HSD11B1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006706 steroid catabolic process	IBA GO_REF:0000033	MODIFY	Summary: Phylogenetically-inferred biological process. HSD11B1 does participate in steroid metabolism, but its predominant physiological role is reductive activation of glucocorticoids (cortisone to cortisol), i.e. metabolism/interconversion rather than catabolism. The catabolic framing fits some oxidative or oxysterol reactions but is imprecise for the core function. Reason: Steroid catabolic process mischaracterizes the core in-vivo activity, which is reductive regeneration of active cortisol (a glucocorticoid metabolic/interconversion process), not steroid breakdown. Generalize/re-target to glucocorticoid metabolic process, which correctly covers the bidirectional interconversion of active and inactive glucocorticoids. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: glucocorticoid metabolic process Supporting Evidence: file:human/HSD11B1/HSD11B1-uniprot.txt functions as a reductase in vivo, thereby increasing the concentration file:human/HSD11B1/HSD11B1-uniprot.txt of active glucocorticoids
GO:0005789 endoplasmic reticulum membrane	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically-inferred localization to the ER membrane, consistent with direct experimental evidence that 11beta-HSD1 is an ER-membrane protein with its catalytic domain in the ER lumen. This is the core cellular location where the enzyme acts. Reason: Well supported by experimental localization data; the enzyme is active in the ER membrane (lumen-facing catalytic domain). Supporting Evidence: PMID:10497248 localization of both 11beta-HSD1 and PMID:10497248 the catalytic domain containing the C terminus is protruding into the ER
GO:0070524 11-beta-hydroxysteroid dehydrogenase (NADP+) activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically-inferred core molecular function. This is the defining catalytic activity of HSD11B1, corroborated by numerous experimental (IDA) annotations and the UniProt catalytic-activity record (EC 1.1.1.146; 11beta-hydroxysteroid + NADP(+) = 11-oxosteroid + NADPH). This is the core molecular function. Reason: Definitive, well-supported core enzymatic activity of the gene product. Supporting Evidence: PMID:15513927 ER-localized membrane protein that catalyzes the interconversion of cortisone file:human/HSD11B1/HSD11B1-uniprot.txt Reaction=cortisone + NADPH + H(+) = cortisol + NADP(+);
GO:0005496 steroid binding	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetically-inferred steroid binding, reflecting the enzyme's binding of steroid substrates (glucocorticoids and other steroid/sterol substrates) in its active site. This is a real but generic molecular function that is subsidiary to the catalytic activity. Reason: Substrate binding is genuine but is an aspect of the catalytic mechanism rather than an independent core function; the informative core MF is the dehydrogenase activity. Supporting Evidence: file:human/HSD11B1/HSD11B1-uniprot.txt besides glucocorticoids, it accepts other steroid and sterol substrates
GO:0004090 carbonyl reductase (NADPH) activity	IEA GO_REF:0000116	MARK AS OVER ANNOTATED	Summary: RHEA-based electronic annotation. HSD11B1 does perform NADPH-dependent carbonyl (oxo) reductions on several substrates (e.g. 7-oxo bile acids, oxysterols), so the term is not wrong, but it is a broad generic parent that is far less informative than the specific 11-beta-hydroxysteroid dehydrogenase and cortisol dehydrogenase activities. Reason: Correct in essence (NADPH-dependent carbonyl reduction occurs) but overly general; the specific dehydrogenase activities better describe the function. Supporting Evidence: file:human/HSD11B1/HSD11B1-uniprot.txt Reaction=cortisone + NADPH + H(+) = cortisol + NADP(+);
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: Electronic annotation from the UniProt Subcellular Location vocabulary mapping, consistent with experimental evidence that 11beta-HSD1 is an ER-membrane protein. Reason: Correct core localization, agreeing with experimental (IDA) and phylogenetic (IBA) evidence. Supporting Evidence: file:human/HSD11B1/HSD11B1-uniprot.txt Endoplasmic reticulum membrane file:human/HSD11B1/HSD11B1-uniprot.txt type II membrane protein
