Cobalamin (vitamin B12) absorption and transport; TCN1/CBLIF/CUBN/AMN/TCN2/CD320

Dietary cobalamin (vitamin B12) reaches the cytoplasm of peripheral cells through a relay of binding proteins and endocytic receptors. In saliva and the acidic stomach, cobalamin is first bound and protected by haptocorrin (TCN1); in the duodenum pancreatic proteases degrade haptocorrin and the cobalamin is transferred to gastric intrinsic factor (CBLIF/GIF), secreted by parietal cells. The intrinsic-factor-cobalamin complex is then recognised in the ileum by the cubam receptor, a complex of the large peripheral membrane protein cubilin (CUBN) and its transmembrane partner amnionless (AMN), which internalises it by receptor-mediated endocytosis; the cobalamin is released and exported to the blood. In plasma, newly absorbed cobalamin is bound by transcobalamin (TCN2), the physiologically essential delivery carrier, and the transcobalamin-cobalamin complex is taken up by peripheral cells through the cell-surface receptor CD320 (TCblR). Inherited defects along this route cause B12-deficiency disorders: CBLIF (hereditary intrinsic factor deficiency / juvenile pernicious anaemia), CUBN and AMN (Imerslund-Grasbeck syndrome, megaloblastic anaemia with proteinuria), TCN2 (transcobalamin deficiency, severe infantile megaloblastic anaemia with immunodeficiency) and CD320 (a usually mild/transient methylmalonic acidaemia detected on newborn screening).

MODULE:cobalamin_absorption_transportDRAFTMetabolic Pathwaymodules/cobalamin_absorption_transport.yaml
cobalamin transportGO:0015889 receptor-mediated endocytosisGO:0006898
GO:0015889
cobalamin transport
The module is grounded in cobalamin transport (GO:0015889); it covers the binding-protein and receptor relay that carries dietary B12 from the gut lumen into peripheral cells.
Reactome:R-HSA-3000137
CUBN:AMN-mediated CBLIF:RCbl uptake and delivery to lysosome
The ileal intrinsic-factor-cobalamin uptake step follows the human Reactome "CUBN:AMN-mediated CBLIF:RCbl uptake" reaction; the plasma-transport/CD320 steps follow R-HSA-3000074/3000112/3000122.
file:human/TCN1/TCN1-ai-review.yaml
TCN1 gene review (human)
The haptocorrin cobalamin-binding step (UniProtKB:P20061, GO:0031419) matches the completed human TCN1 review.
file:human/CBLIF/CBLIF-ai-review.yaml
CBLIF gene review (human)
The intrinsic-factor cobalamin-binding step (UniProtKB:P27352, GO:0031419) matches the completed human CBLIF review.
file:human/CUBN/CUBN-ai-review.yaml
CUBN gene review (human)
The cubilin cargo-receptor step (UniProtKB:O60494, GO:0038024) matches the completed human CUBN review.
file:human/AMN/AMN-ai-review.yaml
AMN gene review (human)
The amnionless cubam co-receptor step (UniProtKB:Q9BXJ7, GO:0038024) matches the completed human AMN review.
file:human/TCN2/TCN2-ai-review.yaml
TCN2 gene review (human)
The transcobalamin plasma-transport step (UniProtKB:P20062, GO:0031419) matches the completed human TCN2 review.
file:human/CD320/CD320-ai-review.yaml
CD320 gene review (human)
The CD320 transcobalamin-receptor uptake step (UniProtKB:Q9NPF0, GO:0038024) matches the completed human CD320 review.
6Nodes
5Parts
0Variant Sets
0Variants
6Annotons
4Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:cobalamin_absorption_transport 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 (6/6 grounded genes reviewed)

5 complete review(s) · 0 with deep research · 0 missing review · 6 reviewed but lacking deep research

Gene Review Complete Deep research
AMN Q9BXJ7 ✓ ✓ ✗
CBLIF P27352 ✓ ✓ ✗
CD320 Q9NPF0 ✓ ✓ ✗
CUBN O60494 ✓ 64/65 ✗
TCN1 P20061 ✓ ✓ ✗
TCN2 P20062 ✓ ✓ ✗

Details

Context
extracellular regionGO:0005576 apical plasma membraneGO:0016324
Cobalamin (B12) absorption and transportMetabolic Pathwaycobalamin_absorption_transport
cobalamin transportGO:0015889 receptor-mediated endocytosisGO:0006898
Context
extracellular regionGO:0005576 apical plasma membraneGO:0016324

Cobalamin (vitamin B12) absorption and transport, grounded to the human proteins TCN1 (UniProtKB:P20061, GO:0031419), CBLIF (P27352, GO:0031419), the cubam receptor (CUBN O60494 + AMN Q9BXJ7, GO:0038024), TCN2 (P20062, GO:0031419) and CD320 (Q9NPF0, GO:0038024). GO molecular-function/location terms were taken from the completed human gene reviews and verified against the local go.db; Reactome reaction ids/titles were verified against the local reactome cache. Each step uses a PANTHER family selector with the human protein as representative; the soluble transcobalamin-family carriers TCN1, CBLIF and TCN2 share PTHR10559, and the ileal cubam receptor is modelled as a PROTEIN_COMPLEX node (cubilin ligand-binding subunit + amnionless membrane anchor). This is a small-molecule trafficking pathway (binding proteins + endocytic receptors, not enzymes). Downstream, internalised cobalamin is released in the lysosome and processed in the cytosol by MMACHC (cblC) and MMADHC (cblD), then routed to adenosylcobalamin (MMAB/MMAA -> MMUT, methylmalonyl-CoA mutase) and methylcobalamin (MTR/MTRR, methionine synthase) — separate modules (MMAA/MMAB/MMUT already in the propionyl-CoA module; MTR/MTRR reviewed). Disorders span the route: CBLIF (juvenile pernicious anaemia), CUBN/AMN (Imerslund-Grasbeck syndrome), TCN2 (transcobalamin deficiency) and CD320 (newborn-screen methylmalonic acidaemia).

