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
4Connections

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.

Function consistency and core coverage

5 gene-function check(s) reflected in core functions · 0 conflict(s) · 3 evidence or coverage gap(s) (10 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
hao1_activity HAO1 (human)
UniProtKB:Q9UJM8
Family Representative 		(S)-2-hydroxy-acid oxidase activity
GO:0003973 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hoga1_activity HOGA1 (human)
UniProtKB:Q86XE5
Family Representative 		(R,S)-4-hydroxy-2-oxoglutarate aldolase activity
GO:0008700 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
agxt_activity AGXT (human)
UniProtKB:P21549
Family Representative 		L-alanine:glyoxylate transaminase activity
GO:0008453 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
grhpr_activity GRHPR (human)
UniProtKB:Q9UBQ7
Family Representative 		glyoxylate reductase (NADPH) activity
GO:0030267 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
agxt2_activity AGXT2 (human)
UniProtKB:Q9BYV1
Family Representative 		L-alanine:glyoxylate transaminase activity
GO:0008453 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hao1_activity FMN-dependent L-2-hydroxyacid oxidase family (HAO)
PANTHER:PTHR10578:SF107
Family 		(S)-2-hydroxy-acid oxidase activity
GO:0003973 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10578:SF107.
hoga1_activity DapA-like aldolase family (HOGA1)
PANTHER:PTHR12128:SF66
Family 		(R,S)-4-hydroxy-2-oxoglutarate aldolase activity
GO:0008700 		Family Supported
Family review supports GO:0008700 for PANTHER:PTHR12128:SF66. 4-Hydroxy-2-oxoglutarate aldolase activity belongs to the bilaterian HOGA1 clade (PTN000950946) inside SF66. The bacterial SF66 members are DHDPS enzymes and are excepted.
agxt_activity Class-V aminotransferase family (AGXT)
PANTHER:PTHR21152
Family 		L-alanine:glyoxylate transaminase activity
GO:0008453 		Family Supported
Family review supports GO:0008453 FAMILY_WIDE. Asserted by glycine_serine_interconversion and glyoxylate_oxalate_metabolism; accepted by AGX1, AGXT and both zebrafish paralogs.
grhpr_activity D-isomer-specific 2-hydroxyacid dehydrogenase family (GRHPR)
PANTHER:PTHR10996:SF137
Family 		glyoxylate reductase (NADPH) activity
GO:0030267 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10996:SF137.
agxt2_activity Class-III aminotransferase family (AGXT2)
PANTHER:PTHR45688
Family 		L-alanine:glyoxylate transaminase activity
GO:0008453 		Family Function Unreviewed
Family review leaves GO:0008483 UNRESOLVED. The actual inventory contains AGXT2 transaminases, ETNPPL and PHYKPL phospholyases, and decarboxylase/racemase proteins. Purified human AGXT2L1/ETNPPL Q8TBG4 degrades phosphoethanolamine, while AGXT2L2/PHYKPL acts on phosphohydroxylysine (PMID:22241472). Q8TBG4 is the source of the CG8745 caution, so that caution argues against transamination, not against catalysis generally. CG8745 lies in mixed SF13, not the dedicated vertebrate ETNPPL SF1; its precise substrate is unresolved. A complete set of function-bearing branches is not delimited, so no exhaustive family or subfamily grant is asserted.

Gene-review completeness (5/5 grounded genes reviewed)

4 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 ✓ 33/34 ✗
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 or subfamily 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 -> grhpr_step Provides Input For
Glyoxylate from HOGA1 can be reduced to glycolate by GRHPR. Glyoxylate reduction is reported in both mitochondria and cytosol, but whether GRHPR protein itself is mitochondrial is not established, so the hand-off may require glyoxylate export to the cytosol. Accumulated 4-hydroxy-2-oxoglutarate in HOGA1 deficiency may inhibit 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:SF107
Representative Members: HAO1 (human)UniProtKB:Q9UJM8

Function

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

Processes

glycolate catabolic processGO:0046296

Locations

peroxisomal matrixGO:0005782

Generates glyoxylate (the oxalate precursor) by catabolising glycolate; a therapeutic target for the primary hyperoxalurias, where its loss lowers oxalate. Human biallelic HAO1 loss on its own causes a benign isolated glycolic aciduria (PMID:24996905).

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:SF66
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

peroxisomal matrixGO:0005782

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:SF137
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), with a minor mitochondrial pool that can reduce hydroxyproline-derived glyoxylate; also reduces hydroxypyruvate to D-glycerate (GO:0016618). Deficiency = primary hyperoxaluria type 2 (PH2), with urinary oxalate and L-glycerate.

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.