1 [1.9–2.3]), and duration >14 days (OR 2.8 [1.7–4.5]). (uneda2024analysisofclinical pages 1-2)

6.2 Quantitative context for steroid availability relevant to HSD11B2 function

A 2024 synthesis on glucocorticoid metabolism notes that ~90% of circulating cortisol is bound to corticosteroid-binding globulin and ~5% to albumin, leaving ~5% free; it further notes cortisone levels are ~10-fold lower than cortisol but have lower binding affinity, leading to comparable free levels—supporting the need for local enzymatic control in MR target tissues. (sagmeister2024evaluationof11βhydroxysteroid pages 52-57)

6.3 Pregnancy steroid ratio signal (2024)

In Trummer et al. 2024, serum-based enzyme activity inference indicated decreased precursor-to-product ratios consistent with reduced 11β‑HSD2 activity in preeclampsia, alongside altered cortisol:cortisone handling across gestation. (trummer2024steroidprofilesand pages 1-2)

Visual evidence (from 2024 primary research)

Trummer et al. 2024 provide a directly relevant table/figure showing (i) precursor-to-product ratios used to infer enzyme activities and (ii) placental immunohistochemical localization of HSD11B2 to syncytiotrophoblast. (trummer2024steroidprofilesand media 87cb528a, trummer2024steroidprofilesand media 4e1233dd, trummer2024steroidprofilesand media f8b6c41d)

Functional-annotation summary table

Annotation category Concise statement Key supporting citations
Enzyme identity Rat Hsd11b2 (UniProt P50233) corresponds to 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), the oxidative/inactivating member of the 11β-HSD pair; literature consistently distinguishes it from reductive 11β-HSD1. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2)
Enzyme reaction 11β-HSD2 catalyzes oxidation/inactivation of active glucocorticoids: cortisol → cortisone and corticosterone → 11-dehydrocorticosterone. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2, seckl202411β‐hydroxysteroiddehydrogenaseand pages 3-3)
Cofactor 11β-HSD2 is described as an NAD+-dependent / NAD-dependent dehydrogenase, consistent with the SDR-family oxidative direction in epithelia. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2, sagmeister2024evaluationof11βhydroxysteroid pages 52-57)
Substrates/products Principal substrates are cortisol and corticosterone; products are the corresponding inactive 11-keto steroids cortisone and 11-dehydrocorticosterone. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2, seckl202411β‐hydroxysteroiddehydrogenaseand pages 3-3)
Primary pathway role The core biological role is pre-receptor glucocorticoid metabolism that protects mineralocorticoid receptor (MR) signaling from glucocorticoid excess. By removing cortisol/corticosterone locally, the enzyme enables aldosterone-selective MR activation. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2, seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2, seckl202411β‐hydroxysteroiddehydrogenaseand pages 5-5)
MR specificity mechanism In MR target epithelia, glucocorticoids circulate at roughly 100–1000-fold higher concentrations than aldosterone; 11β-HSD2 prevents these glucocorticoids from occupying MR, thereby conferring aldosterone specificity. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2, seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2)
Tissue/cell localization Canonical sites include distal nephron/kidney, colon, salivary glands, and sweat glands; these are classic aldosterone-sensitive epithelia. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2, seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2, seckl202411β‐hydroxysteroiddehydrogenaseand pages 3-3)
Placental/fetal localization 11β-HSD2 is highly expressed in placenta/fetal tissues and functions as a barrier to maternal glucocorticoids, limiting fetal cortisol exposure. In placenta, recent human data localize it mainly to syncytiotrophoblast. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2, cao2023expressionofkey pages 6-7, cao2023expressionofkey pages 5-6, trummer2024steroidprofilesand media 87cb528a)
CNS localization/function In adult rodents, CNS expression is restricted largely to hindbrain regions including the nucleus of the solitary tract and subcommissural organ, where 11β-HSD2 supports aldosterone-specific control of salt appetite and influences blood pressure. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 4-5, seckl202411β‐hydroxysteroiddehydrogenaseand pages 5-5)
Protein family/domain inference Functional behavior matches the UniProt annotation placing rat Hsd11b2 in the short-chain dehydrogenase/reductase (SDR) family, with oxidative steroid dehydrogenase activity. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2)
Regulation mechanisms Recent reviews highlight epigenetic regulation of HSD11B2 by DNA methylation and microRNAs in renal/vascular tissues as an important mechanism in salt-sensitive hypertension. (takeda2024epigeneticregulationof pages 9-11, takeda2024epigeneticregulationof pages 1-2)
Specific regulatory miRNAs Reported regulators include miR-20a (reduced 11β-HSD2 activity when overexpressed) and miR-27a-5p in diet-programmed offspring models; these link environmental inputs to HSD11B2 suppression. (takeda2024epigeneticregulationof pages 9-11, takeda2024epigeneticregulationof pages 15-16)
Dietary/environmental regulation Maternal high-fructose exposure has been linked to reduced offspring renal Hsd11b2 via miRNA-mediated mechanisms; placental HSD11B2 can also be altered by nicotine, LPS, cadmium/GR signaling, and melatonin-responsive pathways. (takeda2024epigeneticregulationof pages 15-16, cao2023expressionofkey pages 6-7)
Phenotypes/models Loss of 11β-HSD2 function causes apparent mineralocorticoid excess (AME) with hypertension, hypokalemia, metabolic alkalosis, and elevated urinary cortisol:cortisone metabolite ratios; brain-selective loss increases salt appetite and can raise blood pressure. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2, seckl202411β‐hydroxysteroiddehydrogenaseand pages 4-5)
Rat-relevant functional inference Although much recent literature is cross-species, rat-relevant annotation is strongly supported because rodent hindbrain, kidney, and placental functions described in reviews align with classic Hsd11b2 biology and with the rat UniProt entry’s enzyme/family assignment. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2, seckl202411β‐hydroxysteroiddehydrogenaseand pages 4-5, cao2023expressionofkey pages 5-6)
Pregnancy/preeclampsia relevance In 2024 longitudinal steroid profiling, women with preeclampsia showed altered glucocorticoid handling consistent with disturbed HSD11B2-associated metabolism; the inferred 11β-HSD2 precursor-to-product ratio was decreased, and HSD11B2 localized to syncytiotrophoblast. (trummer2024steroidprofilesand pages 10-12, trummer2024steroidprofilesand pages 9-10, trummer2024steroidprofilesand pages 1-2, trummer2024steroidprofilesand media 87cb528a)
Clinical/real-world relevance: AME 2025 case-series data show HSD11B2 deficiency remains clinically actionable: 3 Chinese children with biallelic variants had low-renin hypertension, hypokalemia, nephrocalcinosis, and growth issues; diagnosis used sequencing and treatment with spironolactone plus potassium normalized BP and potassium. (ding2025casereportclinical pages 6-7, ding2025casereportclinical pages 5-6, ding2025casereportclinical pages 1-2)
Clinical/real-world relevance: pseudoaldosteronism Pharmacologic inhibition of 11β-HSD2 by licorice/glycyrrhizin/glycyrrhetinic acid causes pseudoaldosteronism/AME-like physiology; inhibitors are reported as potent, with low-nanomolar Ki in review-cited work. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2, uneda2024analysisofclinical pages 1-2)
Real-world pharmacovigilance data In a 2024 Japanese adverse-event analysis, 210 pseudoaldosteronism reports were identified among 2471 complete Kampo AE reports; risk factors included female sex (OR 1.7), age ≥70 (OR 5.0), low body weight (OR 2.2), diuretic use (OR 2.1), hypertension (OR 1.6), dementia (OR 7.0), higher Glycyrrhiza dose (OR 2.1), and treatment duration >14 days (OR 2.8). (uneda2024analysisofclinical pages 1-2)
Exposure-associated formulations In the same 2024 database study, formulas with highest reporting odds for pseudoaldosteronism included Shakuyaku-kanzoto ROR 18.3 [13.0–25.9], Yokukansan ROR 8.1 [5.4–12.0], and Ryokeijutsukanto ROR 5.5 [1.4–21.9]. (uneda2024analysisofclinical pages 1-2)
Quantitative data: steroid binding context Review data note that ~90% of circulating cortisol is CBG-bound and ~5% albumin-bound, leaving ~5% free; cortisone concentrations are about 10-fold lower than cortisol but have lower binding affinity, helping explain why local HSD11B2 activity is crucial for receptor selectivity. (sagmeister2024evaluationof11βhydroxysteroid pages 52-57)
Quantitative data: AME rarity Recent clinical review/case-series context indicates fewer than 100 AME cases have been reported worldwide, while >40 pathogenic HSD11B2 variants are known, many in exons 3–5. (ding2025casereportclinical pages 5-6, ding2025casereportclinical pages 4-5)

