Glyoxylate metabolism (Homo sapiens)

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3LumenKidneyTranslocationD-amino acid oxidase-FAD complexBasolateral membraneTissue deposition and CaOx kidney stonesCalciumSLC26A131Primary hyperoxaluria IGluconeogenesisHYPDHPXMP2Mitochondrial intermembrane spaceHOGHOGA1GRHPRPyruvateGOCytosolGlyoxylateOxalateLDHPeroxisomeCytosolGlyoxylateOxalatePyruvateL-AlanineGlycine3-hydroxypyruvateL-SerineL-Alanine3-hydroxypyruvateD-glycerateL-glycerateLDHDAO1HOG4HOGFAD1GlyoxylatePXMP2PXMP2AGTHOGA1HOGA1HOGA1Primary hyperoxaluria IIIPrimary hyperoxaluria IIMitochondrial matrixHydroxyproline1P5CDHAspAT2Hydroxyproline3, 4HepatocyteOxalateGlycolateGlycolateGRGOOxalateLDHLDHLDHGlycolateOxalatePrimary hyperoxaluria IIPyruvateD-glycerateGRPrimary hyperoxaluria II???BloodSecondary hyperoxaluriaDiseaseCatalysisPathwayStimulationProteinMetaboliteConversionConnection to diseaseMultistep processLegendProtein complexProteinProteinAGTAGTAGT


Description

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).

