L-proline biosynthesis I (from L-glutamate)

MetaCyc:PROSYN-PWY

L-proline biosynthesis I phosphorylates L-glutamate to L-glutamyl 5-phosphate, reduces it to L-glutamate 5-semialdehyde, cyclizes that intermediate to (S)-1-pyrroline-5-carboxylate, and reduces it to L-proline.

Pathway type

amino acid biosynthesis

Organism scope

Escherichia coli NCBITaxon:562

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Pathway network

23 nodes · 33 asserted directed edges

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Chemical / cofactor
Protein / complex
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Cell / process context
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 5-kinase `EC:2.7.2.11`	molecular activity
glutamate-5-semialdehyde dehydrogenase `EC:1.2.1.41`	molecular activity
pyrroline-5-carboxylate reductase `EC:1.5.1.2`	molecular activity
L-glutamate `CHEBI:29985`	small molecule
ATP `CHEBI:30616`	small molecule
L-glutamyl 5-phosphate `CHEBI:58274`	small molecule
ADP `CHEBI:456216`	small molecule
NADPH `CHEBI:57783`	small molecule
H+ `CHEBI:15378`	small molecule
L-glutamate 5-semialdehyde `CHEBI:58066`	small molecule
phosphate `CHEBI:43474`	small molecule
NADP(+) `CHEBI:58349`	small molecule
(S)-1-pyrroline-5-carboxylate `CHEBI:17388`	small molecule
H2O `CHEBI:15377`	small molecule
L-proline `CHEBI:60039`	small molecule
Gamma-glutamyl phosphate reductase `UniProtKB:P07004`	protein
cytoplasm `GO:0005737`	cellular component
Glutamate 5-kinase `UniProtKB:P0A7B5`	protein
Pyrroline-5-carboxylate reductase `UniProtKB:P0A9L8`	protein
glutamate 5-kinase reaction `RHEA:14878`	reaction	left to right
glutamate-5-semialdehyde dehydrogenase reaction `RHEA:19543`	reaction	right to left
L-glutamate 5-semialdehyde cyclization `RHEA:28235`	reaction	left to right
NADPH-dependent pyrroline-5-carboxylate reductase reaction `RHEA:14111`	reaction	right to left