Table: This table summarizes the core functional annotation of rat Hsd11b2/11β-HSD2, including its enzymatic role, localization, regulatory mechanisms, disease relevance, and recent quantitative findings. It integrates key recent review and application-focused sources to support narrative annotation with traceable citations.

References (key sources with dates and URLs)

  • Seckl J. 11β‑Hydroxysteroid dehydrogenase and the brain: Not (yet) lost in translation. Journal of Internal Medicine. Nov 2024. https://doi.org/10.1111/joim.13741 (seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2)
  • Takeda Y, Demura M, Yoneda T, Takeda Y. Epigenetic Regulation of the Renin–Angiotensin–Aldosterone System in Hypertension. International Journal of Molecular Sciences. Jul 2024. https://doi.org/10.3390/ijms25158099 (takeda2024epigeneticregulationof pages 1-2)
  • Trummer O et al. Steroid Profiles and Precursor-to-Product Ratios Are Altered in Pregnant Women with Preeclampsia. International Journal of Molecular Sciences. Nov 2024. https://doi.org/10.3390/ijms252312704 (trummer2024steroidprofilesand pages 1-2)
  • Uneda K et al. Analysis of clinical factors associated with Kampo formula-induced pseudoaldosteronism… PLOS ONE. Jan 2024. https://doi.org/10.1371/journal.pone.0296450 (uneda2024analysisofclinical pages 1-2)
  • Cao J et al. Expression of Key Steroidogenic Enzymes in Human Placenta and Associated Adverse Pregnancy Outcomes. Maternal-Fetal Medicine. Sep 2023. https://doi.org/10.1097/fm9.0000000000000167 (cao2023expressionofkey pages 6-7)
  • Ding Y et al. Case report: … HSD11B2 … apparent mineralocorticoid excess. Frontiers in Endocrinology. Jan 2025. https://doi.org/10.3389/fendo.2024.1491825 (ding2025casereportclinical pages 1-2)

References

  1. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2): Jonathan Seckl. 11β‐hydroxysteroid dehydrogenase and the brain: not (yet) lost in translation. Journal of Internal Medicine, 295:20-37, Nov 2024. URL: https://doi.org/10.1111/joim.13741, doi:10.1111/joim.13741. This article has 41 citations and is from a domain leading peer-reviewed journal.

  2. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2): Jonathan Seckl. 11β‐hydroxysteroid dehydrogenase and the brain: not (yet) lost in translation. Journal of Internal Medicine, 295:20-37, Nov 2024. URL: https://doi.org/10.1111/joim.13741, doi:10.1111/joim.13741. This article has 41 citations and is from a domain leading peer-reviewed journal.

  3. (takeda2024epigeneticregulationof pages 9-11): Yoshimichi Takeda, Masashi Demura, Takashi Yoneda, and Yoshiyu Takeda. Epigenetic regulation of the renin–angiotensin–aldosterone system in hypertension. International Journal of Molecular Sciences, 25:8099, Jul 2024. URL: https://doi.org/10.3390/ijms25158099, doi:10.3390/ijms25158099. This article has 26 citations.

  4. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 3-3): Jonathan Seckl. 11β‐hydroxysteroid dehydrogenase and the brain: not (yet) lost in translation. Journal of Internal Medicine, 295:20-37, Nov 2024. URL: https://doi.org/10.1111/joim.13741, doi:10.1111/joim.13741. This article has 41 citations and is from a domain leading peer-reviewed journal.

  5. (sagmeister2024evaluationof11βhydroxysteroid pages 52-57): MS Sagmeister. Evaluation of 11β-hydroxysteroid dehydrogenase type 1 as a therapeutic target to treat sarcopenia in chronic kidney disease. Unknown journal, 2024.

  6. (cao2023expressionofkey pages 6-7): Jiasong Cao, Y. Wang, Shuqi Wang, Yongmei Shen, Wen Li, Zhuo Wei, Shanshan Li, Qimei Lin, and Ying-Jie Chang. Expression of key steroidogenic enzymes in human placenta and associated adverse pregnancy outcomes. Maternal-Fetal Medicine, 5:163-172, Sep 2023. URL: https://doi.org/10.1097/fm9.0000000000000167, doi:10.1097/fm9.0000000000000167. This article has 8 citations.

  7. (trummer2024steroidprofilesand media 87cb528a): Olivia Trummer, Christina Stern, Sharmaine Reintar, Karoline Mayer-Pickel, Mila Cervar-Zivkovic, Ulrich Dischinger, Max Kurlbaum, Berthold Huppertz, Herbert Fluhr, and Barbara Obermayer-Pietsch. Steroid profiles and precursor-to-product ratios are altered in pregnant women with preeclampsia. International Journal of Molecular Sciences, 25:12704, Nov 2024. URL: https://doi.org/10.3390/ijms252312704, doi:10.3390/ijms252312704. This article has 2 citations.

  8. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 4-5): Jonathan Seckl. 11β‐hydroxysteroid dehydrogenase and the brain: not (yet) lost in translation. Journal of Internal Medicine, 295:20-37, Nov 2024. URL: https://doi.org/10.1111/joim.13741, doi:10.1111/joim.13741. This article has 41 citations and is from a domain leading peer-reviewed journal.

  9. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 5-5): Jonathan Seckl. 11β‐hydroxysteroid dehydrogenase and the brain: not (yet) lost in translation. Journal of Internal Medicine, 295:20-37, Nov 2024. URL: https://doi.org/10.1111/joim.13741, doi:10.1111/joim.13741. This article has 41 citations and is from a domain leading peer-reviewed journal.