GO:0047022 7-beta-hydroxysteroid dehydrogenase (NADP+) activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation (EC 1.1.1.201). HSD11B1 has documented 7-oxosteroid reductase / 7beta-hydroxysteroid dehydrogenase activity, interconverting 7-oxo and 7beta-hydroxy sterols/bile acids/neurosteroids (e.g. 7-ketocholesterol to 7beta-hydroxycholesterol). This is a real secondary catalytic activity of the enzyme. Reason: EC-backed secondary activity supported by the UniProt catalytic-activity record and by experimental oxysterol/bile-acid studies; a genuine additional molecular function. Supporting Evidence: file:human/HSD11B1/HSD11B1-uniprot.txt a 7beta-hydroxysteroid + NADP(+) = a 7-oxosteroid + NADPH + PMID:15152005 potential role in 7-ketocholesterol metabolism.
GO:0070524 11-beta-hydroxysteroid dehydrogenase (NADP+) activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation (EC 1.1.1.146) for the core 11beta-HSD activity. Duplicates the IBA and IDA annotations of the same term and is fully supported. Reason: Correct core molecular function; duplicate of the experimentally and phylogenetically supported term. Supporting Evidence: file:human/HSD11B1/HSD11B1-uniprot.txt Reaction=cortisone + NADPH + H(+) = cortisol + NADP(+);
GO:0102196 cortisol dehydrogenase (NADP+) activity	IEA GO_REF:0000116	ACCEPT	Summary: RHEA-based electronic annotation (RHEA:68616, cortisone + NADPH = cortisol + NADP(+)) capturing the physiologically dominant reductive reaction of HSD11B1, the regeneration of active cortisol from cortisone. This is a specific and accurate representation of the core in-vivo function. Reason: Specific, biologically accurate term for the enzyme's predominant in-vivo reductase reaction (cortisone to cortisol); complements the broader 11beta-HSD activity term. Supporting Evidence: file:human/HSD11B1/HSD11B1-uniprot.txt Reaction=cortisone + NADPH + H(+) = cortisol + NADP(+); PMID:15513927 ER-localized membrane protein that catalyzes the interconversion of cortisone
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-194023	ACCEPT	Summary: Reactome-asserted ER-membrane localization for the HSD11B1-containing reaction. Consistent with all other localization evidence for this enzyme. Reason: Correct core localization, supported by experimental and phylogenetic evidence. Supporting Evidence: PMID:10497248 localization of both 11beta-HSD1 and
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-9757706	ACCEPT	Summary: Reactome-asserted ER-membrane localization for a hepatic HSD11B1 reaction (prednisone to prednisolone reduction). Consistent with all other localization evidence. Reason: Correct core localization, supported by experimental and phylogenetic evidence. Supporting Evidence: PMID:10497248 the catalytic domain containing the C terminus is protruding into the ER
GO:0005789 endoplasmic reticulum membrane	IDA PMID:10497248 The N-terminal anchor sequences of 11beta-hydroxysteroid deh...	ACCEPT	Summary: Direct experimental evidence (fluorescence microscopy and protease-protection assays) localizing 11beta-HSD1 to the ER membrane, with the catalytic C-terminal domain protruding into the ER lumen and the N-terminus cytoplasmic (single-pass type II membrane topology). This anchors the core localization. Reason: High-quality direct experimental evidence for the core ER-membrane localization. Supporting Evidence: PMID:10497248 the N terminus of 11beta-HSD1 is cytoplasmic, PMID:10497248 the catalytic domain containing the C terminus is protruding into the ER
GO:0042803 protein homodimerization activity	IDA PMID:15513927 Conformational flexibility in crystal structures of human 11...	ACCEPT	Summary: Crystallographic evidence that human 11beta-HSD1 assembles as a homo-oligomer; the structures show the C-termini of subunits converging to form an oligomerization motif. UniProt records the enzyme as a homodimer. The homodimerization is genuine but is a structural/quaternary property rather than the informative core molecular function. Reason: Homodimerization is directly demonstrated by crystal structures and recorded by UniProt; a real molecular property, kept but not the core catalytic function. Supporting Evidence: PMID:15513927 four 11beta-HSD1 C termini converge to form an as yet file:human/HSD11B1/HSD11B1-uniprot.txt SUBUNIT: Homodimer.
