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.
| 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 11ฮฒโHSD2 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 11ฮฒโHSD2 catalyzes oxidation/inactivation of glucocorticoids: **cortisolโcortisone** and **corticosteroneโ11โdehydrocorticosterone**. |
| 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. Propagation Review Root cause: PROPAGATION BAD Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:104720 ยท mouse Hsd11b2 SUPPORTS SOURCE BUT NOT TARGET Mouse donor annotation links Hsd11b2 to smoothened-pathway readouts; any such effect is indirect, via glucocorticoid inactivation, not a direct pathway-component role, so it does not transfer as a rat 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 | 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. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE Sources checked: MGI:MGI:104720 ยท mouse Hsd11b2 SOURCE WEAK OR INFERRED The mouse donor annotation appears to be a family-level SDR transfer rather than a direct demonstration of NADP(+)-dependent 7-beta-HSD activity; rat Hsd11b2 is an NAD(+)-dependent 11beta-dehydrogenase, so the secondary activity is not supported. 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. Propagation Review Root cause: PROPAGATION BAD Failure modes: LINEAGE OR TAXON MISMATCH CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P80365 ยท human HSD11B2 SUPPORTS SOURCE BUT NOT TARGET Human HSD11B2 donor annotation is correct in its own context (cortisol is the primary human glucocorticoid), but rats are corticosterone-dominated, so the cortisol-specific process does not transfer. 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 11ฮฒโHSD2 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 11ฮฒโHSD2 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 11ฮฒโHSD2 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. |
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