Vitamin D activation and VDR signalling — CYP2R1 25-hydroxylation, CYP27B1 1-alpha-hydroxylation, VDR/RXR genomic action

Vitamin D (cholecalciferol from skin or diet, or ergocalciferol) is a prohormone that must be hydroxylated twice before it can act. A microsomal cytochrome P450 25-hydroxylase, principally CYP2R1 in the liver, converts vitamin D to 25-hydroxyvitamin D (calcidiol), the abundant circulating storage form. The mitochondrial cytochrome P450 CYP27B1, whose renal proximal-tubule expression is induced by PTH and suppressed by calcitriol and FGF23, then performs the rate-limiting 1-alpha-hydroxylation to 1-alpha,25-dihydroxyvitamin D (calcitriol). Calcitriol binds the nuclear vitamin D receptor (VDR), which heterodimerises with RXR on vitamin D response elements and recruits coactivators to regulate target genes driving intestinal calcium and phosphate absorption, skeletal mineralization and feedback on vitamin D metabolism: liganded VDR represses CYP27B1 and induces the 24-hydroxylase CYP24A1, which inactivates both calcidiol and calcitriol. Loss of each step causes a vitamin D-dependent rickets: CYP2R1 (VDDR1B, low 25-hydroxyvitamin D), CYP27B1 (VDDR1A, low calcitriol) and VDR (VDDR2A, hereditary 1,25-dihydroxyvitamin D-resistant rickets with high calcitriol).

MODULE:vitamin_d_activation_signalingDRAFTBiological Processmodules/vitamin_d_activation_signaling.yaml
vitamin D3 biosynthetic processGO:1901755 vitamin D receptor signaling pathwayGO:0070561
Reactome:R-HSA-196791
Vitamin D (calciferol) metabolism
The activation steps follow the human Reactome pathway "Vitamin D (calciferol) metabolism".
Reactome:R-HSA-209845
CYP2R1 25-hydroxylates VD3 to 25(OH)D
The 25-hydroxylation step is the human Reactome reaction R-HSA-209845.
Reactome:R-HSA-209868
CYP27B1 hydroxylates 25(OH)D to 1,25(OH)2D
The 1-alpha-hydroxylation step is the human Reactome reaction R-HSA-209868.
file:human/CYP2R1/CYP2R1-ai-review.yaml
CYP2R1 gene review (human)
The 25-hydroxylase step (UniProtKB:Q6VVX0, GO:0030343, endoplasmic reticulum membrane) matches the completed human CYP2R1 review.
file:human/CYP27B1/CYP27B1-ai-review.yaml
CYP27B1 gene review (human)
The 1-alpha-hydroxylase step (UniProtKB:O15528, GO:0004498, mitochondrial inner membrane) matches the completed human CYP27B1 review.
file:human/VDR/VDR-ai-review.yaml
VDR gene review (human)
The receptor step (UniProtKB:P11473, GO:0004879 nuclear receptor activity, GO:1902098 calcitriol binding, GO:0070561 vitamin D receptor signaling pathway) matches the completed human VDR review.
4Nodes
3Parts
0Variant Sets
0Variants
3Annotons
3Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:vitamin_d_activation_signaling 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.

Function consistency and core coverage

3 gene-function check(s) reflected in core functions · 0 conflict(s) · 3 evidence or coverage gap(s) (6 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
cyp2r1_activity CYP2R1 (human)
UniProtKB:Q6VVX0
Family Representative 		vitamin D 25-hydroxylase activity
GO:0030343 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cyp27b1_activity CYP27B1 (human)
UniProtKB:O15528
Family Representative 		calcidiol 1-monooxygenase activity
GO:0004498 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
vdr_activity VDR (human)
UniProtKB:P11473
Family Representative 		nuclear receptor activity
GO:0004879 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cyp2r1_activity Vitamin D 25-hydroxylase (CYP2R1 subfamily of cytochrome P450 family 2)
PANTHER:PTHR24300:SF48
Family 		vitamin D 25-hydroxylase activity
GO:0030343 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24300:SF48.
cyp27b1_activity 25-hydroxyvitamin D 1-alpha-hydroxylase (CYP27B1, mitochondrial cytochrome P450)
PANTHER:PTHR24279:SF121
Family 		calcidiol 1-monooxygenase activity
GO:0004498 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24279:SF121.
vdr_activity Vitamin D receptor (nuclear receptor subfamily 1 group I member 1)
PANTHER:PTHR24082:SF38
Family 		nuclear receptor activity
GO:0004879 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24082:SF38.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

  • vdr_step ⊣ cyp27b1_step [closed]
    vdr_step is regulated by cyp27b1_step: feedback loop closed

Gene-review completeness (3/3 grounded genes reviewed)

2 complete review(s) · 3 with deep research · 0 missing review · 0 reviewed but lacking deep research

Gene Review Complete Deep research
CYP27B1 O15528 ✓ ✓ ✓
CYP2R1 Q6VVX0 ✓ ✓ ✓
VDR P11473 ✓ 107/108 ✓

Details

Vitamin D activation and VDR signallingBiological Processvitamin_d_activation_signaling
vitamin D3 biosynthetic processGO:1901755 vitamin D receptor signaling pathwayGO:0070561

