Cobalamin (B12) intracellular processing and trafficking; ABCD4/LMBRD1/MMACHC/MMADHC

Once the transcobalamin-cobalamin complex has been endocytosed via CD320 and degraded in the lysosome, the freed cobalamin (vitamin B12) must be exported to the cytosol, stripped of its upper axial ligand, and routed to one of its two coenzyme forms. The lysosomal export step is carried out by a two-protein system: the ABC transporter ABCD4 (cblJ), which provides the ATP-dependent transmembrane cobalamin-transport activity, together with the lysosomal membrane protein LMBRD1 (cblF), which is required to target ABCD4 to the lysosome and acts as its escort subunit. In the cytosol the cblC protein MMACHC processes the cobalamin — reductive decyanation of cyanocobalamin and dealkylation of alkylcobalamins remove the beta-axial ligand to give cob(II)alamin. The cblD protein MMADHC then binds MMACHC-cob(II)alamin and acts as the branch-point/trafficking adaptor that directs cobalamin either to the mitochondrion for adenosylcobalamin synthesis (feeding methylmalonyl-CoA mutase, MMUT) or to the cytosolic methylcobalamin route (feeding methionine synthase, MTR). Defects in each step cause combined or isolated methylmalonic aciduria and homocystinuria: cblJ (ABCD4), cblF (LMBRD1), cblC (MMACHC) and cblD (MMADHC).

MODULE:cobalamin_intracellular_processingDRAFTMetabolic Pathwaymodules/cobalamin_intracellular_processing.yaml
cobalamin metabolic processGO:0009235
GO:0009235
cobalamin metabolic process
The module is grounded in cobalamin metabolic process (GO:0009235); it covers lysosomal cobalamin export and the cytosolic decyanation/dealkylation and branch-point trafficking that prepare B12 for its two coenzyme forms.
Reactome:R-HSA-9759218
Cobalamin (Cbl) metabolism
Step order and intermediates follow the human Reactome "Cobalamin (Cbl) metabolism" pathway (reactions R-HSA-5223313 lysosomal export, R-HSA-3149494/3149563 MMACHC/MMADHC processing).
file:human/ABCD4/ABCD4-ai-review.yaml
ABCD4 gene review (human)
The lysosomal ABC cobalamin-transporter step (UniProtKB:O14678, GO:0015420) matches the completed human ABCD4 review.
file:human/LMBRD1/LMBRD1-ai-review.yaml
LMBRD1 gene review (human)
The lysosomal cobalamin-export escort step (UniProtKB:Q9NUN5, GO:0015889 / lysosomal membrane) matches the completed human LMBRD1 review.
file:human/MMACHC/MMACHC-ai-review.yaml
MMACHC gene review (human)
The cytosolic decyanation/dealkylation step (UniProtKB:Q9Y4U1, GO:0033787) matches the previously completed human MMACHC review (already on main).
file:human/MMADHC/MMADHC-ai-review.yaml
MMADHC gene review (human)
The cblD branch-point trafficking step (UniProtKB:Q9H3L0, GO:0140104) matches the completed human MMADHC review.
4Nodes
3Parts
0Variant Sets
0Variants
4Annotons
2Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:cobalamin_intracellular_processing 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 (4/4 grounded genes reviewed)

4 complete review(s) · 0 with deep research · 0 missing review · 4 reviewed but lacking deep research

Gene Review Complete Deep research
ABCD4 O14678 ✓ ✓ ✗
LMBRD1 Q9NUN5 ✓ ✓ ✗
MMACHC Q9Y4U1 ✓ ✓ ✗
MMADHC Q9H3L0 ✓ ✓ ✗

Details

Context
lysosomal membraneGO:0005765 cytosolGO:0005829
Cobalamin (B12) intracellular processing and traffickingMetabolic Pathwaycobalamin_intracellular_processing
cobalamin metabolic processGO:0009235
Context
lysosomal membraneGO:0005765 cytosolGO:0005829

Cobalamin intracellular processing/trafficking, grounded to the human proteins ABCD4 (UniProtKB:O14678, GO:0015420) and LMBRD1 (Q9NUN5, lysosomal export escort; its standalone transporter MF is an over-annotation, so it is modelled by its BP/escort role via `processes`), MMACHC (Q9Y4U1, GO:0033787; reviewed previously, already on main) and MMADHC (Q9H3L0, GO:0140104). GO molecular-function/BP/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 lysosomal export step is a PROTEIN_COMPLEX node (ABCD4 catalytic transporter + LMBRD1 escort). Upstream, cobalamin is delivered and endocytosed by the absorption/transport module (TCN1/CBLIF/CUBN/AMN/TCN2/CD320). Downstream, MMADHC routes cob(II)alamin to (i) the mitochondrial adenosylcobalamin branch — MMAB (cblB) adenosyltransferase with the MMAA (cblA) chaperone, supplying methylmalonyl-CoA mutase MMUT (all reviewed in the propionyl-CoA module) — or (ii) the cytosolic methylcobalamin branch — methionine synthase MTR (cblG) with its reductase MTRR (cblE) (both reviewed). Disorders: cblJ (ABCD4), cblF (LMBRD1), cblC (MMACHC) and cblD (MMADHC) cause combined or isolated methylmalonic aciduria and homocystinuria.

