glutathione biosynthesis

MetaCyc:GLUTATHIONESYN-PWY

Glutathione biosynthesis ligates L-cysteine to L-glutamate with ATP to form gamma-L-glutamyl-L-cysteine, then ligates glycine to gamma-L-glutamyl-L-cysteine with a second ATP to form glutathione.

Pathway type

cofactor biosynthesis

Organism scope

Escherichia coli NCBITaxon:562

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Pathway network

18 nodes · 22 asserted directed edges

Arrows show recorded subject → object relationships, not necessarily metabolic flow. Select a node for details or an arrow for evidence. Scroll, zoom or find a node to explore.

Reaction / activity
Chemical / cofactor
Protein / complex
Other participant
Solid arrow: mechanistic relation
Dashed arrow: membership, location or cofactor relation

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Components and activities

Declared biological components and source reaction directions
Node	Kind or role	Source direction
Escherichia coli `NCBITaxon:562`	taxon
glutamate--cysteine ligase `EC:6.3.2.2`	molecular activity
glutathione synthase `EC:6.3.2.3`	molecular activity
L-cysteine `CHEBI:35235`	small molecule
L-glutamate `CHEBI:29985`	small molecule
ATP `CHEBI:30616`	small molecule
gamma-L-glutamyl-L-cysteine `CHEBI:58173`	small molecule
ADP `CHEBI:456216`	small molecule
phosphate `CHEBI:43474`	small molecule
H+ `CHEBI:15378`	small molecule
glycine `CHEBI:57305`	small molecule
glutathione `CHEBI:57925`	small molecule
Glutathione synthetase `UniProtKB:P04425`	protein
magnesium(2+) `CHEBI:18420`	cofactor
manganese(2+) `CHEBI:29035`	cofactor
Glutamate--cysteine ligase `UniProtKB:P0A6W9`	protein
Putative glutamate--cysteine ligase 2 `UniProtKB:P77213`	protein
glutamate--cysteine ligase reaction `RHEA:13286`	reaction	left to right
glutathione synthase reaction `RHEA:13558`	reaction	left to right

