Cortisol-cortisone shuttle — pre-receptor glucocorticoid interconversion; HSD11B1/HSD11B2

Tissue glucocorticoid action is set not only by circulating cortisol but by local, pre-receptor interconversion between active cortisol and inactive cortisone, catalysed by two endoplasmic-reticulum-membrane 11beta-hydroxysteroid dehydrogenases with opposite directionality. 11beta-HSD type 1 (HSD11B1) acts predominantly as an NADPH-dependent reductase — its direction fixed by NADPH generated in the ER lumen by hexose-6-phosphate dehydrogenase (H6PD) — regenerating active cortisol from cortisone and thereby amplifying glucocorticoid signalling in liver, adipose tissue and brain (a validated metabolic-syndrome drug target). 11beta-HSD type 2 (HSD11B2) is an NAD+-dependent, essentially unidirectional dehydrogenase that inactivates cortisol to cortisone; in aldosterone-target epithelia (distal nephron, colon, salivary gland) it destroys cortisol locally so that the non-selective mineralocorticoid receptor is protected from illicit activation by cortisol, conferring aldosterone specificity, and in the placenta it shields the fetus from maternal glucocorticoid. Loss of HSD11B2 causes apparent mineralocorticoid excess (AME), a severe juvenile hypertension with hypokalaemia; altered HSD11B1 activity underlies cortisone reductase deficiency and is implicated in the metabolic syndrome.

MODULE:cortisol_cortisone_shuttleDRAFTMetabolic Pathwaymodules/cortisol_cortisone_shuttle.yaml
glucocorticoid metabolic processGO:0008211
GO:0008211
glucocorticoid metabolic process
The module is grounded in glucocorticoid metabolic process (GO:0008211); it covers the pre-receptor cortisol<->cortisone interconversion that governs local glucocorticoid action.
Reactome:R-HSA-194023
HSD11B2,HSD11B1 dimer oxidise CORT to COR
The cortisol->cortisone oxidation is the human Reactome reaction R-HSA-194023; HSD11B1 also runs the reverse (cortisone->cortisol) reduction in vivo.
file:human/HSD11B1/HSD11B1-ai-review.yaml
HSD11B1 gene review (human)
The cortisone->cortisol reductase step (UniProtKB:P28845, GO:0070524) matches the completed human HSD11B1 review.
file:human/HSD11B2/HSD11B2-ai-review.yaml
HSD11B2 gene review (human)
The cortisol->cortisone dehydrogenase step (UniProtKB:P80365, GO:0070523) matches the completed human HSD11B2 review.
3Nodes
2Parts
0Variant Sets
0Variants
2Annotons
2Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:cortisol_cortisone_shuttle deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Gene-review completeness (2/2 grounded genes reviewed)

2 complete review(s) · 0 with deep research · 0 missing review · 2 reviewed but lacking deep research

Gene Review Complete Deep research
HSD11B1 P28845 ✓ ✓ ✗
HSD11B2 P80365 ✓ ✓ ✗

Details

Context
endoplasmic reticulum membraneGO:0005789
Cortisol-cortisone shuttle (pre-receptor glucocorticoid interconversion)Metabolic Pathwaycortisol_cortisone_shuttle
glucocorticoid metabolic processGO:0008211
Context
endoplasmic reticulum membraneGO:0005789

Pre-receptor cortisol<->cortisone shuttle grounded to the human enzymes HSD11B1 (UniProtKB:P28845, GO:0070524, NADP+-dependent, EC 1.1.1.146) and HSD11B2 (P80365, GO:0070523, NAD+-dependent, EC 1.1.1.-). The two enzymes catalyse the same chemical interconversion in opposite directions, so the module is a cycle rather than a linear pathway: HSD11B1 predominantly reduces cortisone to active cortisol (its direction fixed by ER-lumenal H6PD NADPH), while HSD11B2 unidirectionally oxidises cortisol to inactive cortisone. GO molecular-function/location terms were taken from the completed human gene reviews and verified against the local go.db; the shared human Reactome reaction R-HSA-194023 (cortisol->cortisone) was verified against the local reactome cache. Each enzyme uses a PANTHER family selector with the human protein as representative so the module generalises across orthologs/paralogs. Physiologically this shuttle sets tissue glucocorticoid tone: HSD11B1 amplifies it (liver/adipose/brain; metabolic-syndrome target), HSD11B2 confers aldosterone specificity on the mineralocorticoid receptor (kidney/colon) and protects the fetus (placenta). Disorders: apparent mineralocorticoid excess (HSD11B2), cortisone reductase deficiency and metabolic-syndrome association (HSD11B1). Upstream cortisol is made by the adrenal steroidogenesis module (CYP11B1); the sex-steroid biosynthesis enzymes are a separate module.

Connections

hsd11b2_step -> hsd11b1_step Provides Input For
Cortisone generated by HSD11B2 is the substrate that HSD11B1 reduces back to cortisol.
hsd11b1_step -> hsd11b2_step Provides Input For
Cortisol regenerated by HSD11B1 is the substrate that HSD11B2 inactivates to cortisone.
Part 1: glucocorticoid activation (cortisone -> cortisol)
cortisone to cortisol (NADPH-dependent reductase)Reactionhsd11b1_step

Annotons

HSD11B1: 11beta-hydroxysteroid dehydrogenase type 1
hsd11b1_activity
Participant: Family: 11beta-hydroxysteroid dehydrogenase type 1 family (SDR)
Family:
11beta-hydroxysteroid dehydrogenase type 1 family (SDR)PANTHER:PTHR44279
Representative Members: HSD11B1 (human)UniProtKB:P28845

Function

11-beta-hydroxysteroid dehydrogenase (NADP+) activityGO:0070524
Substrates: cortisone NADPH (from ER-lumenal H6PD)
Products: cortisol NADP+

Locations

endoplasmic reticulum membraneGO:0005789

Pre-receptor amplification of glucocorticoid action in liver, adipose and brain; direction set by H6PD-supplied NADPH. Metabolic-syndrome drug target; cortisone reductase deficiency when impaired.

Part 2: glucocorticoid inactivation (cortisol -> cortisone)
cortisol to cortisone (NAD+-dependent dehydrogenase)Reactionhsd11b2_step

Annotons

HSD11B2: 11beta-hydroxysteroid dehydrogenase type 2
hsd11b2_activity
Participant: Family: 11beta-hydroxysteroid dehydrogenase type 2 family (SDR)
Family:
11beta-hydroxysteroid dehydrogenase type 2 family (SDR)PANTHER:PTHR43313
Representative Members: HSD11B2 (human)UniProtKB:P80365

Function

11-beta-hydroxysteroid dehydrogenase (NAD+) activityGO:0070523
Substrates: cortisol NAD+
Products: cortisone NADH

Locations

endoplasmic reticulum membraneGO:0005789

Protects the non-selective mineralocorticoid receptor from cortisol in the distal nephron/colon and shields the fetus in placenta. Deficiency = apparent mineralocorticoid excess (AME), severe juvenile hypertension.