Grounded to the human gene reviews of CYP2R1 (UniProtKB:Q6VVX0, GO:0030343), CYP27B1 (O15528, GO:0004498) and VDR (P11473, GO:0004879/GO:1902098). Reactome reaction ids and titles were checked against the local reactome cache. Family selectors use the PANTHER subfamily recorded in each representative's UniProt cross-reference (PTHR24300:SF48, PTHR24279:SF121, PTHR24082:SF38), with labels copied from interpro/panther/panther.obo. Members deliberately not modelled as parts because no AIGR gene review exists yet: RXRA (obligate VDR heterodimer partner, P19793), CYP24A1 (24-hydroxylase that inactivates calcidiol and calcitriol; loss causes idiopathic infantile hypercalcaemia), CYP27A1 (minor mitochondrial 25-hydroxylase), GC (vitamin D-binding protein) and the endocytic LRP2/CUBN reuptake of GC-bound 25(OH)D in the proximal tubule. HNRNPC (reviewed) is not a pathway member; its overexpression competes with VDR-RXR for vitamin D response elements and causes the VDR-normal form of hereditary vitamin D-resistant rickets (dismech Vitamin_D-Dependent_Rickets_Type_2B). Upstream regulators of CYP27B1 (PTH, FGF23/KL) belong to the phosphate/calcium endocrine modules. Disorders: VDDR1B (CYP2R1), VDDR1A (CYP27B1), VDDR2A (VDR), VDDR2B (HNRNPC overexpression), VDDR3 (CYP3A4 gain of function, accelerated inactivation).

Connections

cyp2r1_step -> cyp27b1_step Provides Input For
25-hydroxyvitamin D made by CYP2R1 is the substrate of CYP27B1.
cyp27b1_step -> vdr_step Provides Input For
Calcitriol made by CYP27B1 is the activating ligand of VDR.
vdr_step -> cyp27b1_step Negatively Regulates
Liganded VDR-RXR binds vitamin D response elements in the CYP27B1 promoter and represses the gene (feedback; PMID:17426122, cited in the VDR review).
Part 1: hepatic 25-hydroxylation of vitamin D
vitamin D3 (calciol) to 25-hydroxyvitamin D3 (calcidiol)Reactioncyp2r1_step

Annotons

CYP2R1: microsomal vitamin D 25-hydroxylase
cyp2r1_activity
Participant: Family: Vitamin D 25-hydroxylase (CYP2R1 subfamily of cytochrome P450 family 2)
Family:
Vitamin D 25-hydroxylase (CYP2R1 subfamily of cytochrome P450 family 2)PANTHER:PTHR24300:SF48
Representative Members: CYP2R1 (human)UniProtKB:Q6VVX0

Function

vitamin D 25-hydroxylase activityGO:0030343
Substrates: vitamin D3 (calciol) or vitamin D2 O2 reduced NADPH--hemoprotein reductase
Products: 25-hydroxyvitamin D (calcidiol)

Locations

endoplasmic reticulum membraneGO:0005789

Principal (but not sole) hepatic vitamin D 25-hydroxylase producing circulating 25-hydroxyvitamin D; Cyp2r1-null mice retain about half of serum 25(OH)D3, implying another 25-hydroxylase. Deficiency = vitamin D-dependent rickets type 1B.

Part 2: renal (and extrarenal) 1-alpha-hydroxylation to calcitriol
25-hydroxyvitamin D3 (calcidiol) to 1-alpha,25-dihydroxyvitamin D3 (calcitriol)Reactioncyp27b1_step

Annotons

CYP27B1: mitochondrial 25-hydroxyvitamin D 1-alpha-hydroxylase
cyp27b1_activity
Participant: Family: 25-hydroxyvitamin D 1-alpha-hydroxylase (CYP27B1, mitochondrial cytochrome P450)
Family:
25-hydroxyvitamin D 1-alpha-hydroxylase (CYP27B1, mitochondrial cytochrome P450)PANTHER:PTHR24279:SF121
Representative Members: CYP27B1 (human)UniProtKB:O15528

Function

calcidiol 1-monooxygenase activityGO:0004498
Substrates: 25-hydroxyvitamin D3 (calcidiol) O2 reduced adrenodoxin
Products: 1-alpha,25-dihydroxyvitamin D3 (calcitriol)

Locations

mitochondrial inner membraneGO:0005743

Adrenodoxin-dependent mitochondrial P450 of the renal proximal tubule (endocrine calcitriol) and of macrophages, keratinocytes and bone cells (local calcitriol). Regulated by PTH (up), FGF23 and calcitriol (down). Deficiency = vitamin D-dependent rickets type 1A.

Part 3: calcitriol-activated nuclear receptor signalling
calcitriol-VDR-RXR regulation of target genesSignaling Pathwayvdr_step

Annotons

VDR: vitamin D receptor (NR1I1)
vdr_activity
Participant: Family: Vitamin D receptor (nuclear receptor subfamily 1 group I member 1)
Family:
Vitamin D receptor (nuclear receptor subfamily 1 group I member 1)PANTHER:PTHR24082:SF38
Representative Members: VDR (human)UniProtKB:P11473

Function

nuclear receptor activityGO:0004879

Processes

vitamin D receptor signaling pathwayGO:0070561

Locations

nucleusGO:0005634

Binds calcitriol (GO:1902098) and, with RXR (RXRA), binds DR3-type vitamin D response elements to activate genes for intestinal calcium/phosphate absorption and to feed back on vitamin D metabolism (repression of CYP27B1, induction of CYP24A1).