Connections

tcn1_step -> cblif_step Provides Input For
After pancreatic proteases degrade haptocorrin in the duodenum, cobalamin is transferred to intrinsic factor (CBLIF).
cblif_step -> cubam_step Provides Input For
The IF-cobalamin complex is the ligand internalised by the ileal cubam receptor.
cubam_step -> tcn2_step Provides Input For
Cobalamin absorbed via cubam is exported to the blood and bound by transcobalamin (TCN2).
tcn2_step -> cd320_step Provides Input For
The TC-cobalamin complex is taken up by peripheral cells through the CD320 receptor.
Part 1: gastric/salivary cobalamin protection (haptocorrin)
cobalamin bound by haptocorrin (TCN1)Reactiontcn1_step

Annotons

TCN1: haptocorrin (transcobalamin I)
tcn1_activity
Participant: Family: Transcobalamin/haptocorrin family
Family:
Transcobalamin/haptocorrin familyPANTHER:PTHR10559
Representative Members: TCN1 (human)UniProtKB:P20061

Function

cobalamin bindingGO:0031419
Substrates: cobalamin (vitamin B12)
Products: haptocorrin-cobalamin complex

Locations

extracellular regionGO:0005576

Binds and protects dietary cobalamin in saliva/stomach; degraded by pancreatic proteases in the duodenum, handing cobalamin to intrinsic factor.

Part 2: intrinsic-factor binding for ileal absorption
cobalamin bound by intrinsic factor (CBLIF)Reactioncblif_step

Annotons

CBLIF: gastric intrinsic factor
cblif_activity
Participant: Family: Transcobalamin/intrinsic-factor family
Family:
Transcobalamin/intrinsic-factor familyPANTHER:PTHR10559
Representative Members: CBLIF (human)UniProtKB:P27352

Function

cobalamin bindingGO:0031419
Substrates: cobalamin (vitamin B12)
Products: intrinsic factor-cobalamin (IF-Cbl) complex

Locations

extracellular regionGO:0005576

Binds cobalamin handed over from haptocorrin; the IF-Cbl complex is recognised by the cubam receptor in the ileum.

Part 3: ileal receptor-mediated uptake (cubam)
IF-cobalamin internalised by the cubam receptor (CUBN/AMN)Protein Complexcubam_step

Annotons

CUBN: cubilin (cubam ligand-binding subunit)
cubn_activity
Participant: Family: Cubilin family
Family:
Cubilin familyPANTHER:PTHR24251
Representative Members: CUBN (human)UniProtKB:O60494

Function

cargo receptor activityGO:0038024
Substrates: intrinsic factor-cobalamin (IF-Cbl) complex
Products: internalised IF-Cbl (endocytosed)

Locations

apical plasma membraneGO:0016324

Ligand-binding subunit of cubam; binds IF-Cbl (and many renal ligands). Deficiency = Imerslund-Grasbeck syndrome (megaloblastic anaemia 1, with proteinuria).

AMN: amnionless (cubam membrane-anchor/endocytic subunit)
amn_activity
Participant: Family: Amnionless family
Family:
Amnionless familyPANTHER:PTHR14995
Representative Members: AMN (human)UniProtKB:Q9BXJ7

Function

cargo receptor activityGO:0038024
Substrates: cubilin (CUBN)
Products: membrane-anchored, endocytosis-competent cubam receptor

Locations

apical plasma membraneGO:0016324

Anchors cubilin to the apical membrane and provides the endocytosis signals for internalisation of the cubilin-IF-Cbl complex.

Part 4: plasma cobalamin transport (transcobalamin)
absorbed cobalamin bound by transcobalamin (TCN2)Reactiontcn2_step

Annotons

TCN2: transcobalamin
tcn2_activity
Participant: Family: Transcobalamin family
Family:
Transcobalamin familyPANTHER:PTHR10559
Representative Members: TCN2 (human)UniProtKB:P20062

Function

cobalamin bindingGO:0031419
Substrates: cobalamin (absorbed, in plasma)
Products: transcobalamin-cobalamin (TC-Cbl) complex

Locations

extracellular regionGO:0005576

Binds newly absorbed cobalamin in plasma; the TC-Cbl complex delivers B12 to peripheral cells.

Part 5: cellular uptake (CD320 receptor)
TC-cobalamin internalised by CD320 (TCblR)Reactioncd320_step

Annotons

CD320: transcobalamin receptor (TCblR)
cd320_activity
Participant: Family: CD320 / LDLR-family transcobalamin receptor
Family:
CD320 / LDLR-family transcobalamin receptorPANTHER:PTHR24270
Representative Members: CD320 (human)UniProtKB:Q9NPF0

Function

cargo receptor activityGO:0038024
Substrates: transcobalamin-cobalamin (TC-Cbl) complex
Products: internalised TC-Cbl (endocytosed for cellular B12 supply)

Locations

plasma membraneGO:0005886

Cell-surface receptor internalising the TC-Cbl complex, supplying cobalamin to peripheral cells. Variant = mild/transient newborn-screen methylmalonic acidaemia.