  10. (takeda2024epigeneticregulationof pages 15-16): Yoshimichi Takeda, Masashi Demura, Takashi Yoneda, and Yoshiyu Takeda. Epigenetic regulation of the renin–angiotensin–aldosterone system in hypertension. International Journal of Molecular Sciences, 25:8099, Jul 2024. URL: https://doi.org/10.3390/ijms25158099, doi:10.3390/ijms25158099. This article has 26 citations.

  11. (trummer2024steroidprofilesand pages 1-2): Olivia Trummer, Christina Stern, Sharmaine Reintar, Karoline Mayer-Pickel, Mila Cervar-Zivkovic, Ulrich Dischinger, Max Kurlbaum, Berthold Huppertz, Herbert Fluhr, and Barbara Obermayer-Pietsch. Steroid profiles and precursor-to-product ratios are altered in pregnant women with preeclampsia. International Journal of Molecular Sciences, 25:12704, Nov 2024. URL: https://doi.org/10.3390/ijms252312704, doi:10.3390/ijms252312704. This article has 2 citations.

  12. (ding2025casereportclinical pages 1-2): Yuan Ding, Ming Cheng, Bingyan Cao, Min Liu, Xuyun Hu, and Di Wu. Case report: clinical characteristics and genetical analysis of hsd11b2 in three chinese children with apparent mineralocorticoid excess: a case series. Frontiers in Endocrinology, Jan 2025. URL: https://doi.org/10.3389/fendo.2024.1491825, doi:10.3389/fendo.2024.1491825. This article has 2 citations.

  13. (uneda2024analysisofclinical pages 1-2): Kazushi Uneda, Yuki Kawai, Akira Kaneko, Takumi Kayo, Shuichiro Akiba, Tomoaki Ishigami, Hiromi Yoshida-Komiya, Masao Suzuki, and Tadamichi Mitsuma. Analysis of clinical factors associated with kampo formula-induced pseudoaldosteronism based on self-reported information from the japanese adverse drug event report database. PLOS ONE, 19:e0296450, Jan 2024. URL: https://doi.org/10.1371/journal.pone.0296450, doi:10.1371/journal.pone.0296450. This article has 9 citations and is from a peer-reviewed journal.

  14. (takeda2024epigeneticregulationof pages 1-2): Yoshimichi Takeda, Masashi Demura, Takashi Yoneda, and Yoshiyu Takeda. Epigenetic regulation of the renin–angiotensin–aldosterone system in hypertension. International Journal of Molecular Sciences, 25:8099, Jul 2024. URL: https://doi.org/10.3390/ijms25158099, doi:10.3390/ijms25158099. This article has 26 citations.

  15. (trummer2024steroidprofilesand media 4e1233dd): Olivia Trummer, Christina Stern, Sharmaine Reintar, Karoline Mayer-Pickel, Mila Cervar-Zivkovic, Ulrich Dischinger, Max Kurlbaum, Berthold Huppertz, Herbert Fluhr, and Barbara Obermayer-Pietsch. Steroid profiles and precursor-to-product ratios are altered in pregnant women with preeclampsia. International Journal of Molecular Sciences, 25:12704, Nov 2024. URL: https://doi.org/10.3390/ijms252312704, doi:10.3390/ijms252312704. This article has 2 citations.

  16. (trummer2024steroidprofilesand media f8b6c41d): Olivia Trummer, Christina Stern, Sharmaine Reintar, Karoline Mayer-Pickel, Mila Cervar-Zivkovic, Ulrich Dischinger, Max Kurlbaum, Berthold Huppertz, Herbert Fluhr, and Barbara Obermayer-Pietsch. Steroid profiles and precursor-to-product ratios are altered in pregnant women with preeclampsia. International Journal of Molecular Sciences, 25:12704, Nov 2024. URL: https://doi.org/10.3390/ijms252312704, doi:10.3390/ijms252312704. This article has 2 citations.

  17. (cao2023expressionofkey pages 5-6): Jiasong Cao, Y. Wang, Shuqi Wang, Yongmei Shen, Wen Li, Zhuo Wei, Shanshan Li, Qimei Lin, and Ying-Jie Chang. Expression of key steroidogenic enzymes in human placenta and associated adverse pregnancy outcomes. Maternal-Fetal Medicine, 5:163-172, Sep 2023. URL: https://doi.org/10.1097/fm9.0000000000000167, doi:10.1097/fm9.0000000000000167. This article has 8 citations.

  18. (trummer2024steroidprofilesand pages 10-12): Olivia Trummer, Christina Stern, Sharmaine Reintar, Karoline Mayer-Pickel, Mila Cervar-Zivkovic, Ulrich Dischinger, Max Kurlbaum, Berthold Huppertz, Herbert Fluhr, and Barbara Obermayer-Pietsch. Steroid profiles and precursor-to-product ratios are altered in pregnant women with preeclampsia. International Journal of Molecular Sciences, 25:12704, Nov 2024. URL: https://doi.org/10.3390/ijms252312704, doi:10.3390/ijms252312704. This article has 2 citations.

  19. (trummer2024steroidprofilesand pages 9-10): Olivia Trummer, Christina Stern, Sharmaine Reintar, Karoline Mayer-Pickel, Mila Cervar-Zivkovic, Ulrich Dischinger, Max Kurlbaum, Berthold Huppertz, Herbert Fluhr, and Barbara Obermayer-Pietsch. Steroid profiles and precursor-to-product ratios are altered in pregnant women with preeclampsia. International Journal of Molecular Sciences, 25:12704, Nov 2024. URL: https://doi.org/10.3390/ijms252312704, doi:10.3390/ijms252312704. This article has 2 citations.

  20. (ding2025casereportclinical pages 6-7): Yuan Ding, Ming Cheng, Bingyan Cao, Min Liu, Xuyun Hu, and Di Wu. Case report: clinical characteristics and genetical analysis of hsd11b2 in three chinese children with apparent mineralocorticoid excess: a case series. Frontiers in Endocrinology, Jan 2025. URL: https://doi.org/10.3389/fendo.2024.1491825, doi:10.3389/fendo.2024.1491825. This article has 2 citations.

  21. (ding2025casereportclinical pages 5-6): Yuan Ding, Ming Cheng, Bingyan Cao, Min Liu, Xuyun Hu, and Di Wu. Case report: clinical characteristics and genetical analysis of hsd11b2 in three chinese children with apparent mineralocorticoid excess: a case series. Frontiers in Endocrinology, Jan 2025. URL: https://doi.org/10.3389/fendo.2024.1491825, doi:10.3389/fendo.2024.1491825. This article has 2 citations.

  22. (ding2025casereportclinical pages 4-5): Yuan Ding, Ming Cheng, Bingyan Cao, Min Liu, Xuyun Hu, and Di Wu. Case report: clinical characteristics and genetical analysis of hsd11b2 in three chinese children with apparent mineralocorticoid excess: a case series. Frontiers in Endocrinology, Jan 2025. URL: https://doi.org/10.3389/fendo.2024.1491825, doi:10.3389/fendo.2024.1491825. This article has 2 citations.

