Glycine formation and glycine-serine interconversion

Routes that supply the cellular glycine pool and interconvert glycine with L-serine, as found in fungi, bacteria and animals. Glycine is formed by up to three enzymatically unrelated, pyridoxal 5'-phosphate-dependent reactions: aldol cleavage of L-threonine to glycine and acetaldehyde by threonine aldolase; transamination of glyoxylate with L-alanine by alanine:glyoxylate aminotransferase; and the reversible tetrahydrofolate-dependent serine hydroxymethyltransferase (SHMT) reaction, which converts L-serine and tetrahydrofolate to glycine and 5,10-methylenetetrahydrofolate. Run in reverse, SHMT turns glycine made by the first two reactions into L-serine, giving a serine supply that does not depend on the phosphorylated pathway. Eukaryotes commonly have compartment-specific SHMT isozymes in the cytosol and in the mitochondrial matrix, and the direction of net flux through each depends on nutrient supply. In budding yeast, threonine aldolase is the main glycine source during growth on glucose, while the glucose-repressed glyoxylate transamination route supplies glycine and, through SHMT, serine on non-fermentable carbon sources. The relative weight of the routes differs between lineages; in mammals SHMT is the main source of glycine. The phosphorylated serine pathway, the glycine cleavage system, and downstream folate one-carbon reactions are separate modules.

