Glyoxylate metabolism and oxalate detoxification (the primary hyperoxalurias); AGXT/GRHPR/HOGA1/HAO1/AGXT2

Glyoxylate is a reactive two-carbon metabolite that, if not detoxified, is oxidised to oxalate — an end product that cannot be further metabolised and precipitates as insoluble calcium oxalate, damaging the kidney. Hepatic glyoxylate handling therefore determines systemic oxalate load, and its enzymes define the primary hyperoxalurias. Glyoxylate arises from two main sources: peroxisomal glycolate oxidase (HAO1), an FMN enzyme that oxidises glycolate to glyoxylate (generating H2O2), and mitochondrial 4-hydroxy-2-oxoglutarate aldolase (HOGA1), the terminal enzyme of hydroxyproline catabolism, which cleaves 4-hydroxy-2-oxoglutarate to glyoxylate and pyruvate. Glyoxylate is then detoxified by two routes: the peroxisomal, pyridoxal-phosphate-dependent alanine-glyoxylate aminotransferase (AGXT/AGT) transaminates it back to glycine (using L-alanine), and the cytosolic NADPH- dependent glyoxylate/hydroxypyruvate reductase (GRHPR) reduces it to glycolate; a mitochondrial aminotransferase (AGXT2) provides an additional transamination route (and also degrades the NO-synthase inhibitors ADMA/SDMA). When detoxification fails, glyoxylate is oxidised to oxalate. Inherited defects each cause a primary hyperoxaluria: PH1 (AGXT), PH2 (GRHPR) and PH3 (HOGA1); HAO1, which makes glyoxylate, is a validated drug target (the siRNA lumasiran silences HAO1 to lower oxalate).

MODULE:glyoxylate_oxalate_metabolismDRAFTMetabolic Pathwaymodules/glyoxylate_oxalate_metabolism.yaml
glyoxylate metabolic processGO:0046487
GO:0046487
glyoxylate metabolic process
The module is grounded in glyoxylate metabolic process (GO:0046487); it covers hepatic glyoxylate generation and detoxification that controls oxalate synthesis.
Reactome:R-HSA-389661
Glyoxylate metabolism and glycine degradation
Step order and reactions follow the human Reactome glyoxylate-metabolism reactions R-HSA-389842 (HAO1), R-HSA-6784423 (HOGA1), R-HSA-389684 (AGXT), R-HSA-389826 (GRHPR) and R-HSA-904864 (AGXT2).
file:human/HAO1/HAO1-ai-review.yaml
HAO1 gene review (human)
The glycolate-oxidase (glyoxylate-generating) step (UniProtKB:Q9UJM8, GO:0003973) matches the completed human HAO1 review.
file:human/HOGA1/HOGA1-ai-review.yaml
HOGA1 gene review (human)
The 4-hydroxy-2-oxoglutarate aldolase (hydroxyproline-derived glyoxylate) step (UniProtKB:Q86XE5, GO:0008700) matches the completed human HOGA1 review.
file:human/AGXT/AGXT-ai-review.yaml
AGXT gene review (human)
The peroxisomal glyoxylate-to-glycine transamination step (UniProtKB:P21549, GO:0008453) matches the completed human AGXT review.
file:human/GRHPR/GRHPR-ai-review.yaml
GRHPR gene review (human)
The cytosolic glyoxylate-to-glycolate reduction step (UniProtKB:Q9UBQ7, GO:0030267) matches the completed human GRHPR review.
file:human/AGXT2/AGXT2-ai-review.yaml
AGXT2 gene review (human)
The mitochondrial glyoxylate transamination (and ADMA-degrading) step (UniProtKB:Q9BYV1, GO:0008453) matches the completed human AGXT2 review.
6Nodes
5Parts
0Variant Sets
0Variants
5Annotons
3Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:glyoxylate_oxalate_metabolism 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 (5/5 grounded genes reviewed)

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

Gene Review Complete Deep research
AGXT P21549 ✓ ✓ ✗
AGXT2 Q9BYV1 ✓ ✓ ✗
GRHPR Q9UBQ7 ✓ ✓ ✗
HAO1 Q9UJM8 ✓ ✓ ✗
HOGA1 Q86XE5 ✓ ✓ ✗

Details

Context
peroxisomeGO:0005777 mitochondrial matrixGO:0005759 cytosolGO:0005829
Glyoxylate metabolism and oxalate detoxificationMetabolic Pathwayglyoxylate_oxalate_metabolism
glyoxylate metabolic processGO:0046487
Context
peroxisomeGO:0005777 mitochondrial matrixGO:0005759 cytosolGO:0005829

Glyoxylate/oxalate metabolism, grounded to the human enzymes HAO1 (UniProtKB:Q9UJM8, GO:0003973, EC 1.1.3.15), HOGA1 (Q86XE5, GO:0008700, EC 4.1.3.16), AGXT (P21549, GO:0008453, EC 2.6.1.44), GRHPR (Q9UBQ7, GO:0030267, EC 1.1.1.79) and AGXT2 (Q9BYV1, GO:0008453, EC 2.6.1.44). 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 (five distinct families — these enzymes are not paralogs). The pathway is a compartmentalised generation/detoxification balance: glyoxylate is generated in the peroxisome (HAO1 from glycolate) and mitochondrion (HOGA1 from hydroxyproline), and detoxified by transamination to glycine (peroxisomal AGXT, mitochondrial AGXT2) or reduction to glycolate (cytosolic GRHPR); the AGT/glyoxylate and glycolate/GRHPR pools are exchanged across compartments. When these routes are overwhelmed, glyoxylate is oxidised to oxalate (in part by HAO1's minor glyoxylate- oxidase activity and LDH), which precipitates as calcium oxalate. Disorders: primary hyperoxaluria type 1 (AGXT), type 2 (GRHPR) and type 3 (HOGA1); HAO1 is the lumasiran drug target and AGXT2 a modifier (also of plasma ADMA / cardiovascular-renal phenotypes). Glycine produced by AGXT/AGXT2 feeds one-carbon/glycine metabolism (the glycine-cleavage module).