Artifacts

Citations

  1. ding2025casereportclinical pages 1-2
  2. uneda2024analysisofclinical pages 1-2
  3. trummer2024steroidprofilesand pages 1-2
  4. takeda2024epigeneticregulationof pages 1-2
  5. cao2023expressionofkey pages 6-7
  6. takeda2024epigeneticregulationof pages 9-11
  7. takeda2024epigeneticregulationof pages 15-16
  8. cao2023expressionofkey pages 5-6
  9. trummer2024steroidprofilesand pages 10-12
  10. trummer2024steroidprofilesand pages 9-10
  11. ding2025casereportclinical pages 6-7
  12. ding2025casereportclinical pages 5-6
  13. ding2025casereportclinical pages 4-5
  14. 13.0–25.9
  15. 5.4–12.0
  16. 1.4–21.9
  17. 1.2–2.6
  18. 3.2–7.8
  19. 1.5–3.2
  20. 1.3–4.8
  21. 1.1–2.4
  22. 4.2–11.6
  23. 1.9–2.3
  24. 1.7–4.5
  25. https://doi.org/10.1111/joim.13741
  26. https://doi.org/10.3390/ijms25158099
  27. https://doi.org/10.3390/ijms252312704
  28. https://doi.org/10.3389/fendo.2024.1491825
  29. https://doi.org/10.1371/journal.pone.0296450
  30. https://doi.org/10.1097/fm9.0000000000000167
  31. https://doi.org/10.1111/joim.13741,
  32. https://doi.org/10.3390/ijms25158099,
  33. https://doi.org/10.1097/fm9.0000000000000167,
  34. https://doi.org/10.3390/ijms252312704,
  35. https://doi.org/10.3389/fendo.2024.1491825,
  36. https://doi.org/10.1371/journal.pone.0296450,