Mechanistic edges

Mechanistic edges and their cited evidence
Subject	Predicate and description	Object	Evidence
L-glutamate `CHEBI:29985`	consumes	glutamate--cysteine ligase reaction `RHEA:13286`	RHEA:13286 Source assertion: Rhea lists CHEBI:29985 on the substrates side of RHEA:13286 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13286']/rh:substrates; rh:contains/rh:compound/rh:accession`
ATP `CHEBI:30616`	consumes	glutamate--cysteine ligase reaction `RHEA:13286`	RHEA:13286 Source assertion: Rhea lists CHEBI:30616 on the substrates side of RHEA:13286 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13286']/rh:substrates; rh:contains/rh:compound/rh:accession`
L-cysteine `CHEBI:35235`	consumes	glutamate--cysteine ligase reaction `RHEA:13286`	RHEA:13286 Source assertion: Rhea lists CHEBI:35235 on the substrates side of RHEA:13286 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13286']/rh:substrates; rh:contains/rh:compound/rh:accession`
glutamate--cysteine ligase reaction `RHEA:13286`	produces	H+ `CHEBI:15378`	RHEA:13286 Source assertion: Rhea lists CHEBI:15378 on the products side of RHEA:13286 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13286']/rh:products; rh:contains/rh:compound/rh:accession`
glutamate--cysteine ligase reaction `RHEA:13286`	produces	phosphate `CHEBI:43474`	RHEA:13286 Source assertion: Rhea lists CHEBI:43474 on the products side of RHEA:13286 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13286']/rh:products; rh:contains/rh:compound/rh:accession`
glutamate--cysteine ligase reaction `RHEA:13286`	produces	ADP `CHEBI:456216`	RHEA:13286 Source assertion: Rhea lists CHEBI:456216 on the products side of RHEA:13286 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13286']/rh:products; rh:contains/rh:compound/rh:accession`
glutamate--cysteine ligase reaction `RHEA:13286`	produces	gamma-L-glutamyl-L-cysteine `CHEBI:58173`	RHEA:13286 Source assertion: Rhea lists CHEBI:58173 on the products side of RHEA:13286 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13286']/rh:products; rh:contains/rh:compound/rh:accession`
ATP `CHEBI:30616`	consumes	glutathione synthase reaction `RHEA:13558`	RHEA:13558 Source assertion: Rhea lists CHEBI:30616 on the substrates side of RHEA:13558 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13558']/rh:substrates; rh:contains/rh:compound/rh:accession`
glycine `CHEBI:57305`	consumes	glutathione synthase reaction `RHEA:13558`	RHEA:13558 Source assertion: Rhea lists CHEBI:57305 on the substrates side of RHEA:13558 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13558']/rh:substrates; rh:contains/rh:compound/rh:accession`
gamma-L-glutamyl-L-cysteine `CHEBI:58173`	consumes	glutathione synthase reaction `RHEA:13558`	RHEA:13558 Source assertion: Rhea lists CHEBI:58173 on the substrates side of RHEA:13558 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13558']/rh:substrates; rh:contains/rh:compound/rh:accession`
glutathione synthase reaction `RHEA:13558`	produces	H+ `CHEBI:15378`	RHEA:13558 Source assertion: Rhea lists CHEBI:15378 on the products side of RHEA:13558 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13558']/rh:products; rh:contains/rh:compound/rh:accession`
glutathione synthase reaction `RHEA:13558`	produces	phosphate `CHEBI:43474`	RHEA:13558 Source assertion: Rhea lists CHEBI:43474 on the products side of RHEA:13558 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13558']/rh:products; rh:contains/rh:compound/rh:accession`
glutathione synthase reaction `RHEA:13558`	produces	ADP `CHEBI:456216`	RHEA:13558 Source assertion: Rhea lists CHEBI:456216 on the products side of RHEA:13558 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13558']/rh:products; rh:contains/rh:compound/rh:accession`
glutathione synthase reaction `RHEA:13558`	produces	glutathione `CHEBI:57925`	RHEA:13558 Source assertion: Rhea lists CHEBI:57925 on the products side of RHEA:13558 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/13558']/rh:products; rh:contains/rh:compound/rh:accession`
glutamate--cysteine ligase `EC:6.3.2.2`	catalyzes	glutamate--cysteine ligase reaction `RHEA:13286`	RHEA:13285 Source assertion: Rhea associates EC:6.3.2.2 with the reaction family containing RHEA:13286. Source location `rh:ec` PMID:11675389 Escherichia coli gamma-glutamylcysteine synthetase. Two active site metal ions affect substrate and inhibitor binding. Source location `PubMed ArticleTitle`
glutathione synthase `EC:6.3.2.3`	catalyzes	glutathione synthase reaction `RHEA:13558`	RHEA:13557 Source assertion: Rhea associates EC:6.3.2.3 with the reaction family containing RHEA:13558. Source location `rh:ec` PMID:8810901 A pseudo-michaelis quaternary complex in the reverse reaction of a ligase: structure of Escherichia coli B glutathione synthetase complexed with ADP, glutathione, and sulfate at 2.0 A resolution. Source location `PubMed ArticleTitle`
glutamate--cysteine ligase reaction `RHEA:13286`	precedes	glutathione synthase reaction `RHEA:13558`	MetaCyc:GLUTATHIONESYN-PWY Source assertion: MetaCyc pathway ordering places RHEA:13286 before RHEA:13558 in this pathway. Shared intermediate: CHEBI:58173. Source location `Pathway/reaction-ordering and reaction-layout; Rhea-to-MetaCyc cross-references`
Glutathione synthetase `UniProtKB:P04425`	enables	glutathione synthase reaction `RHEA:13558`	UniProtKB:P04425 Source assertion: UniProt annotates UniProtKB:P04425 with catalytic activity for the reaction family of RHEA:13558. Annotation evidence: curated source annotation; organism taxon: NCBITaxon:83333. Source location `comments[commentType='CATALYTIC ACTIVITY'].reaction.reactionCrossReferences`
Glutathione synthetase `UniProtKB:P04425`	has_cofactor	magnesium(2+) `CHEBI:18420`	UniProtKB:P04425 Source assertion: UniProt lists CHEBI:18420 as a cofactor of UniProtKB:P04425 (evidence: ECO:0000250). Binds 1 Mg(2+) or Mn(2+) ion per subunit. Source location `comments[commentType='COFACTOR'].cofactors and note`
Glutathione synthetase `UniProtKB:P04425`	has_cofactor	manganese(2+) `CHEBI:29035`	UniProtKB:P04425 Source assertion: UniProt lists CHEBI:29035 as a cofactor of UniProtKB:P04425 (evidence: ECO:0000250). Binds 1 Mg(2+) or Mn(2+) ion per subunit. Source location `comments[commentType='COFACTOR'].cofactors and note`
Glutamate--cysteine ligase `UniProtKB:P0A6W9`	enables	glutamate--cysteine ligase reaction `RHEA:13286`	UniProtKB:P0A6W9 Source assertion: UniProt annotates UniProtKB:P0A6W9 with catalytic activity for the reaction family of RHEA:13286. Annotation evidence: curated source annotation; organism taxon: NCBITaxon:83333. Source location `comments[commentType='CATALYTIC ACTIVITY'].reaction.reactionCrossReferences`
Putative glutamate--cysteine ligase 2 `UniProtKB:P77213`	enables	glutamate--cysteine ligase reaction `RHEA:13286`	UniProtKB:P77213 Source assertion: UniProt annotates UniProtKB:P77213 with catalytic activity for the reaction family of RHEA:13286. Annotation evidence: ECO:0000255; organism taxon: NCBITaxon:83333. Source location `comments[commentType='CATALYTIC ACTIVITY'].reaction.reactionCrossReferences`