Connections

hao1_step -> agxt_step Provides Input For
Glyoxylate from HAO1 is detoxified to glycine by peroxisomal AGXT.
hao1_step -> grhpr_step Provides Input For
Glyoxylate from HAO1 is reduced to glycolate by cytosolic GRHPR.
hoga1_step -> agxt2_step Provides Input For
Mitochondrial glyoxylate from HOGA1 is transaminated by AGXT2.
Part 1: glyoxylate generation from glycolate (peroxisomal)
glycolate to glyoxylateReactionhao1_step

Annotons

HAO1: glycolate oxidase (hydroxyacid oxidase 1)
hao1_activity
Participant: Family: FMN-dependent L-2-hydroxyacid oxidase family (HAO)
Family:
FMN-dependent L-2-hydroxyacid oxidase family (HAO)PANTHER:PTHR10578
Representative Members: HAO1 (human)UniProtKB:Q9UJM8

Function

(S)-2-hydroxy-acid oxidase activityGO:0003973
Substrates: glycolate O2
Products: glyoxylate H2O2

Locations

peroxisomal matrixGO:0005782

Generates glyoxylate (the oxalate precursor); a therapeutic target for the primary hyperoxalurias (its loss is protective).

Part 2: glyoxylate generation from hydroxyproline (mitochondrial)
4-hydroxy-2-oxoglutarate to glyoxylate + pyruvateReactionhoga1_step

Annotons

HOGA1: 4-hydroxy-2-oxoglutarate aldolase
hoga1_activity
Participant: Family: DapA-like aldolase family (HOGA1)
Family:
DapA-like aldolase family (HOGA1)PANTHER:PTHR12128
Representative Members: HOGA1 (human)UniProtKB:Q86XE5

Function

(R,S)-4-hydroxy-2-oxoglutarate aldolase activityGO:0008700
Substrates: 4-hydroxy-2-oxoglutarate
Products: glyoxylate pyruvate

Locations

mitochondrial matrixGO:0005759

Terminal enzyme of hydroxyproline catabolism; generates mitochondrial glyoxylate. Deficiency = primary hyperoxaluria type 3 (PH3).

Part 3: glyoxylate detoxification by transamination (peroxisomal)
glyoxylate + L-alanine to glycine + pyruvateReactionagxt_step

Annotons

AGXT: alanine-glyoxylate aminotransferase (peroxisomal)
agxt_activity
Participant: Family: Class-V aminotransferase family (AGXT)
Family:
Class-V aminotransferase family (AGXT)PANTHER:PTHR21152
Representative Members: AGXT (human)UniProtKB:P21549

Function

L-alanine:glyoxylate transaminase activityGO:0008453
Substrates: glyoxylate L-alanine
Products: glycine pyruvate

Locations

peroxisomeGO:0005777

Principal glyoxylate detoxification route; deficiency = primary hyperoxaluria type 1 (PH1, the most severe). A common variant mistargets AGT to mitochondria.

Part 4: glyoxylate detoxification by reduction (cytosolic)
glyoxylate + NADPH to glycolateReactiongrhpr_step

Annotons

GRHPR: glyoxylate/hydroxypyruvate reductase
grhpr_activity
Participant: Family: D-isomer-specific 2-hydroxyacid dehydrogenase family (GRHPR)
Family:
D-isomer-specific 2-hydroxyacid dehydrogenase family (GRHPR)PANTHER:PTHR10996
Representative Members: GRHPR (human)UniProtKB:Q9UBQ7

Function

glyoxylate reductase (NADPH) activityGO:0030267
Substrates: glyoxylate NADPH
Products: glycolate NADP+

Locations

cytosolGO:0005829

Cytosolic glyoxylate detoxification (reduction); deficiency = primary hyperoxaluria type 2 (PH2).

Part 5: glyoxylate detoxification by transamination (mitochondrial)
glyoxylate transamination to glycine (mitochondrial)Reactionagxt2_step

Annotons

AGXT2: alanine-glyoxylate aminotransferase 2 (mitochondrial)
agxt2_activity
Participant: Family: Class-III aminotransferase family (AGXT2)
Family:
Class-III aminotransferase family (AGXT2)PANTHER:PTHR45688
Representative Members: AGXT2 (human)UniProtKB:Q9BYV1

Function

L-alanine:glyoxylate transaminase activityGO:0008453
Substrates: glyoxylate amino donor (D-alanine / beta-aminoisobutyrate)
Products: glycine 2-oxo acid

Locations

mitochondrial matrixGO:0005759

Mitochondrial glyoxylate detoxification and dimethylarginine (ADMA/SDMA) metabolism; a modifier of oxalate and cardiovascular/renal phenotypes.