📄 View Raw YAML

 
id: P50233
gene_symbol: Hsd11b2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:10116
  label: Rattus norvegicus
description: 'Hsd11b2 encodes NAD-dependent 11beta-hydroxysteroid dehydrogenase type 2, an endoplasmic-reticulum
  enzyme that oxidizes active 11beta-hydroxyglucocorticoids such as corticosterone to inactive 11-keto
  forms. Its core pre-receptor role is to confer aldosterone specificity on the otherwise non-selective
  mineralocorticoid receptor in aldosterone-sensitive epithelia (distal nephron, colon), and to act as
  a placental/fetal barrier limiting fetal glucocorticoid exposure; this is the inactivating dehydrogenase,
  distinct from the reductive Hsd11b1. The review accepts glucocorticoid metabolism and NAD-dependent
  dehydrogenase activity, keeps steroid/NAD binding and renal/placental physiological contexts as non-core,
  and marks stimulus-response expression annotations and Smoothened signaling as over-extensions. Falcon
  (Edison Scientific) deep research corroborates the inactivating NAD-dependent dehydrogenase activity and
  the mineralocorticoid-receptor-protection role.'
existing_annotations:
  - term:
      id: GO:0070523
      label: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity is retained for Hsd11b2 because 
        it matches the documented core enzymatic role or its direct pathway consequence (IBA, 
        GO_REF:0000033).
      action: ACCEPT
      reason: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity is directly supported by the
        curated function of Hsd11b2 and is not merely a downstream phenotype or expression response.
      supported_by:
        - reference_id: UniProtKB:P50233
          supporting_text: 'FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids
            such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone,
            in the presence of NAD(+).'
        - reference_id: file:rat/Hsd11b2/Hsd11b2-deep-research-falcon.md
          supporting_text: |-
            11β‑HSD2 is described as **NAD-dependent/NAD+-dependent**, consistent with SDR-family dehydrogenase directionality in epithelia.
  - term:
      id: GO:0008211
      label: glucocorticoid metabolic process
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: glucocorticoid metabolic process is retained for Hsd11b2 because it matches the 
        documented core enzymatic role or its direct pathway consequence (IBA, GO_REF:0000033).
      action: ACCEPT
      reason: glucocorticoid metabolic process is directly supported by the curated function of
        Hsd11b2 and is not merely a downstream phenotype or expression response.
      supported_by:
        - reference_id: UniProtKB:P50233
          supporting_text: 'FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids
            such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone,
            in the presence of NAD(+).'
        - reference_id: file:rat/Hsd11b2/Hsd11b2-deep-research-falcon.md
          supporting_text: |-
            11β‑HSD2 catalyzes oxidation/inactivation of glucocorticoids: **cortisol→cortisone** and **corticosterone→11‑dehydrocorticosterone**.
  - term:
      id: GO:0005783
      label: endoplasmic reticulum
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: endoplasmic reticulum is retained as contextual support for Hsd11b2, but it is not 
        the core function (IEA, GO_REF:0000044).
      action: KEEP_AS_NON_CORE
      reason: endoplasmic reticulum records localization, cofactor/substrate binding, oligomeric 
        state, or physiological context rather than the defining molecular activity of Hsd11b2.
      supported_by:
        - reference_id: UniProtKB:P50233
          supporting_text: 'FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids
            such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone,
            in the presence of NAD(+).'
  - term:
      id: GO:0034650
      label: cortisol metabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: cortisol metabolic process is an over-annotation for the rat enzyme; it is an
        electronic ortholog transfer from human, where cortisol is the primary substrate (IEA,
        GO_REF:0000107).
      action: MARK_AS_OVER_ANNOTATED
      reason: Rats are a corticosterone-dominated glucocorticoid species, and rat 11beta-HSD2 acts
        principally on corticosterone, not cortisol. GO:0034650 is specific to cortisol
        (11-beta-17,21-trihydroxypregn-4-ene-3,20-dione). This electronic annotation derives from
        ortholog transfer out of the human context, where cortisol is the primary substrate; in the
        rat the relevant glucocorticoid metabolic process is the corticosterone-directed activity
        captured by GO:0008211, so the cortisol-specific term over-annotates the rat gene.
      supported_by:
        - reference_id: UniProtKB:P50233
          supporting_text: 'FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids
            such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone,
            in the presence of NAD(+).'
  - term:
      id: GO:0045880
      label: positive regulation of smoothened signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: positive regulation of smoothened signaling pathway should not be retained for 
        Hsd11b2 based on the combined gene function and cited/source evidence (IEA, GO_REF:0000107).
      action: REMOVE
      reason: The available evidence supports Hsd11b2's curated activity rather than positive 
        regulation of smoothened signaling pathway; this annotation is unsupported, assigned to the 
        wrong biological context, or too misleading to keep as non-core.
      supported_by:
        - reference_id: UniProtKB:P50233
          supporting_text: 'FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids
            such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone,
            in the presence of NAD(+).'
  - term:
      id: GO:0047022
      label: 7-beta-hydroxysteroid dehydrogenase (NADP+) activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 7-beta-hydroxysteroid dehydrogenase (NADP+) activity is an over-annotation for 
        Hsd11b2; Hsd11b2 is an NAD(+)-dependent 11beta-hydroxysteroid oxidase, not a documented 
        NADP(+)-dependent 7-beta dehydrogenase.
      action: MARK_AS_OVER_ANNOTATED
      reason: This activity appears to be an electronic or family-level transfer from related SDR 
        enzymes. UniProtKB:P50233 supports NAD(+)-dependent oxidation of 
        11beta-hydroxyglucocorticoids such as corticosterone; it does not support NADP(+)-dependent 
        7-beta-hydroxysteroid dehydrogenase activity as a genuine secondary function.
      supported_by:
        - reference_id: UniProtKB:P50233
          supporting_text: 'FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids
            such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone,
            in the presence of NAD(+).'
  - term:
      id: GO:0070523
      label: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity is retained for Hsd11b2 because 
        it matches the documented core enzymatic role or its direct pathway consequence (IEA, 
        GO_REF:0000120).
      action: ACCEPT
      reason: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity is directly supported by the 
        curated function of Hsd11b2 and is not merely a downstream phenotype or expression response.
      supported_by:
        - reference_id: UniProtKB:P50233
          supporting_text: 'FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids
            such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone,
            in the presence of NAD(+).'
  - term:
      id: GO:0045880
      label: positive regulation of smoothened signaling pathway
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: positive regulation of smoothened signaling pathway should not be retained for 
        Hsd11b2 based on the combined gene function and cited/source evidence (ISO, GO_REF:0000121).
      action: REMOVE
      reason: The available evidence supports Hsd11b2's curated activity rather than positive 
        regulation of smoothened signaling pathway; this annotation is unsupported, assigned to the 
        wrong biological context, or too misleading to keep as non-core.
      supported_by:
        - reference_id: UniProtKB:P50233
          supporting_text: 'FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids
            such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone,
            in the presence of NAD(+).'
  - term:
      id: GO:0047022
      label: 7-beta-hydroxysteroid dehydrogenase (NADP+) activity
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: 7-beta-hydroxysteroid dehydrogenase (NADP+) activity is an over-annotation for 
        Hsd11b2; Hsd11b2 is an NAD(+)-dependent 11beta-hydroxysteroid oxidase, not a documented 
        NADP(+)-dependent 7-beta dehydrogenase.
      action: MARK_AS_OVER_ANNOTATED
      reason: This activity appears to be an electronic or family-level transfer from related SDR 
        enzymes. UniProtKB:P50233 supports NAD(+)-dependent oxidation of 
        11beta-hydroxyglucocorticoids such as corticosterone; it does not support NADP(+)-dependent 
        7-beta-hydroxysteroid dehydrogenase activity as a genuine secondary function.
      supported_by:
        - reference_id: UniProtKB:P50233