Connections

lysosomal_export_step -> mmachc_step Provides Input For
Cobalamin exported to the cytosol by ABCD4:LMBRD1 is processed by MMACHC.
mmachc_step -> mmadhc_step Provides Input For
MMACHC-bound cob(II)alamin is handed to MMADHC for routing to the two coenzyme branches.
Part 1: lysosomal cobalamin export (ABC transporter + escort)
cobalamin export from lysosomal lumen to cytosol (ABCD4:LMBRD1)Protein Complexlysosomal_export_step

Annotons

ABCD4: lysosomal ABC cobalamin transporter (cblJ)
abcd4_activity
Participant: Family: ABC transporter subfamily D (ABCD4)
Family:
ABC transporter subfamily D (ABCD4)PANTHER:PTHR11384
Representative Members: ABCD4 (human)UniProtKB:O14678

Function

ABC-type vitamin B12 transporter activityGO:0015420
Substrates: cobalamin (lysosomal lumen) ATP
Products: cobalamin (cytosol) ADP + phosphate

Locations

lysosomal membraneGO:0005765

ATP-driven transmembrane cobalamin transporter releasing B12 from the lysosome to the cytosol. Deficiency = cblJ-type MMA + homocystinuria.

LMBRD1: lysosomal cobalamin-export escort (cblF)
lmbrd1_activity
Participant: Family: LMBR1-domain family (LMBRD1)
Family:
LMBR1-domain family (LMBRD1)PANTHER:PTHR16130
Representative Members: LMBRD1 (human)UniProtKB:Q9NUN5

Processes

cobalamin transportGO:0015889 protein localization to lysosomeGO:0061462

Locations

lysosomal membraneGO:0005765

Non-catalytic escort/targeting subunit that recruits ABCD4 to the lysosomal membrane; the LMBRD1:ABCD4 complex effects cobalamin export. (Its own transporter MF annotations are over-annotations — captured here as a BP/escort role.)

Reactome:R-HSA-5223313
ABCD4:LMBRD1 transports RCbl from lysosomal lumen to cytosol (human Reactome reaction)
file:human/LMBRD1/LMBRD1-ai-review.yaml
lysosomal membrane escort that targets ABCD4 to the lysosome; has no intrinsic transport/ATPase activity itself (that is ABCD4); deficiency = cblF MMA + homocystinuria
Part 2: cytosolic decyanation/dealkylation (removes the beta-axial ligand)
cobalamin decyanation/dealkylation to cob(II)alamin (MMACHC)Reactionmmachc_step

Annotons

MMACHC: cyanocobalamin reductase / cobalamin dealkylase (cblC)
mmachc_activity
Participant: Family: MMACHC / CblC family
Family:
MMACHC / CblC familyPANTHER:PTHR31457
Representative Members: MMACHC (human)UniProtKB:Q9Y4U1

Function

cyanocobalamin reductase (cyanide-eliminating) (NADP+) activityGO:0033787
Substrates: cyanocobalamin / alkylcobalamin NADPH glutathione (for dealkylation)
Products: cob(II)alamin cyanide / alkyl-glutathione

Locations

cytosolGO:0005829

Processes incoming cobalamin by removing its upper axial ligand, yielding cob(II)alamin for downstream coenzyme synthesis. (Reviewed previously; already on main.)

Part 3: branch-point trafficking (AdoCbl vs MeCbl)
cob(II)alamin routed to the AdoCbl or MeCbl branch (MMADHC)Reactionmmadhc_step

Annotons

MMADHC: cobalamin branch-point trafficking protein (cblD)
mmadhc_activity
Participant: Family: MMADHC / CblD family
Family:
MMADHC / CblD familyPANTHER:PTHR13192
Representative Members: MMADHC (human)UniProtKB:Q9H3L0

Function

molecular carrier activityGO:0140104
Substrates: MMACHC-cob(II)alamin
Products: cob(II)alamin routed to the mitochondrial (AdoCbl) or cytosolic (MeCbl) branch

Locations

cytosolGO:0005829

Branch-point/trafficking adaptor downstream of MMACHC; its mutation position determines isolated MMA, isolated homocystinuria, or combined disease.