MODULE:glycine_serine_interconversionDRAFTMetabolic Pathwaymodules/glycine_serine_interconversion.yaml
glycine biosynthetic processGO:0006545
GO:0006545
glycine biosynthetic process
Module-level process for glycine formation by the three routes.
YeastPathways:PWY3O-261
superpathway of serine and glycine biosynthesis (S. cerevisiae, SGD YeastPathways)
The YeastCyc superpathway combines the phosphorylated serine pathway (modelled separately as phosphorylated_serine_biosynthesis) with SHMT (SHM1, SHM2), threonine aldolase (GLY1) and alanine:glyoxylate aminotransferase (AGX1). The three glycine reactions and their catalysts are all retained here.
YeastPathways:GLYSYN-PWY
glycine biosynthesis I (S. cerevisiae, SGD YeastPathways)
Single-reaction frame for SHMT (SHM1, SHM2); folded into the SHMT part.
YeastPathways:GLYSYN-THR-PWY
glycine biosynthesis IV (S. cerevisiae, SGD YeastPathways)
Single-reaction frame for threonine aldolase (GLY1); folded into the threonine aldolase variant.
YeastPathways:GLYSYN-ALA-PWY
glycine biosynthesis III (S. cerevisiae, SGD YeastPathways)
Single-reaction frame for alanine:glyoxylate aminotransferase (AGX1); folded into the glyoxylate variant.
YeastPathways:PWY3O-230
serine biosynthesis from glyoxylate (S. cerevisiae, SGD YeastPathways)
YeastCyc lists only the SHMT reaction (SHM1, SHM2) for this frame, although its comment describes the AGX1 step that precedes it. Here it is represented by the glyoxylate variant followed by the SHMT part.
PMID:8132653
Cloning and molecular characterization of three genes, including two genes encoding serine hydroxymethyltransferases, whose inactivation is required to render yeast auxotrophic for glycine.
SHM1 encodes mitochondrial and SHM2 cytosolic SHMT; loss of SHM1, SHM2 and GLY1 is needed for complete glycine auxotrophy.
Gene disruption studies demonstrated that inactivation of SHM1, SHM2, and GLY1 is required to yield yeast that are completely auxotrophic for glycine.
PMID:9163906
Identification of Saccharomyces cerevisiae GLY1 as a threonine aldolase: a key enzyme in glycine biosynthesis.
GLY1 encodes threonine aldolase and is the main glycine source on glucose; on ethanol glycine is made via alanine:glyoxylate aminotransferase.
On ethanol as carbon source simultaneous disruption of GLY1, SHM1 and SHM2 did not lead to glycine auxotrophy because glycine biosynthesis proceeds via alanine glyoxylate aminotransferase.
PMID:9151955
The GLY1 gene of Saccharomyces cerevisiae encodes a low-specific L-threonine aldolase that catalyzes cleavage of L-allo-threonine and L-threonine to glycine--expression of the gene in Escherichia coli and purification and characterization of the enzyme.
Purified Gly1 is a PLP-dependent low-specificity L-threonine aldolase.
The enzyme catalyzes the cleavage of not only L-allo-threonine to glycine but also L-threonine.
PMID:14745783
Alanine : glyoxylate aminotransferase of Saccharomyces cerevisiae-encoding gene AGX1 and metabolic significance.
AGX1 (YFL030W) encodes alanine:glyoxylate aminotransferase; its loss in a gly1 shm1 shm2 background gives complete glycine auxotrophy.
Additional disruption of AGX1 revealed a complete glycine auxotrophy.
PMID:16226833
Crystal structure and confirmation of the alanine:glyoxylate aminotransferase activity of the YFL030w yeast protein.
Structure and activity confirm Agx1 as a highly specific PLP-dependent alanine:glyoxylate aminotransferase.
In this paper we show that YFL030w codes for an alanine:glyoxylate aminotransferase, highly specific for its amino donor and acceptor substrates.
PMID:3933486
Characteristics of alanine:glyoxylate aminotransferase from Saccharomyces cerevisiae, a regulatory enzyme in the glyoxylate pathway of glycine and serine biosynthesis from tricarboxylic acid-cycle intermediates.
The yeast enzyme is strongly induced on ethanol or acetate relative to glucose.
The transamination of glyoxylate is mainly catalysed by this enzyme in ethanol-grown cells.
PMID:9398220
Role of mitochondrial and cytoplasmic serine hydroxymethyltransferase isozymes in de novo purine synthesis in Saccharomyces cerevisiae.
The two SHMT isozymes run in different directions depending on nutrition: cytosolic SHMT makes glycine from serine, mitochondrial SHMT makes serine from glycine.
When grown on glycine, the mitochondrial SHMT was the predominant isozyme catalyzing the synthesis of serine from glycine and one-carbon units.
PMID:1326413
Genetic analysis of serine biosynthesis and glucose repression in yeast.
Yeast makes serine and glycine by a glycolytic (3-phosphoglycerate) route and a glucose-repressible gluconeogenic (glyoxylate) route.
Serine and glycine biosynthesis in yeast proceed by two pathways: a "glycolytic" pathway, using 3-phosphoglycerate, and a "gluconeogenic" pathway, using glyoxylate.
PMID:15948949
Transcriptional regulation of the one-carbon metabolism regulon in Saccharomyces cerevisiae by Bas1p.
Cited by YeastPathways for glycine-responsive, Bas1-dependent regulation of SHM2 and other one-carbon genes; regulatory context only.
file:yeast/GLY1/GLY1-ai-review.yaml
GLY1 gene review (S. cerevisiae)
Core function GO:0004793 in glycine biosynthesis, cytosol.
file:yeast/AGX1/AGX1-ai-review.yaml
AGX1 gene review (S. cerevisiae)
Core function GO:0008453 in glycine biosynthesis; compartment unresolved.
file:yeast/SHM2/SHM2-ai-review.yaml
SHM2 gene review (S. cerevisiae)
Core function GO:0004372 in glycine biosynthesis and tetrahydrofolate interconversion, cytosol.
file:yeast/SHM1/SHM1-ai-review.yaml
SHM1 gene review (S. cerevisiae)
Core function GO:0004372 in tetrahydrofolate interconversion, mitochondrion.
7Nodes
2Parts
2Variant Sets
4Variants
4Annotons
1Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:glycine_serine_interconversion deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Reaction chaining (advisory)

✓ every PRECEDES step chains, or its break is acknowledged via chaining_status.