          supporting_text: 'FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids
            such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone,
            in the presence of NAD(+).'
  - term:
      id: GO:0047022
      label: 7-beta-hydroxysteroid dehydrogenase (NADP+) activity
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: 7-beta-hydroxysteroid dehydrogenase (NADP+) activity is an over-annotation for 
        Hsd11b2; Hsd11b2 is an NAD(+)-dependent 11beta-hydroxysteroid oxidase, not a documented 
        NADP(+)-dependent 7-beta dehydrogenase.
      action: MARK_AS_OVER_ANNOTATED
      reason: This activity appears to be an electronic or family-level transfer from related SDR 
        enzymes. UniProtKB:P50233 supports NAD(+)-dependent oxidation of 
        11beta-hydroxyglucocorticoids such as corticosterone; it does not support NADP(+)-dependent 
        7-beta-hydroxysteroid dehydrogenase activity as a genuine secondary function.
      supported_by:
        - reference_id: UniProtKB:P50233
          supporting_text: 'FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids
            such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone,
            in the presence of NAD(+).'
  - term:
      id: GO:0034650
      label: cortisol metabolic process
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: cortisol metabolic process is an over-annotation for the rat enzyme; it is an
        ortholog (ISO) transfer from human, where cortisol is the primary substrate (ISO,
        GO_REF:0000121).
      action: MARK_AS_OVER_ANNOTATED
      reason: Rats are a corticosterone-dominated glucocorticoid species, and rat 11beta-HSD2 acts
        principally on corticosterone, not cortisol. GO:0034650 is specific to cortisol
        (11-beta-17,21-trihydroxypregn-4-ene-3,20-dione). This ISO annotation derives from ortholog
        transfer out of the human context, where cortisol is the primary substrate; in the rat the
        relevant glucocorticoid metabolic process is the corticosterone-directed activity captured
        by GO:0008211, so the cortisol-specific term over-annotates the rat gene.
      supported_by:
        - reference_id: UniProtKB:P50233
          supporting_text: 'FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids
            such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone,
            in the presence of NAD(+).'
  - term:
      id: GO:0070523
      label: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity is retained for Hsd11b2 because 
        it matches the documented core enzymatic role or its direct pathway consequence (ISO, 
        GO_REF:0000121).
      action: ACCEPT
      reason: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity is directly supported by the 
        curated function of Hsd11b2 and is not merely a downstream phenotype or expression response.
      supported_by:
        - reference_id: UniProtKB:P50233
          supporting_text: 'FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids
            such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone,
            in the presence of NAD(+).'
  - term:
      id: GO:0008211
      label: glucocorticoid metabolic process
    evidence_type: IDA
    original_reference_id: PMID:11755176
    review:
      summary: glucocorticoid metabolic process is retained for Hsd11b2 because it matches the 
        documented core enzymatic role or its direct pathway consequence (IDA, PMID:11755176).
      action: ACCEPT
      reason: glucocorticoid metabolic process is directly supported by the curated function of 
        Hsd11b2 and is not merely a downstream phenotype or expression response.
      supported_by:
        - reference_id: PMID:11755176
          supporting_text: Type 2 11betaHSD has only oxidase activity converting corticosterone to
            11-dehydrocorticosterone.
          reference_section_type: ABSTRACT
        - reference_id: file:rat/Hsd11b2/Hsd11b2-deep-research-falcon.md
          supporting_text: |-
            11β‑HSD2 is the inactivating dehydrogenase
          reference_section_type: OTHER
  - term:
      id: GO:0007565
      label: female pregnancy
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: female pregnancy is retained as contextual support for Hsd11b2, but it is not the 
        core function (ISO, GO_REF:0000121).
      action: KEEP_AS_NON_CORE
      reason: female pregnancy records localization, cofactor/substrate binding, oligomeric state, 
        or physiological context rather than the defining molecular activity of Hsd11b2.
      supported_by:
        - reference_id: UniProtKB:P50233
          supporting_text: 'FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids
            such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone,
            in the presence of NAD(+).'
  - term:
      id: GO:0001666
      label: response to hypoxia
    evidence_type: IEP
    original_reference_id: PMID:19470702
    review:
      summary: response to hypoxia reflects an expression, phenotype, or systemic context for 
        Hsd11b2, not a direct core gene-product function (IEP, PMID:19470702).
      action: MARK_AS_OVER_ANNOTATED
      reason: The cited/source evidence links Hsd11b2 to changes in expression or a downstream 
        physiological state; it does not establish Hsd11b2 as an effector of response to hypoxia.
      supported_by:
        - reference_id: PMID:19470702
          supporting_text: We first demonstrated that adaptation to CIH led to a significant 
            increase in 11HSD2 transcript levels and activity in the myocardium.
          reference_section_type: ABSTRACT
  - term:
      id: GO:0007565
      label: female pregnancy
    evidence_type: IEP
    original_reference_id: PMID:19050325
    review:
      summary: female pregnancy is retained as contextual support for Hsd11b2, but it is not the 
        core function (IEP, PMID:19050325).
      action: KEEP_AS_NON_CORE
      reason: female pregnancy records localization, cofactor/substrate binding, oligomeric state, 
        or physiological context rather than the defining molecular activity of Hsd11b2.
      supported_by:
        - reference_id: PMID:19050325
          supporting_text: The final third of gestation is accompanied by reciprocal changes in
            placental and fetal metabolism of corticosterone due to changes in 11HSD1 and 11HSD2.
          reference_section_type: ABSTRACT
        - reference_id: file:rat/Hsd11b2/Hsd11b2-deep-research-falcon.md
          supporting_text: |-
            11β‑HSD2 is highly expressed in **placenta and fetal tissues** where it **minimizes fetal exposure to maternal glucocorticoids**
          reference_section_type: OTHER
  - term:
      id: GO:0009410
      label: response to xenobiotic stimulus
    evidence_type: IEP
    original_reference_id: PMID:10792625
    review:
      summary: response to xenobiotic stimulus reflects an expression, phenotype, or systemic 
        context for Hsd11b2, not a direct core gene-product function (IEP, PMID:10792625).
      action: MARK_AS_OVER_ANNOTATED
      reason: The cited/source evidence links Hsd11b2 to changes in expression or a downstream 
        physiological state; it does not establish Hsd11b2 as an effector of response to xenobiotic 
        stimulus.
      supported_by:
        - reference_id: PMID:10792625
          supporting_text: Four weeks after an injection of STZ, the renal 11beta-HSD2 and mRNA 
            levels were significantly lower in diabetic rats than in control rats, and the mean 
            systolic blood pressure was 14.8% higher in diabetic rats than in controls.
          reference_section_type: ABSTRACT
  - term:
      id: GO:0032094
      label: response to food
    evidence_type: IEP
    original_reference_id: PMID:18548384
    review:
      summary: response to food reflects an expression, phenotype, or systemic context for Hsd11b2, 
        not a direct core gene-product function (IEP, PMID:18548384).
      action: MARK_AS_OVER_ANNOTATED
      reason: The cited/source evidence links Hsd11b2 to changes in expression or a downstream 
        physiological state; it does not establish Hsd11b2 as an effector of response to food.
      supported_by:
        - reference_id: PMID:18548384
          supporting_text: This study demonstrated that maternal food restriction has both long-term
            and tissue-specific effects on gene expression of factors involved in glucocorticoid 
            sensitivity.
          reference_section_type: ABSTRACT
  - term:
      id: GO:0032868
      label: response to insulin
    evidence_type: IEP
    original_reference_id: PMID:9495277
    review:
      summary: response to insulin reflects an expression, phenotype, or systemic context for 
        Hsd11b2, not a direct core gene-product function (IEP, PMID:9495277).
      action: MARK_AS_OVER_ANNOTATED
      reason: The cited/source evidence links Hsd11b2 to changes in expression or a downstream 
        physiological state; it does not establish Hsd11b2 as an effector of response to insulin.
      supported_by:
        - reference_id: PMID:9495277
          supporting_text: The renal 11beta-HSD2 activity and level of mRNA expression were 
            significantly decreased in diabetic rats.
          reference_section_type: ABSTRACT
  - term:
      id: GO:0048545
      label: response to steroid hormone