References

MetaCyc:GLUTATHIONESYN-PWY MetaCyc glutathione biosynthesis pathway (source version: 22.5)
RHEA:13285 Rhea glutamate--cysteine ligase reaction (source version: 139)
RHEA:13286 Rhea gamma-glutamylcysteine-forming glutamate--cysteine ligase direction (source version: 139)
RHEA:13557 Rhea glutathione synthase reaction (source version: 139)
RHEA:13558 Rhea glutathione-forming glutathione synthase direction (source version: 139)
PMID:11675389 Kelly et al., Journal of Biological Chemistry, 2002
PMID:8810901 Hara et al., Biochemistry, 1996
UniProtKB:P04425 UniProtKB:P04425 authority record (source version: 2026_03)
UniProtKB:P0A6W9 UniProtKB:P0A6W9 authority record (source version: 2026_03)
UniProtKB:P77213 UniProtKB:P77213 authority record (source version: 2026_03)

Curation history

2026-10-05T06:25:52Z codex
- EDIT — Review causal chemistry and add sourced molecular context
  Reviewed the entire record against MetaCyc 22.5 native pathway XML (including nested pathways), Rhea 139 explicit sides and directions, ENZYME 02-Sep-2026, PubMed records, and reviewed UniProt 2026_03 annotations within the record's taxon scope. Replaced generated structured-source quotations with source_assertion and source_locator. Typed molecular activities and participants. Reaction count 2 to 2; 0 directed-ID corrections; 3 protein annotations, 2 cofactor annotations and 0 sourced locations. All Rhea reaction substrate/product sets checked against independent Rhea authority; native pathway leaf coverage and source exceptions recorded in reports/causal_graph_review/metacyc-review.json. Full source URLs, versions and byte hashes are in metacyc-sources.json. All 50 MetaCyc records passed native schema validation; six targeted chemistry/evidence regression tests passed. Missing protein or cofactor annotations are not treated as biological absence; qualifications and exclusions are preserved in the ledger.
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