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Bibliography

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  1. Huang A, Burke J, Bunker RD, Mok YF, Griffin MD, Baker EN, Loomes KM; ''Regulation of human 4-hydroxy-2-oxoglutarate aldolase by pyruvate and α-ketoglutarate: implications for primary hyperoxaluria type-3''; https://pubmed.ncbi.nlm.nih.gov/31696211/, 2019 PubMed Europe PMC Scholia
  2. Atlante A, Seccia TM, Marra E, Minervini GM, Vulpis V, Pirrelli A, Passarella S; ''Carrier-mediated transport controls hydroxyproline catabolism in heart mitochondria from spontaneously hypertensive rat.''; FEBS Lett, 1996 PubMed Europe PMC Scholia
  3. Grant Pearce F, Hudson AO, Loomes K, Dobson RCJ; ''Dihydrodipicolinate Synthase: Structure, Dynamics, Function, and Evolution''; https://pubmed.ncbi.nlm.nih.gov/28271480/, 2017 PubMed Europe PMC Scholia
  4. Li X, Knight J, Fargue S, Buchalski B, Guan Z, Inscho EW, Liebow A, Fitzgerald K, Querbes W, Todd Lowther, Holmes RP; ''Metabolism of (13)C5-hydroxyproline in mouse models of Primary Hyperoxaluria and its inhibition by RNAi therapeutics targeting liver glycolate oxidase and hydroxyproline dehydrogenase.''; https://europepmc.org/article/med/26655602, 2015 PubMed Europe PMC Scholia
  5. Stevens JS, Al-Awqati Q; ''Lactate dehydrogenase 5: identification of a druggable target to reduce oxaluria''; https://pubmed.ncbi.nlm.nih.gov/31107247/, 2019 PubMed Europe PMC Scholia
  6. Lai C, Pursell N, Gierut J, Saxena U, Zhou W, Dills M, Diwanji R, Dutta C, Koser M, Nazef N, Storr R, Kim B, Martin-Higueras C, Salido E, Wang W, Abrams M, Dudek H, Brown BD; ''Specific Inhibition of Hepatic Lactate Dehydrogenase Reduces Oxalate Production in Mouse Models of Primary Hyperoxaluria.''; Mol Ther, 2018 PubMed Europe PMC Scholia
  7. Jiang H, Gao X, Gong J, Yang Q, Lan R, Wang T, Liu J, Yin C, Wang S, Liu Z; ''Downregulated Expression of Solute Carrier Family 26 Member 6 in NRK-52E Cells Attenuates Oxalate-Induced Intracellular Oxidative Stress.''; Oxid Med Cell Longev, 2018 PubMed Europe PMC Scholia
  8. Wanders RJ, Waterham HR, Ferdinandusse S; ''Metabolic Interplay between Peroxisomes and Other Subcellular Organelles Including Mitochondria and the Endoplasmic Reticulum.''; Front Cell Dev Biol, 2015 PubMed Europe PMC Scholia
  9. Rokka A, Antonenkov VD, Soininen R, Immonen HL, Pirilä PL, Bergmann U, Sormunen RT, Weckström M, Benz R, Hiltunen JK; ''Pxmp2 is a channel-forming protein in Mammalian peroxisomal membrane.''; PLoS One, 2009 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
128248view23:55, 29 January 2024EweitzSoften and use solid-lined rounded rectangles for disease nodes
127754view13:54, 2 December 2023EgonwChEBI id for Ca2+ instead of the "Ca" atom
122169view15:00, 14 March 2022EmiliaAgasiCorrected enzyme names and added RHEA IDs to missing interactions
122080view11:45, 10 March 2022EmiliaAgasiUpdated data nodes and added sources
122079view10:58, 10 March 2022DeSlChanged elbow-connector to straight interaction for L-Alanine
122078view10:57, 10 March 2022DeSlConnecting L-serine to same anchor as L-alanine
122077view10:56, 10 March 2022DeSlConnecting L-Alanine to same anchor as enzyme
122076view10:47, 10 March 2022DeSlConnected L-Alanine and Glycine to same anchor
122064view14:00, 9 March 2022EmiliaAgasiChanged identifiers
122050view12:49, 9 March 2022EmiliaAgasiOntology Term : 'primary hyperoxaluria' added !
122049view12:48, 9 March 2022EmiliaAgasiOntology Term : 'hyperoxaluria pathway' added !
122023view10:15, 9 March 2022EmiliaAgasireactions modified
122021view10:12, 9 March 2022EmiliaAgasiCHEBI modification
122019view10:08, 9 March 2022EmiliaAgasiConnected diseases to interaction nodes and modified RHEA IDs
121940view14:39, 8 March 2022EmiliaAgasiAdded source and corrected enzyme identifier of LDH5
121919view12:40, 8 March 2022EmiliaAgasiAdded complex in legend and corrected naming error
121772view13:48, 3 March 2022DeSlCondensed pathway, updated layout of legend
121771view13:34, 3 March 2022DeSlSmall layout changes, aligning
121688view07:59, 25 February 2022EgonwRemoved the RHEA prefix
121657view13:28, 23 February 2022EmiliaAgasiAdded reference
121655view13:23, 23 February 2022EmiliaAgasiAdded missing data nodes
121632view14:57, 22 February 2022EgonwUpdated a UniProt data source
121571view14:12, 21 February 2022Alexandraboschaddition of Rhea interactions
121560view12:44, 21 February 2022Alexandraboschchanged 'basic interaction' arrows to 'MIM conversion' where applicable and chnaged translocation arrows from dashed to solid lines + added them to the legend
121547view10:19, 21 February 2022Alexandraboschaddition of Rhea interactions
121472view15:59, 17 February 2022EmiliaAgasiOntology Term : 'D-alanine metabolic pathway' added !
121471view15:57, 17 February 2022EmiliaAgasiOntology Term : 'native cell' added !
121470view15:55, 17 February 2022EmiliaAgasiOntology Term : 'inherited metabolic disorder' added !