    evidence_type: IEP
    original_reference_id: PMID:18032797
    review:
      summary: response to steroid hormone reflects an expression, phenotype, or systemic context 
        for Hsd11b2, not a direct core gene-product function (IEP, PMID:18032797).
      action: MARK_AS_OVER_ANNOTATED
      reason: The cited/source evidence links Hsd11b2 to changes in expression or a downstream 
        physiological state; it does not establish Hsd11b2 as an effector of response to steroid 
        hormone.
      supported_by:
        - reference_id: PMID:18032797
          supporting_text: DHEA treatment markedly increased mRNA expression and activity of 
            11beta-HSD2 in a rat cortical collecting duct cell line and in kidneys of C57BL/6J mice 
            and Sprague-Dawley rats.
          reference_section_type: ABSTRACT
  - term:
      id: GO:0051384
      label: response to glucocorticoid
    evidence_type: IEP
    original_reference_id: PMID:19490994
    review:
      summary: response to glucocorticoid reflects an expression, phenotype, or systemic context for
        Hsd11b2, not a direct core gene-product function (IEP, PMID:19490994).
      action: MARK_AS_OVER_ANNOTATED
      reason: The cited/source evidence links Hsd11b2 to changes in expression or a downstream 
        physiological state; it does not establish Hsd11b2 as an effector of response to 
        glucocorticoid.
      supported_by:
        - reference_id: PMID:19490994
          supporting_text: Placental 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) is 
            the key enzyme which protects the fetus from overexposure to glucocorticoids (GCs) by 
            their oxidation into inactive derivates.
          reference_section_type: ABSTRACT
  - term:
      id: GO:0002017
      label: regulation of blood volume by renal aldosterone
    evidence_type: IMP
    original_reference_id: PMID:15718388
    review:
      summary: regulation of blood volume by renal aldosterone is retained as contextual support for
        Hsd11b2, but it is not the core function (IMP, PMID:15718388).
      action: KEEP_AS_NON_CORE
      reason: regulation of blood volume by renal aldosterone records localization, 
        cofactor/substrate binding, oligomeric state, or physiological context rather than the 
        defining molecular activity of Hsd11b2.
      supported_by:
        - reference_id: PMID:15718388
          supporting_text: These data indicate that COX-2 plays a modulating role in the development
            of hypertension due to 11betaHSD2 deficiency and that 11betaHSD2 regulates renal COX-2
            expression by preventing glucocorticoid access to MRs during postnatal development.
          reference_section_type: ABSTRACT
        - reference_id: file:rat/Hsd11b2/Hsd11b2-deep-research-falcon.md
          supporting_text: |-
            11β‑HSD2 enables aldosterone-specific MR signaling** in target cells by locally removing active glucocorticoids.
          reference_section_type: OTHER
  - term:
      id: GO:0005496
      label: steroid binding
    evidence_type: IPI
    original_reference_id: PMID:15761036
    review:
      summary: steroid binding is retained as contextual support for Hsd11b2, but it is not the core
        function (IPI, PMID:15761036).
      action: KEEP_AS_NON_CORE
      reason: steroid binding records localization, cofactor/substrate binding, oligomeric state, or
        physiological context rather than the defining molecular activity of Hsd11b2.
      supported_by:
        - reference_id: PMID:15761036
          supporting_text: the high-affinity, low-capacity 11beta HSD2 isoform, present at only one
            thousandth the level of the low-affinity isoform may significantly affect the level of
            CORT
          reference_section_type: ABSTRACT
  - term:
      id: GO:0051287
      label: NAD binding
    evidence_type: IDA
    original_reference_id: PMID:15761036
    review:
      summary: NAD binding is retained as contextual support for Hsd11b2, but it is not the core 
        function (IDA, PMID:15761036).
      action: KEEP_AS_NON_CORE
      reason: NAD binding records localization, cofactor/substrate binding, oligomeric state, or
        physiological context rather than the defining molecular activity of Hsd11b2.
      supported_by:
        - reference_id: PMID:15761036
          supporting_text: the nicotinamide adenine dinucleotide-dependent 11beta HSD2 high-affinity
            unidirectional oxidase
          reference_section_type: ABSTRACT
  - term:
      id: GO:0008211
      label: glucocorticoid metabolic process
    evidence_type: IDA
    original_reference_id: PMID:16763064
    review:
      summary: glucocorticoid metabolic process is retained for Hsd11b2 because it matches the 
        documented core enzymatic role or its direct pathway consequence (IDA, PMID:16763064).
      action: ACCEPT
      reason: glucocorticoid metabolic process is directly supported by the curated function of 
        Hsd11b2 and is not merely a downstream phenotype or expression response.
      supported_by:
        - reference_id: PMID:16763064
          supporting_text: 11 beta-Hydroxysteroid-dehydrogenase type 2 (HSD2), an enzyme that 
            inactivates glucocorticoids, was strongly expressed and active in quiescent SC.
          reference_section_type: ABSTRACT
references:
  - id: GO_REF:0000024
    title: GO reference used by source annotation pipeline
    findings:
      - statement: Source annotation pipeline provenance for Hsd11b2 annotations including 
          7-beta-hydroxysteroid dehydrogenase (NADP+) activity.
        supporting_text: GO_REF entry used only to trace source annotation method; biological 
          support was assessed from UniProt and cached literature where available.
        reference_section_type: TITLE
  - id: GO_REF:0000033
    title: GO reference used by source annotation pipeline
    findings:
      - statement: Source annotation pipeline provenance for Hsd11b2 annotations including 
          11-beta-hydroxysteroid dehydrogenase (NAD+) activity; glucocorticoid metabolic process.
        supporting_text: GO_REF entry used only to trace source annotation method; biological 
          support was assessed from UniProt and cached literature where available.
        reference_section_type: TITLE
  - id: GO_REF:0000044
    title: GO reference used by source annotation pipeline
    findings:
      - statement: Source annotation pipeline provenance for Hsd11b2 annotations including 
          endoplasmic reticulum.
        supporting_text: GO_REF entry used only to trace source annotation method; biological 
          support was assessed from UniProt and cached literature where available.
        reference_section_type: TITLE
  - id: GO_REF:0000107
    title: GO reference used by source annotation pipeline
    findings:
      - statement: Source annotation pipeline provenance for Hsd11b2 annotations including cortisol 
          metabolic process; positive regulation of smoothened signaling pathway.
        supporting_text: GO_REF entry used only to trace source annotation method; biological 
          support was assessed from UniProt and cached literature where available.
        reference_section_type: TITLE
  - id: GO_REF:0000120
    title: GO reference used by source annotation pipeline
    findings:
      - statement: Source annotation pipeline provenance for Hsd11b2 annotations including 
          11-beta-hydroxysteroid dehydrogenase (NAD+) activity; 7-beta-hydroxysteroid dehydrogenase 
          (NADP+) activity.
        supporting_text: GO_REF entry used only to trace source annotation method; biological 
          support was assessed from UniProt and cached literature where available.
        reference_section_type: TITLE
  - id: GO_REF:0000121
    title: GO reference used by source annotation pipeline
    findings:
      - statement: Source annotation pipeline provenance for Hsd11b2 annotations including 
          11-beta-hydroxysteroid dehydrogenase (NAD+) activity; 7-beta-hydroxysteroid dehydrogenase 
          (NADP+) activity; cortisol metabolic process; female pregnancy; positive regulation of 
          smoothened signaling pathway.
        supporting_text: GO_REF entry used only to trace source annotation method; biological 
          support was assessed from UniProt and cached literature where available.
        reference_section_type: TITLE
  - id: PMID:9495277
    title: Gene expression of 11beta-hydroxysteroid dehydrogenase type 1 and type 2 in the kidneys 
      of insulin-dependent diabetic rats.
    findings:
      - statement: For Hsd11b2, this publication was assessed for annotations including response to 
          insulin.
        supporting_text: The renal 11beta-HSD2 activity and level of mRNA expression were 
          significantly decreased in diabetic rats.
        reference_section_type: ABSTRACT
  - id: PMID:10792625
    title: Effects of spironolactone on systolic blood pressure in experimental diabetic rats.
    findings:
      - statement: For Hsd11b2, this publication was assessed for annotations including response to 
          xenobiotic stimulus.
        supporting_text: Four weeks after an injection of STZ, the renal 11beta-HSD2 and mRNA levels
          were significantly lower in diabetic rats than in control rats, and the mean systolic 
