Glycine metabolism, including IMDs (Homo sapiens)

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5, 11374 mitochondria~ 72% of patients had a mutation in GLDC, 24% in AMT, and 4 % is called :variant NKH.(1 patient presented a mutation in GCSH).NKHClassic NKH2Fe-2SPNPOopo-HNAD+SHMTmt FAS IIGMP-lipoateGLRX5Pyridoxal-phosphatepyridoxamine 5'-phosphateNFU1glycineLIASP-protein:GLDCACSMserineOctanoyl-HNH3BOLA3Lipoyl-HH4-folateCO2IBA57LipoateLIPT14Fe-4SclusterApo-H2, 6102, 6, 9H-protein:GCSH12T-protein:AMTL-protein:DLDCH2=folateGlycineNADHH+41, 8pyridoxine 5'-phosphate7PNPODPNPOD affects the availability of pyridoxal-P, therefore having a secondary effect on the activity of the P-protein from the glycine cleavage system.Variant NKHOctanoyl-ACPLIPT2ISCU2Fe-2S2Fe-2SISC1ISC2HSPAS9HSCBDiseaseCatalysisPathwayStimulationProteinMetaboliteConversionConnection to diseaseLegendUnkown biologicalinteraction


The main disorder related to glycine (NonKetotic Hyperglycinemia, NKH) is a malfunctioning of the glycine cleavage enzyme, which consists out of four subunits (P-, H-, T- and L-protein). These subunits work together (however not as a complex) to convert glycine and H4-folate into methylene-tetrahydrofolate (CH2=folate), as depicted on the lefthand side of this pathway. This disorder is also known as glycine encephalopathy, with cerebral dysfunctioning as the common denominator. Besides "classical" NKH, there are several patients without mutations in the cleavage enzyme, however presenting variants within a protein related to the formation of lipoyl-H, as depicted on the righthand side of this pathway. The individual relationship between these proteins and the formation of iron-sulfur clusters (Fe-S) are not completely known, however there are indications that mutations within the NFU1, BOLA3 and GLXR5 gene can lead to a similar phenotype as NKH; most patients present with either less or more severe neurological symptoms compared to "classical" NKH. For clarity, the influence of pyridoxal-P has been added to this pathway, where a variant within the PNPO gene can lead to secondary effects on the activity of the P-protein from the cleavage system.

This pathway was inspired by Chapter 5 (edition 4) of the book of Blau (ISBN 3642403360 (978-3642403361)), Fig. 5.1.

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  1. Hiraga K, Kochi H, Hayasaka K, Kikuchi G, Nyhan WL; ''Defective glycine cleavage system in nonketotic hyperglycinemia. Occurrence of a less active glycine decarboxylase and an abnormal aminomethyl carrier protein.''; J Clin Invest, 1981 PubMed Europe PMC Scholia
  2. Uzarska MA, Nasta V, Weiler BD, Spantgar F, Ciofi-Baffoni S, Saviello MR, Gonnelli L, Mühlenhoff U, Banci L, Lill R; ''Mitochondrial Bol1 and Bol3 function as assembly factors for specific iron-sulfur proteins.''; Elife, 2016 PubMed Europe PMC Scholia
  3. Douce R, Bourguignon J, Neuburger M, Rébeillé F; ''The glycine decarboxylase system: a fascinating complex.''; Trends Plant Sci, 2001 PubMed Europe PMC Scholia
  4. Kure S, Kato K, Dinopoulos A, Gail C, DeGrauw TJ, Christodoulou J, Bzduch V, Kalmanchey R, Fekete G, Trojovsky A, Plecko B, Breningstall G, Tohyama J, Aoki Y, Matsubara Y; ''Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia.''; Hum Mutat, 2006 PubMed Europe PMC Scholia
  5. Baker PR 2nd, Friederich MW, Swanson MA, Shaikh T, Bhattacharya K, Scharer GH, Aicher J, Creadon-Swindell G, Geiger E, MacLean KN, Lee WT, Deshpande C, Freckmann ML, Shih LY, Wasserstein M, Rasmussen MB, Lund AM, Procopis P, Cameron JM, Robinson BH, Brown GK, Brown RM, Compton AG, Dieckmann CL, Collard R, Coughlin CR 2nd, Spector E, Wempe MF, Van Hove JL; ''Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5.''; Brain, 2014 PubMed Europe PMC Scholia
  6. Cameron JM, Janer A, Levandovskiy V, Mackay N, Rouault TA, Tong WH, Ogilvie I, Shoubridge EA, Robinson BH; ''Mutations in iron-sulfur cluster scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes.''; Am J Hum Genet, 2011 PubMed Europe PMC Scholia
  7. Musayev FN, Di Salvo ML, Ko TP, Schirch V, Safo MK; ''Structure and properties of recombinant human pyridoxine 5'-phosphate oxidase.''; Protein Sci, 2003 PubMed Europe PMC Scholia
  8. Koyata H, Hiraga K; ''The glycine cleavage system: structure of a cDNA encoding human H-protein, and partial characterization of its gene in patients with hyperglycinemias.''; Am J Hum Genet, 1991 PubMed Europe PMC Scholia
  9. Navarro-Sastre A, Tort F, Stehling O, Uzarska MA, Arranz JA, Del Toro M, Labayru MT, Landa J, Font A, Garcia-Villoria J, Merinero B, Ugarte M, Gutierrez-Solana LG, Campistol J, Garcia-Cazorla A, Vaquerizo J, Riudor E, Briones P, Elpeleg O, Ribes A, Lill R; ''A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins.''; Am J Hum Genet, 2011 PubMed Europe PMC Scholia
  10. Clay HB, Parl AK, Mitchell SL, Singh L, Bell LN, Murdock DG; ''Altering the Mitochondrial Fatty Acid Synthesis (mtFASII) Pathway Modulates Cellular Metabolic States and Bioactive Lipid Profiles as Revealed by Metabolomic Profiling.''; PLoS One, 2016 PubMed Europe PMC Scholia
  11. Nenad Blau, Carlo Dionisi Vici, K Michael Gibson, Marinus Duran; ''Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases''; Springer (ISBN-13: 978-3642403361), 2014
  12. Mayr JA, Zimmermann FA, Fauth C, Bergheim C, Meierhofer D, Radmayr D, Zschocke J, Koch J, Sperl W; ''Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation.''; Am J Hum Genet, 2011 PubMed Europe PMC Scholia