Mechanistic edges

Mechanistic edges and their cited evidence
Subject	Predicate and description	Object	Evidence
L-glutamate `CHEBI:29985`	consumes	glutamate 5-kinase reaction `RHEA:14878`	RHEA:14878 Source assertion: Rhea lists CHEBI:29985 on the substrates side of RHEA:14878 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/14878']/rh:substrates; rh:contains/rh:compound/rh:accession`
ATP `CHEBI:30616`	consumes	glutamate 5-kinase reaction `RHEA:14878`	RHEA:14878 Source assertion: Rhea lists CHEBI:30616 on the substrates side of RHEA:14878 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/14878']/rh:substrates; rh:contains/rh:compound/rh:accession`
glutamate 5-kinase reaction `RHEA:14878`	produces	ADP `CHEBI:456216`	RHEA:14878 Source assertion: Rhea lists CHEBI:456216 on the products side of RHEA:14878 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/14878']/rh:products; rh:contains/rh:compound/rh:accession`
glutamate 5-kinase reaction `RHEA:14878`	produces	L-glutamyl 5-phosphate `CHEBI:58274`	RHEA:14878 Source assertion: Rhea lists CHEBI:58274 on the products side of RHEA:14878 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/14878']/rh:products; rh:contains/rh:compound/rh:accession`
H+ `CHEBI:15378`	consumes	glutamate-5-semialdehyde dehydrogenase reaction `RHEA:19543`	RHEA:19543 Source assertion: Rhea lists CHEBI:15378 on the substrates side of RHEA:19543 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/19543']/rh:substrates; rh:contains/rh:compound/rh:accession`
NADPH `CHEBI:57783`	consumes	glutamate-5-semialdehyde dehydrogenase reaction `RHEA:19543`	RHEA:19543 Source assertion: Rhea lists CHEBI:57783 on the substrates side of RHEA:19543 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/19543']/rh:substrates; rh:contains/rh:compound/rh:accession`
L-glutamyl 5-phosphate `CHEBI:58274`	consumes	glutamate-5-semialdehyde dehydrogenase reaction `RHEA:19543`	RHEA:19543 Source assertion: Rhea lists CHEBI:58274 on the substrates side of RHEA:19543 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/19543']/rh:substrates; rh:contains/rh:compound/rh:accession`
glutamate-5-semialdehyde dehydrogenase reaction `RHEA:19543`	produces	phosphate `CHEBI:43474`	RHEA:19543 Source assertion: Rhea lists CHEBI:43474 on the products side of RHEA:19543 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/19543']/rh:products; rh:contains/rh:compound/rh:accession`
glutamate-5-semialdehyde dehydrogenase reaction `RHEA:19543`	produces	L-glutamate 5-semialdehyde `CHEBI:58066`	RHEA:19543 Source assertion: Rhea lists CHEBI:58066 on the products side of RHEA:19543 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/19543']/rh:products; rh:contains/rh:compound/rh:accession`
glutamate-5-semialdehyde dehydrogenase reaction `RHEA:19543`	produces	NADP(+) `CHEBI:58349`	RHEA:19543 Source assertion: Rhea lists CHEBI:58349 on the products side of RHEA:19543 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/19543']/rh:products; rh:contains/rh:compound/rh:accession`
L-glutamate 5-semialdehyde `CHEBI:58066`	consumes	L-glutamate 5-semialdehyde cyclization `RHEA:28235`	RHEA:28235 Source assertion: Rhea lists CHEBI:58066 on the substrates side of RHEA:28235 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/28235']/rh:substrates; rh:contains/rh:compound/rh:accession`
L-glutamate 5-semialdehyde cyclization `RHEA:28235`	produces	H2O `CHEBI:15377`	RHEA:28235 Source assertion: Rhea lists CHEBI:15377 on the products side of RHEA:28235 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/28235']/rh:products; rh:contains/rh:compound/rh:accession`
L-glutamate 5-semialdehyde cyclization `RHEA:28235`	produces	H+ `CHEBI:15378`	RHEA:28235 Source assertion: Rhea lists CHEBI:15378 on the products side of RHEA:28235 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/28235']/rh:products; rh:contains/rh:compound/rh:accession`
L-glutamate 5-semialdehyde cyclization `RHEA:28235`	produces	(S)-1-pyrroline-5-carboxylate `CHEBI:17388`	RHEA:28235 Source assertion: Rhea lists CHEBI:17388 on the products side of RHEA:28235 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/28235']/rh:products; rh:contains/rh:compound/rh:accession`
H+ `CHEBI:15378`	consumes	NADPH-dependent pyrroline-5-carboxylate reductase reaction `RHEA:14111`	RHEA:14111 Source assertion: Rhea lists CHEBI:15378 on the substrates side of RHEA:14111 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/14111']/rh:substrates; rh:contains/rh:compound/rh:accession`
(S)-1-pyrroline-5-carboxylate `CHEBI:17388`	consumes	NADPH-dependent pyrroline-5-carboxylate reductase reaction `RHEA:14111`	RHEA:14111 Source assertion: Rhea lists CHEBI:17388 on the substrates side of RHEA:14111 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/14111']/rh:substrates; rh:contains/rh:compound/rh:accession`
NADPH `CHEBI:57783`	consumes	NADPH-dependent pyrroline-5-carboxylate reductase reaction `RHEA:14111`	RHEA:14111 Source assertion: Rhea lists CHEBI:57783 on the substrates side of RHEA:14111 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/14111']/rh:substrates; rh:contains/rh:compound/rh:accession`
NADPH-dependent pyrroline-5-carboxylate reductase reaction `RHEA:14111`	produces	NADP(+) `CHEBI:58349`	RHEA:14111 Source assertion: Rhea lists CHEBI:58349 on the products side of RHEA:14111 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/14111']/rh:products; rh:contains/rh:compound/rh:accession`