          blood pressure was 14.8% higher in diabetic rats than in controls.
        reference_section_type: ABSTRACT
  - id: PMID:11755176
    title: Effect of cellular differentiation on 11beta-hydroxysteroid dehydrogenase activity in the
      intestine.
    findings:
      - statement: For Hsd11b2, this publication was assessed for annotations including 
          glucocorticoid metabolic process.
        supporting_text: Type 2 11betaHSD has only oxidase activity converting corticosterone to 
          11-dehydrocorticosterone.
        reference_section_type: ABSTRACT
  - id: PMID:15718388
    title: Interactions between 11beta-hydroxysteroid dehydrogenase and COX-2 in kidney.
    findings:
      - statement: For Hsd11b2, this publication was assessed for annotations including regulation 
          of blood volume by renal aldosterone.
        supporting_text: These data indicate that COX-2 plays a modulating role in the development 
          of hypertension due to 11betaHSD2 deficiency and that 11betaHSD2 regulates renal COX-2 
          expression by preventing glucocorticoid access to MRs during postnatal development.
        reference_section_type: ABSTRACT
  - id: PMID:15761036
    title: '11{beta}-Hydroxysteroid dehydrogenase 2 in rat leydig cells: its role in blunting glucocorticoid
      action at physiological levels of substrate.'
    findings:
      - statement: For Hsd11b2, this publication was assessed for annotations including NAD binding;
          steroid binding.
        supporting_text: We showed that 11beta HSD2 is present in rat Leydig cells by PCR 
          amplification, immunohistochemical staining, enzyme histochemistry, immunoprecipitation, 
          and Western blotting.
        reference_section_type: ABSTRACT
  - id: PMID:16763064
    title: Expression and functional state of the corticosteroid receptors and 11 
      beta-hydroxysteroid dehydrogenase type 2 in Schwann cells.
    findings:
      - statement: For Hsd11b2, this publication was assessed for annotations including 
          glucocorticoid metabolic process.
        supporting_text: 11 beta-Hydroxysteroid-dehydrogenase type 2 (HSD2), an enzyme that 
          inactivates glucocorticoids, was strongly expressed and active in quiescent SC.
        reference_section_type: ABSTRACT
  - id: PMID:18032797
    title: DHEA induces 11 -HSD2 by acting on CCAAT/enhancer-binding proteins.
    findings:
      - statement: For Hsd11b2, this publication was assessed for annotations including response to 
          steroid hormone.
        supporting_text: DHEA treatment markedly increased mRNA expression and activity of 
          11beta-HSD2 in a rat cortical collecting duct cell line and in kidneys of C57BL/6J mice 
          and Sprague-Dawley rats.
        reference_section_type: ABSTRACT
  - id: PMID:18548384
    title: Tissue-specific programming expression of glucocorticoid receptors and 11 beta-HSDs by 
      maternal perinatal undernutrition in the HPA axis of adult male rats.
    findings:
      - statement: For Hsd11b2, this publication was assessed for annotations including response to 
          food.
        supporting_text: This study demonstrated that maternal food restriction has both long-term 
          and tissue-specific effects on gene expression of factors involved in glucocorticoid 
          sensitivity.
        reference_section_type: ABSTRACT
  - id: PMID:19050325
    title: Reciprocal changes in maternal and fetal metabolism of corticosterone in rat during 
      gestation.
    findings:
      - statement: For Hsd11b2, this publication was assessed for annotations including female 
          pregnancy.
        supporting_text: The final third of gestation is accompanied by reciprocal changes in 
          placental and fetal metabolism of corticosterone due to changes in 11HSD1 and 11HSD2.
        reference_section_type: ABSTRACT
  - id: PMID:19470702
    title: Chronic intermittent hypoxia induces 11beta-hydroxysteroid dehydrogenase in rat heart.
    findings:
      - statement: For Hsd11b2, this publication was assessed for annotations including response to 
          hypoxia.
        supporting_text: We first demonstrated that adaptation to CIH led to a significant increase 
          in 11HSD2 transcript levels and activity in the myocardium.
        reference_section_type: ABSTRACT
  - id: PMID:19490994
    title: Dexamethasone and betamethasone administration during pregnancy affects expression and 
      function of 11 beta-hydroxysteroid dehydrogenase type 2 in the rat placenta.
    findings:
      - statement: For Hsd11b2, this publication was assessed for annotations including response to 
          glucocorticoid.
        supporting_text: Placental 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) is the
          key enzyme which protects the fetus from overexposure to glucocorticoids (GCs) by their
          oxidation into inactive derivates.
        reference_section_type: ABSTRACT
  - id: file:rat/Hsd11b2/Hsd11b2-deep-research-falcon.md
    title: 'Falcon (Edison Scientific) deep research report: rat Hsd11b2 (11-beta-hydroxysteroid
      dehydrogenase type 2, UniProt P50233)'
    findings:
      - statement: 11beta-HSD2 is the inactivating (oxidative) member of the 11beta-HSD pair,
          distinct from the reductive 11beta-HSD1.
        supporting_text: |-
          11β‑HSD2 is the inactivating dehydrogenase
        reference_section_type: OTHER
      - statement: The catalyzed reaction is the oxidation/inactivation of active glucocorticoids
          to their inert 11-keto forms.
        supporting_text: |-
          11β‑HSD2 catalyzes oxidation/inactivation of glucocorticoids: **cortisol→cortisone** and **corticosterone→11‑dehydrocorticosterone**.
        reference_section_type: OTHER
      - statement: The enzyme uses NAD(+) as cofactor, consistent with SDR-family oxidative
          directionality in epithelia.
        supporting_text: |-
          11β‑HSD2 is described as **NAD-dependent/NAD+-dependent**, consistent with SDR-family dehydrogenase directionality in epithelia.
        reference_section_type: OTHER
      - statement: By locally removing active glucocorticoids the enzyme confers aldosterone
          specificity on the otherwise non-selective mineralocorticoid receptor.
        supporting_text: |-
          11β‑HSD2 enables aldosterone-specific MR signaling** in target cells by locally removing active glucocorticoids.
        reference_section_type: OTHER
      - statement: Glucocorticoids circulate far in excess of aldosterone; the enzyme prevents
          them occupying MR while aldosterone, not a substrate, signals through MR.
        supporting_text: |-
          aldosterone is not a substrate and can therefore signal through MR.
        reference_section_type: OTHER
      - statement: Canonical sites of action are the classic aldosterone-sensitive epithelia.
        supporting_text: |-
          Canonical sites include **distal nephron/kidney**, **colon**, **salivary glands**, and **sweat glands**
        reference_section_type: OTHER
      - statement: The enzyme acts as a placental/fetal barrier limiting fetal exposure to
          maternal glucocorticoids.
        supporting_text: |-
          11β‑HSD2 is highly expressed in **placenta and fetal tissues** where it **minimizes fetal exposure to maternal glucocorticoids**
        reference_section_type: OTHER
      - statement: In adult rodent CNS the enzyme is restricted to discrete hindbrain regions
          supporting aldosterone-specific control of salt appetite and blood pressure.
        supporting_text: |-
          nucleus of the solitary tract** and **subcommissural organ**, where 11β-HSD2 supports aldosterone-specific control of **salt appetite** and influences **blood pressure**.
        reference_section_type: OTHER
      - statement: Loss of enzyme function causes apparent mineralocorticoid excess (AME),
          underscoring its physiological role.
        supporting_text: |-
          Loss of 11β‑HSD2 function causes **AME**
        reference_section_type: OTHER
core_functions:
  - description: Hsd11b2 inactivates active glucocorticoids through NAD-dependent
      11beta-hydroxysteroid dehydrogenase activity, oxidizing corticosterone (and cortisol
      in species that produce it) to inactive 11-keto forms and thereby conferring aldosterone
      specificity on the mineralocorticoid receptor.
    supported_by:
      - reference_id: UniProtKB:P50233
        supporting_text: 'FUNCTION: Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids
          such as corticosterone to inactive 11-ketoglucocorticoids such as 11-dehydrocorticosterone,
          in the presence of NAD(+).'
      - reference_id: file:rat/Hsd11b2/Hsd11b2-deep-research-falcon.md
        supporting_text: |-
          11β‑HSD2 catalyzes oxidation/inactivation of glucocorticoids: **cortisol→cortisone** and **corticosterone→11‑dehydrocorticosterone**.
      - reference_id: file:rat/Hsd11b2/Hsd11b2-deep-research-falcon.md
        supporting_text: |-
          11β‑HSD2 enables aldosterone-specific MR signaling** in target cells by locally removing active glucocorticoids.
    molecular_function:
      id: GO:0070523
      label: 11-beta-hydroxysteroid dehydrogenase (NAD+) activity
    directly_involved_in:
      - id: GO:0008211
        label: glucocorticoid metabolic process