Glyoxylate metabolism (WP5166)

Homo sapiens

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The glyoxylate metabolism in hepatocytes is affected by primary hyperoxaluria (PH) types 1-3, leading to glyoxylate accumulation and hence, increased oxalate production, which is transported out of the hepatocytes by SLC26a1 transporters on the basolateral membrane into the blood and consequently, the kidneys, where it causes the occurrence of CaOx (calcium + oxalate) crystal deposition and hence, kidney stones. PH1 is caused due to a mutation of the AGT (glyoxylate aminotransferase) trimer, responsible for the conversion of glyoxylate into pyruvate in the peroxisome. PH2 is caused by mutations of glyoxylate reductase (GR), that converts 3-hydroxypyruvate into D-glycerate in the cytosol. It also catalyses the conversion of glyoxylate into glycolate. PH3 is linked to mutations on the HOGA1 gene, yielding the tetramer 4‐hydroxy‐2‐oxoglutarate aldolase, which acts in the mitochondrion to convert 4-hydroxy-2-oxoglutarate to glyoxylate. Secondary hyperoxaluria is caused by (1) increased absorption of dietary oxalate through the GI tract or (2) increased consumption of dietary oxalate. There is an abundance of knowledge gaps in this pathway, specifically regarding the peroxisomal and mitochondrial transporters for several metabolites. This pathway is based on Physicians Guide to the Diagnosis, Treatment, and Follow-up of Inherited Metabolic Diseases by Nenad Blau Chapter 28 (Hyperoxalurias) (ISBN 3642403360).

Authors

Emilia Agasi , Alexandra Bosch , Egon Willighagen , Denise Slenter , and Eric Weitz

Activity

last edited

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Organisms

Homo sapiens

Communities

Inherited Metabolic Disorders (IMD) Pathways Rare Diseases

Annotations

Pathway Ontology

hyperoxaluria pathway glycine metabolic pathway D-alanine metabolic pathway primary hyperoxaluria type 1 pathway disease pathway primary hyperoxaluria type 2 pathway primary hyperoxaluria pathway

Disease Ontology

inherited metabolic disorder primary hyperoxaluria primary hyperoxaluria type 1 primary hyperoxaluria type 3 primary hyperoxaluria type 2

Cell Type Ontology

native cell hepatocyte

Participants
Query Drugst.One

Label Type Compact URI Comment
C5H6NO3 Metabolite chebi:62612 (3R,5S)-1-pyrroline-3-hydroxy-5-carboxylate
Calcium Metabolite chebi:29108
HOG Metabolite chebi:17742 4-hydroxy-2-oxoglutarate
Pyruvate Metabolite chebi:15361
Glyoxylate Metabolite chebi:36655
Oxalate Metabolite chebi:30623
Pyruvate Metabolite chebi:15361
L-Alanine Metabolite chebi:57972
Glycine Metabolite chebi:57305
3-hydroxypyruvate Metabolite chebi:17180
L-Serine Metabolite chebi:33384
D-glycerate Metabolite chebi:16659
L-glycerate Metabolite wikidata:Q27102017
HOG Metabolite chebi:17742 What is happening here?
4-hydroxy-2-oxoglutarate
FAD Metabolite chebi:16238 Flavin adenine dinucleotide
Hydroxyproline Metabolite chebi:18095 trans-4-hydroxy-L-proline
Glycolate Metabolite chebi:29805
C5H8NO5 Metabolite chebi:6331 erythro-4-hydroxy-L-glutamate(1−)
SLC26A1 Protein uniprot:Q9H2B4
HYPDH Protein uniprot:Q9UF12 Hydroxyproline dehydrogenase
PXMP2 Protein uniprot:Q9NR77 Peroxisomal membrane protein 2
HOGA1 Protein uniprot:Q86XE5 4-hydroxy-2-oxoglutarate aldolase 1
GRHPR Protein uniprot:Q9UBQ7 Also called D-glycerate dehydrogenase (GDH), and hydroxypyruvate reductase
Abbreviated with GR or GRHPR
GO Protein uniprot:Q9UJM8
LDH5 Protein uniprot:P00338 L-lactate dehydrogenase
DAO Protein uniprot:P14920 D-amino-acid oxidase
SPT Protein uniprot:P21549 Serine-pyruvate transaminase
Also: Alanine-glyoxylate aminotransferase
HOGA1 Protein uniprot:Q86XE5 4-hydroxy-2-oxoglutarate aldolase
1P5CDH Protein uniprot:P30038 Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial
AspAT Protein uniprot:P00505 aspartate aminotransferase
GO Protein uniprot:Q9UJM8 Glycolate oxidase
Hydroxyacid oxidase
LDH5 Protein uniprot:P00338 L-lactate dehydrogenase
Consists of four M-subunits (found in muscle and liver), coded by LDHA gene
Unknown peroxisomalglyoxylate carrier Protein reactome:R-HSA-6784434 Cytosolic glyoxylate can enter the peroxisome but the carrier that mediates its entry has not been identified (Wanders et al. 2016).
Unknownglyoxylatecarrier Protein reactome:R-HSA-6784436
Unknown mitochondrialHPRO carrier Protein reactome:R-HSA-6784213 Id: R-HSA-8953316.2 (found on Reactome)
AGT Protein uniprot:P21549 Serine-pyruvate transaminase
Also: Alanine-glyoxylate aminotransferase