121469view15:51, 17 February 2022EmiliaAgasiOntology Term : 'glycine metabolic pathway' added !
121468view15:50, 17 February 2022EmiliaAgasiOntology Term : 'disease pathway' added !
121467view15:49, 17 February 2022EmiliaAgasiModified description
121466view15:49, 17 February 2022EmiliaAgasiAdded different connection points for byproduct of enzymatic reactions
121465view15:45, 17 February 2022EmiliaAgasiAdded missing identifiers and secondary PH
121420view11:20, 17 February 2022EmiliaAgasiModified description
121407view10:13, 17 February 2022EmiliaAgasiOntology Term : 'primary hyperoxaluria pathway' added !
121406view10:13, 17 February 2022EmiliaAgasiOntology Term : 'primary hyperoxaluria type 2 pathway' added !
121405view10:12, 17 February 2022EmiliaAgasiOntology Term : 'primary hyperoxaluria type 1 pathway' added !
121404view10:12, 17 February 2022EmiliaAgasiOntology Term : 'primary hyperoxaluria type 2' added !
121403view10:11, 17 February 2022EmiliaAgasiOntology Term : 'primary hyperoxaluria type 3' added !
121402view10:10, 17 February 2022EmiliaAgasiOntology Term : 'primary hyperoxaluria type 1' added !
121401view10:10, 17 February 2022EmiliaAgasiOntology Term : 'hepatocyte' added !
121397view10:03, 17 February 2022EmiliaAgasiAdded additional literature
121185view15:41, 10 February 2022EmiliaAgasiMade some enzymes complexes, changed mitochondrion, added transporters, added OMIM disease links
121136view15:51, 9 February 2022EmiliaAgasiConnected all points and added interactions using Rhea, found missing identifiers, improved layout
121105view14:26, 8 February 2022EmiliaAgasiNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
1P5CDHProtein1.2.1.88 (BRENDA)
  • 1-pyrroline-5-carboxylate dehydrogenase
  • Add "EC" with EC identifier?
3-hydroxypyruvateMetaboliteCHEBI:17180 (ChEBI)
?R-HSA-6784213 (Reactome)
  • Unknown mitochondrial HPRO carrier
  • Id: R-HSA-8953316.2 (found on Reactome)
?R-HSA-6784434 (Reactome)
  • Unknown peroxisomal glyoxylate carrier
  • Cytosolic glyoxylate can enter the peroxisome but the carrier that mediates its entry has not been identified (Wanders et al. 2016).
  • ChEBI 36080
?R-HSA-6784436 (Reactome)
  • Unknown glyoxylate carrier
  • CHEBI:36080
AGTProteinA2V838 (Uniprot-TrEMBL)
  • Serine-pyruvate transaminase
  • Also: Alanine-glyoxylate aminotransferase
AspATProteinP00505 (Uniprot-TrEMBL) aspartate aminotransferase
CalciumMetaboliteCHEBI:22984 (ChEBI)
D-glycerateMetaboliteCHEBI:16659 (ChEBI)
D-glycerateMetaboliteQ27102017 (Wikidata)
DAOProteinP14920 (Uniprot-TrEMBL) D-amino-acid oxidase
FADMetaboliteCHEBI:16238 (ChEBI) Flavin adenine dinucleotide
GOProteinQ9UJM8 (Uniprot-TrEMBL)
  • Glycolate oxidase
  • Hydroxyacid oxidase
GRHPRProteinQ9UBQ7 (Uniprot-TrEMBL)
  • Also called D-glycerate dehydrogenase (GDH), and hydroxypyruvate reductase
  • EC:1.1.1.81
  • Proper identifier TBD
GRProteinQ9UBQ7 (Uniprot-TrEMBL) Glyoxylate reductase/hydroxypyruvate reductase
GluconeogenesisPathwayWP4361 (WikiPathways) https://www.wikipathways.org/index.php/Pathway:WP4361
GlycineMetaboliteCHEBI:57305 (ChEBI)
GlycolateMetaboliteCHEBI:29805 (ChEBI)
GlyoxylateMetaboliteCHEBI:36655 (ChEBI)
HOGA1ProteinQ86XE5 (Uniprot-TrEMBL) 4-hydroxy-2-oxoglutarate aldolase 1
HOGMetaboliteCHEBI:17742 (ChEBI)
  • What is happening here?
  • 4-hydroxy-2-oxoglutarate
HYPDHProteinQ9UF12 (Uniprot-TrEMBL) Hydroxyproline dehydrogenase
HydroxyprolineMetaboliteCHEBI:18095 (ChEBI) trans-4-hydroxy-L-proline
L-AlanineMetaboliteCHEBI:57972 (ChEBI)
L-SerineMetaboliteCHEBI:33384 (ChEBI)
L-glycerateMetaboliteQ27102017 (Wikidata)
LDHProtein1.1.1.27 (BRENDA)
  • In book it says "(R)-lactate dehydrogenase" - investigate
  • L-Lactate dehydrogenase
LDHProteinV9HWB9 (Uniprot-TrEMBL) L-lactate dehydrogenase
OxalateMetaboliteCHEBI:30623 (ChEBI)
PXMP2ProteinQ9NR77 (Uniprot-TrEMBL) Peroxisomal membrane protein 2
PyruvateMetaboliteCHEBI:15361 (ChEBI)
SLC26A1ProteinQ9H2B4 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
3-hydroxypyruvateD-glyceratemim-conversionRHEA:17907 (Rhea)
GRHPRmim-catalysisRHEA:17905 (Rhea)
GlycolateArrowRHEA:25312 (Rhea)
GlycolateGlyoxylateArrowRHEA:25312 (Rhea)
GlycolateGlyoxylatemim-conversionRHEA:21265 (Rhea)
GlyoxylateGlycolateArrowRHEA:10994 (Rhea)
GlyoxylateOxalateArrowRHEA:14837 (Rhea)
GlyoxylateOxalatemim-conversionRHEA:14838 (Rhea)
GlyoxylatePyruvatemim-conversionRHEA:24249 (Rhea)
HOGGlyoxylatemim-conversionRHEA:18170 (Rhea)
L-Alaninemim-conversionRHEA:24249 (Rhea)
L-Serinemim-conversionRHEA:22853 (Rhea)
Pyruvate3-hydroxypyruvatemim-conversionRHEA:22853 (Rhea)
Pyruvatemim-conversionRHEA:18170 (Rhea)
mim-catalysisRHEA:18169 (Rhea)
mim-catalysisRHEA:22855 (Rhea)
mim-catalysisRHEA:24251 (Rhea)
mim-conversionRHEA:22853 (Rhea)
mim-conversionRHEA:24249 (Rhea)
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP5166"
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