NADPH-dependent pyrroline-5-carboxylate reductase reaction `RHEA:14111`	produces	L-proline `CHEBI:60039`	RHEA:14111 Source assertion: Rhea lists CHEBI:60039 on the products side of RHEA:14111 in this directed reaction. Source location `rdf:Description[@rdf:about='http://rdf.rhea-db.org/14111']/rh:products; rh:contains/rh:compound/rh:accession`
glutamate 5-kinase `EC:2.7.2.11`	catalyzes	glutamate 5-kinase reaction `RHEA:14878`	RHEA:14877 Source assertion: Rhea associates EC:2.7.2.11 with the reaction family containing RHEA:14878. Source location `rh:ec` PMID:6319365 gamma-Glutamyl kinase, the first enzyme of the proline biosynthetic pathway, was purified to homogeneity from an Escherichia coli strain resistant to the proline analog 3,4-dehydroproline. Source location `PubMed Abstract`
glutamate-5-semialdehyde dehydrogenase `EC:1.2.1.41`	catalyzes	glutamate-5-semialdehyde dehydrogenase reaction `RHEA:19543`	RHEA:19541 Source assertion: Rhea associates EC:1.2.1.41 with the reaction family containing RHEA:19543. Source location `rh:ec` PMID:7035170 Glutamate-semialdehyde dehydrogenase, catalysing the reduction in vivo of gamma-glutamyl phosphate to glutamate 5-semialdehyde in the pathway of proline biosynthesis in Escherichia coli, has been purified to homogeneity. Source location `PubMed Abstract`
pyrroline-5-carboxylate reductase `EC:1.5.1.2`	catalyzes	NADPH-dependent pyrroline-5-carboxylate reductase reaction `RHEA:14111`	RHEA:14109 Source assertion: Rhea associates EC:1.5.1.2 with the reaction family containing RHEA:14111. Source location `rh:ec` PMID:6296787 The sequence of the Escherichia coli proC gene which encodes for delta 1-pyrroline-5-carboxylate (PCA) reductase was determined. Source location `PubMed Abstract`
glutamate 5-kinase reaction `RHEA:14878`	precedes	glutamate-5-semialdehyde dehydrogenase reaction `RHEA:19543`	MetaCyc:PROSYN-PWY Source assertion: MetaCyc pathway ordering places RHEA:14878 before RHEA:19543 in this pathway. Shared intermediate: CHEBI:58274. Source location `Pathway/reaction-ordering and reaction-layout; Rhea-to-MetaCyc cross-references`
glutamate-5-semialdehyde dehydrogenase reaction `RHEA:19543`	precedes	L-glutamate 5-semialdehyde cyclization `RHEA:28235`	MetaCyc:PROSYN-PWY Source assertion: MetaCyc pathway ordering places RHEA:19543 before RHEA:28235 in this pathway. Shared intermediate: CHEBI:58066. Source location `Pathway/reaction-ordering and reaction-layout; Rhea-to-MetaCyc cross-references`
L-glutamate 5-semialdehyde cyclization `RHEA:28235`	precedes	NADPH-dependent pyrroline-5-carboxylate reductase reaction `RHEA:14111`	MetaCyc:PROSYN-PWY Source assertion: MetaCyc pathway ordering places RHEA:28235 before RHEA:14111 in this pathway. Shared intermediate: CHEBI:17388. Source location `Pathway/reaction-ordering and reaction-layout; Rhea-to-MetaCyc cross-references`
Gamma-glutamyl phosphate reductase `UniProtKB:P07004`	enables	glutamate-5-semialdehyde dehydrogenase reaction `RHEA:19543`	UniProtKB:P07004 Source assertion: UniProt annotates UniProtKB:P07004 with catalytic activity for the reaction family of RHEA:19543. Annotation evidence: ECO:0000255, ECO:0000269; organism taxon: NCBITaxon:83333. Source location `comments[commentType='CATALYTIC ACTIVITY'].reaction.reactionCrossReferences`
Gamma-glutamyl phosphate reductase `UniProtKB:P07004`	located_in	cytoplasm `GO:0005737`	UniProtKB:P07004 Source assertion: UniProt locates UniProtKB:P07004 in Cytoplasm (SL-0086, mapped by UniProt to GO:0005737). Annotation evidence: ECO:0000255. Source location `comments[commentType='SUBCELLULAR LOCATION'].subcellularLocations; UniProt location vocabulary GO mapping`
Glutamate 5-kinase `UniProtKB:P0A7B5`	enables	glutamate 5-kinase reaction `RHEA:14878`	UniProtKB:P0A7B5 Source assertion: UniProt annotates UniProtKB:P0A7B5 with catalytic activity for the reaction family of RHEA:14878. Annotation evidence: ECO:0000255, ECO:0000269; organism taxon: NCBITaxon:83333. Source location `comments[commentType='CATALYTIC ACTIVITY'].reaction.reactionCrossReferences`
L-proline `CHEBI:60039`	inhibits	Glutamate 5-kinase `UniProtKB:P0A7B5`	UniProtKB:P0A7B5 Source assertion: UniProt activity-regulation annotation: Inhibited by proline and ADP Source location `comments[commentType='ACTIVITY REGULATION'].texts`
ADP `CHEBI:456216`	inhibits	Glutamate 5-kinase `UniProtKB:P0A7B5`	UniProtKB:P0A7B5 Source assertion: UniProt activity-regulation annotation: Inhibited by proline and ADP Source location `comments[commentType='ACTIVITY REGULATION'].texts`
Glutamate 5-kinase `UniProtKB:P0A7B5`	located_in	cytoplasm `GO:0005737`	UniProtKB:P0A7B5 Source assertion: UniProt locates UniProtKB:P0A7B5 in Cytoplasm (SL-0086, mapped by UniProt to GO:0005737). Annotation evidence: ECO:0000255. Source location `comments[commentType='SUBCELLULAR LOCATION'].subcellularLocations; UniProt location vocabulary GO mapping`
Pyrroline-5-carboxylate reductase `UniProtKB:P0A9L8`	enables	NADPH-dependent pyrroline-5-carboxylate reductase reaction `RHEA:14111`	UniProtKB:P0A9L8 Source assertion: UniProt annotates UniProtKB:P0A9L8 with catalytic activity for the reaction family of RHEA:14111. Annotation evidence: ECO:0000255, ECO:0000269; organism taxon: NCBITaxon:83333. Source location `comments[commentType='CATALYTIC ACTIVITY'].reaction.reactionCrossReferences`
Pyrroline-5-carboxylate reductase `UniProtKB:P0A9L8`	located_in	cytoplasm `GO:0005737`	UniProtKB:P0A9L8 Source assertion: UniProt locates UniProtKB:P0A9L8 in Cytoplasm (SL-0086, mapped by UniProt to GO:0005737). Annotation evidence: ECO:0000255, ECO:0000269. Source location `comments[commentType='SUBCELLULAR LOCATION'].subcellularLocations; UniProt location vocabulary GO mapping`