GO:0042803 protein homodimerization activity	IDA PMID:17919905 The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibit...	ACCEPT	Summary: X-ray co-crystal structure of 11beta-HSD1 (in complex with NADP and an inhibitor) supporting the oligomeric assembly of the enzyme. Consistent with the UniProt homodimer annotation. Reason: Structural evidence supports homodimerization; genuine quaternary structure, retained as a non-core property. Supporting Evidence: PMID:17919905 The binding mode was determined through the X-ray co-crystal file:human/HSD11B1/HSD11B1-uniprot.txt SUBUNIT: Homodimer.
GO:0042803 protein homodimerization activity	IDA PMID:18069989 Structural characterization and pharmacodynamic effects of a...	ACCEPT	Summary: X-ray crystallographic characterization of an orally active 11beta-HSD1 inhibitor complex, contributing structural support for the homodimeric assembly of the enzyme, as recorded by UniProt. Reason: Structural evidence supports homodimerization; retained as a real non-core property. Supporting Evidence: file:human/HSD11B1/HSD11B1-uniprot.txt SUBUNIT: Homodimer.
GO:0042803 protein homodimerization activity	IDA PMID:18485702 Pyridine amides as potent and selective inhibitors of 11beta...	ACCEPT	Summary: X-ray crystal structure of 11beta-HSD1 in complex with NADP and an inhibitor, contributing structural evidence consistent with the homodimeric assembly recorded by UniProt. Reason: Structural evidence supports homodimerization; retained as a real non-core property. Supporting Evidence: file:human/HSD11B1/HSD11B1-uniprot.txt SUBUNIT: Homodimer.
GO:0042803 protein homodimerization activity	IDA PMID:18553955 Discovery of novel, potent benzamide inhibitors of 11beta-hy...	ACCEPT	Summary: Crystallographic study of benzamide inhibitor complexes of 11beta-HSD1, contributing structural support for the enzyme's homodimeric assembly recorded by UniProt. Reason: Structural evidence supports homodimerization; retained as a real non-core property. Supporting Evidence: file:human/HSD11B1/HSD11B1-uniprot.txt SUBUNIT: Homodimer.
GO:0042803 protein homodimerization activity	IDA PMID:19217779 Discovery and optimization of piperidyl benzamide derivative...	ACCEPT	Summary: Crystallographic study of piperidyl benzamide inhibitor complexes of 11beta-HSD1, contributing structural support for the enzyme's homodimeric assembly recorded by UniProt. Reason: Structural evidence supports homodimerization; retained as a real non-core property. Supporting Evidence: file:human/HSD11B1/HSD11B1-uniprot.txt SUBUNIT: Homodimer.
GO:0050661 NADP binding	IDA PMID:15513927 Conformational flexibility in crystal structures of human 11...	KEEP AS NON CORE	Summary: NADP(H) is the obligate cofactor of 11beta-HSD1, and crystal structures were solved as ternary complexes containing NADP. NADP binding is a genuine molecular function but is a cofactor-binding aspect of the catalytic mechanism rather than the informative core MF. Reason: Cofactor binding is real and structurally demonstrated but subsidiary to the dehydrogenase activity, which is the core function. Supporting Evidence: PMID:15513927 two ternary complexes of 11beta-HSD1 file:human/HSD11B1/HSD11B1-uniprot.txt cosubstrate NADPH
GO:0050661 NADP binding	IDA PMID:17919905 The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibit...	KEEP AS NON CORE	Summary: X-ray co-crystal structure with NADP demonstrating cofactor binding. Genuine but subsidiary to the core dehydrogenase activity. Reason: Structurally demonstrated cofactor binding, retained as a non-core molecular function. Supporting Evidence: PMID:17919905 The binding mode was determined through the X-ray co-crystal
GO:0050661 NADP binding	IDA PMID:18069989 Structural characterization and pharmacodynamic effects of a...	KEEP AS NON CORE	Summary: Structural characterization of an 11beta-HSD1 complex demonstrating NADP cofactor binding. Genuine but subsidiary to the core dehydrogenase activity. Reason: Structurally demonstrated cofactor binding, retained as a non-core molecular function. Supporting Evidence: file:human/HSD11B1/HSD11B1-uniprot.txt cosubstrate NADPH
GO:0050661 NADP binding	IDA PMID:18485702 Pyridine amides as potent and selective inhibitors of 11beta...	KEEP AS NON CORE	Summary: Crystal structure of 11beta-HSD1 in complex with NADP demonstrating cofactor binding. Genuine but subsidiary to the core dehydrogenase activity. Reason: Structurally demonstrated cofactor binding, retained as a non-core molecular function. Supporting Evidence: file:human/HSD11B1/HSD11B1-uniprot.txt cosubstrate NADPH