References

  1. Carrier-mediated transport controls hydroxyproline catabolism in heart mitochondria from spontaneously hypertensive rat. Atlante A, Seccia TM, Marra E, Minervini GM, Vulpis V, Pirrelli A, et al. FEBS Lett. 1996 Nov 4;396(2–3):279–84. PubMed Europe PMC Scholia
  2. Pxmp2 is a channel-forming protein in Mammalian peroxisomal membrane. Rokka A, Antonenkov VD, Soininen R, Immonen HL, Pirilä PL, Bergmann U, et al. PLoS One. 2009;4(4):e5090. PubMed Europe PMC Scholia
  3. Metabolism of (13)C5-hydroxyproline in mouse models of Primary Hyperoxaluria and its inhibition by RNAi therapeutics targeting liver glycolate oxidase and hydroxyproline dehydrogenase. Li X, Knight J, Fargue S, Buchalski B, Guan Z, Inscho EW, et al. Biochim Biophys Acta. 2016 Feb;1862(2):233–9. PubMed Europe PMC Scholia
  4. Metabolic Interplay between Peroxisomes and Other Subcellular Organelles Including Mitochondria and the Endoplasmic Reticulum. Wanders RJA, Waterham HR, Ferdinandusse S. Front Cell Dev Biol. 2016 Jan 28;3:83. PubMed Europe PMC Scholia
  5. Dihydrodipicolinate Synthase: Structure, Dynamics, Function, and Evolution. Grant Pearce F, Hudson AO, Loomes K, Dobson RCJ. Subcell Biochem. 2017;83:271–89. PubMed Europe PMC Scholia
  6. Specific Inhibition of Hepatic Lactate Dehydrogenase Reduces Oxalate Production in Mouse Models of Primary Hyperoxaluria. Lai C, Pursell N, Gierut J, Saxena U, Zhou W, Dills M, et al. Mol Ther. 2018 Aug 1;26(8):1983–95. PubMed Europe PMC Scholia
  7. Downregulated Expression of Solute Carrier Family 26 Member 6 in NRK-52E Cells Attenuates Oxalate-Induced Intracellular Oxidative Stress. Jiang H, Gao X, Gong J, Yang Q, Lan R, Wang T, et al. Oxid Med Cell Longev. 2018 Oct 10;2018:1724648. PubMed Europe PMC Scholia
  8. Lactate dehydrogenase 5: identification of a druggable target to reduce oxaluria. Stevens JS, Al-Awqati Q. J Clin Invest. 2019 May 20;129(6):2201–4. PubMed Europe PMC Scholia
  9. Regulation of human 4-hydroxy-2-oxoglutarate aldolase by pyruvate and α-ketoglutarate: implications for primary hyperoxaluria type-3. Huang A, Burke J, Bunker RD, Mok YF, Griffin MD, Baker EN, et al. Biochem J. 2019 Nov 15;476(21):3369–83. PubMed Europe PMC Scholia