Lactate fermentation and the Rapoport-Luebering (2,3-BPG) shunt — GSD XI, BPGM deficiency

Two branch reactions of glycolysis, prominent in anaerobic tissue and in erythrocytes (which depend entirely on glycolysis and lack mitochondria). (1) Lactate fermentation: lactate dehydrogenase (a tetramer of the LDHA/M and LDHB/H subunits) reduces the glycolytic end-product pyruvate to L-lactate using NADH, regenerating the NAD+ that glyceraldehyde-3-phosphate dehydrogenase needs to sustain glycolytic flux when oxidative phosphorylation is unavailable or saturated; the LDHA-rich isoenzymes favour pyruvate to lactate (anaerobic/glycolytic tissue) while LDHB-rich isoenzymes favour the reverse oxidation of lactate to pyruvate (oxidative tissue). (2) The Rapoport-Luebering shunt: bisphosphoglycerate mutase (BPGM) diverts 1,3-bisphosphoglycerate to 2,3-bisphosphoglycerate (and hydrolyses it onward to 3-phosphoglycerate), bypassing the ATP-generating phosphoglycerate-kinase step; 2,3-bisphosphoglycerate is the principal allosteric effector that binds deoxyhemoglobin and lowers its oxygen affinity, tuning O2 delivery to tissues. Both branches feed off glycolytic intermediates (pyruvate and 1,3-bisphosphoglycerate respectively). Inherited defects: LDHA deficiency causes glycogen storage disease type XI (exertional myopathy, myoglobinuria, skin lesions); LDHB deficiency is usually clinically silent; and BPGM deficiency lowers 2,3-BPG, raising hemoglobin oxygen affinity and causing secondary erythrocytosis.

MODULE:lactate_fermentation_and_bpg_shuntDRAFTMetabolic Pathwaymodules/lactate_fermentation_and_bpg_shunt.yaml
glycolytic processGO:0006096
GO:0006096
glycolytic process
Both branches act on glycolytic intermediates (GO:0006096): LDH on pyruvate (NAD+ regeneration / lactate fermentation) and BPGM on 1,3-bisphosphoglycerate (2,3-BPG shunt).
Reactome:R-HSA-71849
LDH tetramer reduces PYR to LACT
Reactions follow the human Reactome reactions R-HSA-71849 (LDH pyruvate -> lactate) and R-HSA-6798335 (BPGM 1,3-BPG -> 2,3-BPG).
file:human/LDHA/LDHA-ai-review.yaml
LDHA gene review (human)
The lactate-fermentation step (UniProtKB:P00338, GO:0004459) matches the completed human LDHA review.
file:human/LDHB/LDHB-ai-review.yaml
LDHB gene review (human)
The lactate-oxidising isozyme of the same step (UniProtKB:P07195, GO:0004459) matches the completed human LDHB review.
file:human/BPGM/BPGM-ai-review.yaml
BPGM gene review (human)
The 2,3-bisphosphoglycerate shunt step (UniProtKB:P07738, GO:0004082) matches the completed human BPGM review.
3Nodes
2Parts
0Variant Sets
0Variants
2Annotons
0Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:lactate_fermentation_and_bpg_shunt 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 (3/3 grounded genes reviewed)

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

Gene Review Complete Deep research
BPGM P07738 ✓ ✓ ✗
LDHA P00338 ✓ ✓ ✗
LDHB P07195 ✓ ✓ ✗

Details

Context
cytosolGO:0005829
Lactate fermentation and 2,3-BPG shuntMetabolic Pathwaylactate_fermentation_and_bpg_shunt
glycolytic processGO:0006096
Context
cytosolGO:0005829

Two erythrocyte/anaerobic glycolysis branch reactions grounded to the human enzymes lactate dehydrogenase LDHA (UniProtKB:P00338) / LDHB (P07195) (GO:0004459, EC 1.1.1.27) and bisphosphoglycerate mutase BPGM (P07738, GO:0004082, EC 5.4.2.4). GO molecular-function terms were taken from the human GOA records; Reactome reaction ids and titles were verified against the local reactome cache. The LDH node uses PANTHER PTHR43128 (LDHA/LDHB/LDHC) with LDHA and LDHB as representatives; BPGM shares PANTHER PTHR11931 with the phosphoglycerate mutases (PGAM1/PGAM2; glycolysis payoff module). The two branches are independent (no direct connection): LDH draws pyruvate from the end of the glycolysis payoff phase (pyruvate kinase) and its lactate feeds the Cori cycle / gluconeogenesis, while BPGM diverts 1,3-bisphosphoglycerate produced by GAPDH, bypassing the PGK1 ATP-generating step (so the shunt trades ATP yield for 2,3-BPG-based control of hemoglobin oxygen affinity). LDH pyruvate<->lactate also connects to the pyruvate-metabolism module (PDC/PC oxidative fate). Disorders: LDHA -> GSD XI (exertional myopathy); LDHB -> usually asymptomatic; BPGM -> bisphosphoglycerate mutase deficiency (low 2,3-BPG, high Hb-O2 affinity, erythrocytosis).

Part 1: lactate fermentation (NAD+ regeneration)
pyruvate + NADH to L-lactate + NAD+Reactionldh_step

Annotons

LDHA/LDHB: L-lactate dehydrogenase
ldh_activity
Participant: Family: L-lactate dehydrogenase family (LDHA/LDHB/LDHC)
Family:
L-lactate dehydrogenase family (LDHA/LDHB/LDHC)PANTHER:PTHR43128
Representative Members: LDHA (human, M/muscle subunit)UniProtKB:P00338 LDHB (human, H/heart subunit)UniProtKB:P07195

Function

L-lactate dehydrogenase (NAD+) activityGO:0004459
Substrates: pyruvate NADH
Products: L-lactate NAD+

Locations

cytosolGO:0005829

Reduces pyruvate to lactate, regenerating NAD+ so glycolysis can continue anaerobically (LDHA/M4 favours this direction); the reverse oxidation of lactate to pyruvate (LDHB/H4, oxidative tissue) feeds gluconeogenesis/the Cori cycle. LDHA deficiency = GSD XI.

Part 2: Rapoport-Luebering shunt (2,3-BPG synthesis, Hb O2-affinity control)
1,3-bisphosphoglycerate to 2,3-bisphosphoglycerateReactionbpgm_step

Annotons

BPGM: bisphosphoglycerate mutase
bpgm_activity
Participant: Family: Cofactor-dependent phosphoglycerate mutase family (BPGM/PGAM)
Family:
Cofactor-dependent phosphoglycerate mutase family (BPGM/PGAM)PANTHER:PTHR11931
Representative Members: BPGM (human)UniProtKB:P07738

Function

bisphosphoglycerate mutase activityGO:0004082
Substrates: 1,3-bisphospho-D-glycerate
Products: 2,3-bisphospho-D-glycerate

Locations

cytosolGO:0005829

Trifunctional erythrocyte enzyme of the Rapoport-Luebering shunt: makes 2,3-bisphosphoglycerate from 1,3-bisphosphoglycerate (bypassing the ATP-generating PGK1 step) and degrades it to 3-phosphoglycerate. 2,3-BPG lowers hemoglobin O2 affinity; BPGM deficiency causes erythrocytosis.