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120413view09:33, 30 November 2021Fehrhartboxed pathway nodes
119482view11:50, 1 July 2021DeSlConverted line in legend to graphical line.
119481view11:49, 1 July 2021DeSl
119102view09:48, 17 June 2021FinterlyAdded ISBN for book citation
117662view11:54, 22 May 2021EweitzModified title
116628view11:15, 9 May 2021EweitzModified title
114253view07:16, 1 January 2021MaintBotReplaced the HMDB id with undefined stereochemistry with the R form, matching the compound it reacted from
114230view21:41, 27 December 2020Andraconnect unconnected lines
114132view10:31, 23 December 2020DeSlUpdated vis. of legend, including unknown bio. interactions.
114131view10:28, 23 December 2020DeSlAdded vis. for cleavage system.
114130view10:27, 23 December 2020DeSlChanged mitochondria text vis.
114129view10:26, 23 December 2020DeSlAdded legend.
114118view10:20, 23 December 2020DeSlOntology Term : 'glycine encephalopathy' added !
114117view10:20, 23 December 2020DeSlOntology Term : 'glycine biosynthetic pathway' added !
114116view10:19, 23 December 2020DeSlOntology Term : 'pyridoxamine 5'-phosphate oxidase deficiency' added !
114115view10:18, 23 December 2020DeSlAdded last lit ref on LIAS
114114view10:16, 23 December 2020DeSlAdded more lit ref., and mitochondrial drawing
114113view10:12, 23 December 2020DeSlAdded more lit. refs
114112view10:07, 23 December 2020DeSlAdded lit. ref. and description for full PW.
114098view14:35, 22 December 2020EgonwRhea identifiers without RHEA:
114093view12:18, 22 December 2020DeSlNew pathway

External references


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NameTypeDatabase referenceComment
2Fe-2SMetaboliteCHEBI:49601 (ChEBI)
4Fe-4S clusterMetaboliteCHEBI:33722 (ChEBI) Cofactor for mitochondrial lipoyl synthase through LIAS []
BOLA3ProteinQ53S33 (Uniprot-TrEMBL)
CH2=folateMetaboliteCHEBI:1989 (ChEBI) aka methylene-tetrahydrofolate, 5,10-Methylenetetrahydrofolate (annotated with naturally occuring diastereoisomer ID, named [6R]-5,10-methylene-THF.).
GMP-lipoateMetaboliteCHEBI:86459 (ChEBI)
H-protein: GCSHProteinP23434 (Uniprot-TrEMBL)
  • "The H-protein is responsible for interacting with the three other proteins and acts as a shuttle for some of the intermediate products in glycine decarboxylation." []
  • After removing CO2 from glycine, the remaining amino-methyl group ir transferred to lipoate on the H-protein
ISCUProteinQ9H1K1 (Uniprot-TrEMBL)
L-protein: DLDProteinP09622 (Uniprot-TrEMBL)
  • aka GCSL
  • reduced lipoate is re-oxidized by the L-protein
LIASProteinO43766 (Uniprot-TrEMBL)
LipoateMetabolite30314 (ChEBI)
NFU1ProteinQ9UMS0 (Uniprot-TrEMBL)
P-protein: GLDCProteinP23378 (Uniprot-TrEMBL)
PNPOProteinQ9NVS9 (Uniprot-TrEMBL)
Pyridoxal-phosphateMetaboliteCHEBI:597326 (ChEBI)
T-protein: AMTProteinP48728 (Uniprot-TrEMBL) aka GCST
mt FAS IIPathway
pyridoxamine 5'-phosphateMetaboliteCHEBI:58451 (ChEBI)
pyridoxine 5'-phosphateMetaboliteCHEBI:58589 (ChEBI)

Annotated Interactions

SourceTargetTypeDatabase referenceComment
pyridoxamine 5'-phosphatePyridoxal-phosphatemim-conversion15818 (Rhea)
pyridoxine 5'-phosphatePyridoxal-phosphatemim-conversion15150 (Rhea)
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