GO:0050661 NADP binding	IDA PMID:18553955 Discovery of novel, potent benzamide inhibitors of 11beta-hy...	KEEP AS NON CORE	Summary: Crystallographic evidence of NADP cofactor binding by 11beta-HSD1. Genuine but subsidiary to the core dehydrogenase activity. Reason: Structurally demonstrated cofactor binding, retained as a non-core molecular function. Supporting Evidence: file:human/HSD11B1/HSD11B1-uniprot.txt cosubstrate NADPH
GO:0050661 NADP binding	IDA PMID:19217779 Discovery and optimization of piperidyl benzamide derivative...	KEEP AS NON CORE	Summary: Crystallographic evidence of NADP cofactor binding by 11beta-HSD1. Genuine but subsidiary to the core dehydrogenase activity. Reason: Structurally demonstrated cofactor binding, retained as a non-core molecular function. Supporting Evidence: file:human/HSD11B1/HSD11B1-uniprot.txt cosubstrate NADPH
GO:0070524 11-beta-hydroxysteroid dehydrogenase (NADP+) activity	IDA PMID:10497248 The N-terminal anchor sequences of 11beta-hydroxysteroid deh...	ACCEPT	Summary: Direct experimental measurement of 11beta-HSD1 enzymatic activity (glucocorticoid interconversion with defined kinetics for corticosterone and 11-dehydrocorticosterone) in the study that also established ER-membrane topology. Supports the core catalytic function. Reason: Direct experimental evidence for the core 11beta-HSD (NADP+) activity. Supporting Evidence: PMID:10497248 regulate the ratio of PMID:10497248 active endogenous glucocorticoids to their inactive keto-metabolites
GO:0070524 11-beta-hydroxysteroid dehydrogenase (NADP+) activity	IDA PMID:15152005 Appropriate function of 11beta-hydroxysteroid dehydrogenase ...	ACCEPT	Summary: Direct experimental evidence that the ER-lumen-oriented 11beta-HSD1 carries out efficient glucocorticoid oxidoreduction (cortisol oxidation shown to depend on luminal orientation), establishing the core catalytic activity and its pre-receptor role. Reason: Direct experimental evidence for the core 11beta-HSD (NADP+) activity. Supporting Evidence: PMID:15152005 11beta-HSD1) exerts an important pre-receptor function PMID:15152005 essential for efficient oxidation of cortisol.
GO:0070524 11-beta-hydroxysteroid dehydrogenase (NADP+) activity	IDA PMID:17070044 Adamantane sulfone and sulfonamide 11-beta-HSD1 Inhibitors.	ACCEPT	Summary: Enzyme-inhibition study demonstrating 11beta-HSD1 catalytic activity in liver, fat and brain (target of adamantane sulfone/sulfonamide inhibitors), consistent with the core dehydrogenase activity of the enzyme. Reason: Experimental evidence of the core enzymatic activity via inhibitor-based assays. Supporting Evidence: PMID:17070044 strongly inhibit liver, fat, and brain HSD1
GO:0070524 11-beta-hydroxysteroid dehydrogenase (NADP+) activity	IDA PMID:17919905 The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibit...	ACCEPT	Summary: Enzyme-inhibition and X-ray co-crystal study confirming the 11beta-HSD1 catalytic activity used as the assay target, consistent with the core dehydrogenase function. Reason: Experimental evidence of the core enzymatic activity in an inhibitor/structure study. Supporting Evidence: PMID:17919905 2-anilinothiazolones were prepared as inhibitors of
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MARK AS OVER ANNOTATED	Summary: High-throughput mass-spectrometry membrane-proteome study of an NK-like cell line that identified HSD11B1 among ~1843 proteins. "Membrane" is a generic parent of the specific and well-supported ER-membrane localization, and the annotation derives from a broad proteomics screen rather than targeted localization. Reason: Not wrong (the enzyme is a membrane protein) but uninformatively general relative to the specific ER membrane localization; sourced from a high-throughput proteomics dataset. Supporting Evidence: PMID:19946888 identified 1843 proteins with high confidence scores

Gene Description

Existing Annotations Review

Core Functions

NADP(H)-dependent 11-beta-hydroxysteroid dehydrogenase / oxoreductase that interconverts inactive and active glucocorticoids, acting predominantly in vivo as a reductase converting cortisone to cortisol at the ER membrane, thereby amplifying pre-receptor glucocorticoid action.

References

📚 Additional Documentation

Notes

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