Glycine metabolism, including IMDs (WP5028)

Homo sapiens

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.


Denise Slenter , Egon Willighagen , Andra Waagmeester , Eric Weitz , Finterly Hu , and Friederike Ehrhart


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Homo sapiens


Rare Diseases


Pathway Ontology

glycine biosynthetic pathway

Disease Ontology

pyridoxamine 5'-phosphate oxidase deficiency glycine encephalopathy


Label Type Compact URI Comment
H4-folate Metabolite chebi:137944 AKA Tetrahydrofolic acid (THFA), or tetrahydrofolate
Pyridoxal-phosphate Metabolite chebi:597326
NAD+ Metabolite chebi:15846
2Fe-2S Metabolite chebi:49601
4Fe-4Scluster Metabolite chebi:33722 Cofactor for mitochondrial lipoyl synthase through LIAS []
serine Metabolite chebi:17115
glycine Metabolite chebi:15428
GMP-lipoate Metabolite chebi:86459
pyridoxamine 5'-phosphate Metabolite chebi:58451
CO2 Metabolite chebi:16526
NH3 Metabolite chebi:16134
Lipoate Metabolite chebi:30314
CH2=folate Metabolite chebi:1989 aka methylene-tetrahydrofolate, 5,10-Methylenetetrahydrofolate (annotated with naturally occuring diastereoisomer ID, named [6R]-5,10-methylene-THF.).
Glycine Metabolite chebi:15428
NADH Metabolite chebi:16908
H+ Metabolite chebi:15378
pyridoxine 5'-phosphate Metabolite chebi:58589
2Fe-2S Metabolite chebi:49601
2Fe-2S Metabolite chebi:49601
LIPT1 Protein uniprot:Q9Y234
SHMT Protein uniprot:P34896 Annotated with Cytosolic ID, another form is known to be active in mitochondria.
NFU1 Protein uniprot:Q9UMS0
LIAS Protein uniprot:O43766
GLRX5 Protein uniprot:Q86SX6
P-protein:GLDC Protein uniprot:P23378
IBA57 Protein uniprot:Q5T440
BOLA3 Protein uniprot:Q53S33
PNPO Protein uniprot:Q9NVS9
H-protein:GCSH Protein uniprot:P23434 '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
T-protein:AMT Protein uniprot:P48728 aka GCST
L-protein:DLD Protein uniprot:P09622 aka GCSL
reduced lipoate is re-oxidized by the L-protein
LIPT2 Protein uniprot:A6NK58
ISCU Protein uniprot:Q9H1K1
HSCB Protein uniprot:Q8IWL3


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  7. Mutations in iron-sulfur cluster scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes. Cameron JM, Janer A, Levandovskiy V, Mackay N, Rouault TA, Tong WH, et al. Am J Hum Genet. 2011 Oct 7;89(4):486–95. PubMed Europe PMC Scholia
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  10. Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. Baker PR 2nd, Friederich MW, Swanson MA, Shaikh T, Bhattacharya K, Scharer GH, et al. Brain. 2014 Feb;137(Pt 2):366–79. PubMed Europe PMC Scholia
  11. Altering the Mitochondrial Fatty Acid Synthesis (mtFASII) Pathway Modulates Cellular Metabolic States and Bioactive Lipid Profiles as Revealed by Metabolomic Profiling. Clay HB, Parl AK, Mitchell SL, Singh L, Bell LN, Murdock DG. PLoS One. 2016 Mar 10;11(3):e0151171. PubMed Europe PMC Scholia
  12. Mitochondrial Bol1 and Bol3 function as assembly factors for specific iron-sulfur proteins. Uzarska MA, Nasta V, Weiler BD, Spantgar F, Ciofi-Baffoni S, Saviello MR, et al. Elife. 2016 Aug 17;5:e16673. PubMed Europe PMC Scholia