References

MetaCyc:PROSYN-PWY MetaCyc L-proline biosynthesis I (from L-glutamate) pathway (source version: 22.5)
RHEA:14877 Rhea glutamate 5-kinase reaction (source version: 139)
RHEA:14878 Rhea left-to-right glutamate 5-kinase direction (source version: 139)
RHEA:19541 Rhea glutamate-5-semialdehyde dehydrogenase reaction (source version: 139)
RHEA:19543 Rhea L-glutamate 5-semialdehyde-producing direction (source version: 139)
RHEA:28234 Rhea spontaneous L-glutamate 5-semialdehyde cyclization reaction (source version: 139)
RHEA:28235 Rhea L-glutamate 5-semialdehyde cyclization direction (source version: 139)
RHEA:14109 Rhea NADPH-dependent pyrroline-5-carboxylate reductase reaction (source version: 139)
RHEA:14111 Rhea L-proline-producing pyrroline-5-carboxylate reductase direction (source version: 139)
PMID:6319365 Smith et al., Journal of Bacteriology, 1984
PMID:7035170 Hayzer and Leisinger, European Journal of Biochemistry, 1982
PMID:6296787 Deutch et al., Nucleic Acids Research, 1982
PMID:39514317 Newton et al., Proceedings of the National Academy of Sciences, 2024
UniProtKB:P07004 UniProtKB:P07004 authority record (source version: 2026_03)
UniProtKB:P0A7B5 UniProtKB:P0A7B5 authority record (source version: 2026_03)
UniProtKB:P0A9L8 UniProtKB:P0A9L8 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 4 to 4; 0 directed-ID corrections; 3 protein annotations, 0 cofactor annotations and 3 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. Did not add the suggested ProB-ProA interaction/channeling requirement: primary PMID:39514317 demonstrates that channeling is unnecessary in E. coli.
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