  • glycine_formation_routes → shmt_step [NOT_CHECKED]
    Glycine made by threonine aldolase or alanine:glyoxylate aminotransferase is the substrate of SHMT in the serine-forming direction (the glyoxylate route to serine). In the opposite direction SHMT works in parallel with these routes as a glycine source.

Function consistency and core coverage

7 gene-function check(s) reflected in core functions · 0 conflict(s) · 2 evidence or coverage gap(s) (13 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
threonine_aldolase_activity GLY1 (Saccharomyces cerevisiae)
UniProtKB:P37303
Family Representative 		threonine aldolase activity
GO:0004793 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
threonine_aldolase_activity ltaE (Escherichia coli)
UniProtKB:P75823
Family Representative 		threonine aldolase activity
GO:0004793 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
alanine_glyoxylate_aminotransferase_activity AGX1 (Saccharomyces cerevisiae)
UniProtKB:P43567
Family Representative 		L-alanine:glyoxylate transaminase activity
GO:0008453 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
alanine_glyoxylate_aminotransferase_activity AGXT (human)
UniProtKB:P21549
Family Representative 		L-alanine:glyoxylate transaminase activity
GO:0008453 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cytosolic_shmt_activity SHM2 (Saccharomyces cerevisiae)
UniProtKB:P37291
Family Representative 		glycine hydroxymethyltransferase activity
GO:0004372 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cytosolic_shmt_activity SHMT1 (human)
UniProtKB:P34896
Family Representative 		glycine hydroxymethyltransferase activity
GO:0004372 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cytosolic_shmt_activity glyA (Escherichia coli)
UniProtKB:P0A825
Family Representative 		glycine hydroxymethyltransferase activity
GO:0004372 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
mitochondrial_shmt_activity SHM1 (Saccharomyces cerevisiae)
UniProtKB:P37292
Family Representative 		glycine hydroxymethyltransferase activity
GO:0004372 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mitochondrial_shmt_activity SHMT2 (human)
UniProtKB:P34897
Family Representative 		glycine hydroxymethyltransferase activity
GO:0004372 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
threonine_aldolase_activity low-specificity L-threonine aldolases
PANTHER:PTHR48097:SF9
Family 		threonine aldolase activity
GO:0004793 		Family Supported
Family review supports GO:0004793 for PANTHER:PTHR48097:SF9. Asserted by glycine_serine_interconversion; accepted by GLY1.
alanine_glyoxylate_aminotransferase_activity class-V aminotransferases (AGT clade)
PANTHER:PTHR21152
Family 		L-alanine:glyoxylate transaminase activity
GO:0008453 		Family Supported
Family review supports GO:0008453 FAMILY_WIDE. Asserted by glycine_serine_interconversion and glyoxylate_oxalate_metabolism; accepted by AGX1, AGXT and both zebrafish paralogs.
cytosolic_shmt_activity serine hydroxymethyltransferases
PANTHER:PTHR11680
Family 		glycine hydroxymethyltransferase activity
GO:0004372 		Family Supported
Family review supports GO:0004372 FAMILY_WIDE. Asserted by serine_biosynthesis_one_carbon and glycine_serine_interconversion; accepted by SHM1, SHM2, SHMT1, SHMT2 and GlyA.
mitochondrial_shmt_activity serine hydroxymethyltransferases
PANTHER:PTHR11680
Family 		glycine hydroxymethyltransferase activity
GO:0004372 		Family Supported
Family review supports GO:0004372 FAMILY_WIDE. Asserted by serine_biosynthesis_one_carbon and glycine_serine_interconversion; accepted by SHM1, SHM2, SHMT1, SHMT2 and GlyA.

Gene-review completeness (7/9 grounded genes reviewed)

7 complete review(s) · 4 with deep research · 2 missing review · 3 reviewed but lacking deep research

Gene Review Complete Deep research
AGX1 P43567 ✓ ✓ ✓
AGXT P21549 ✓ ✓ ✗
GLY1 P37303 ✓ ✓ ✓
glyA (Escherichia coli) P0A825 ✗ — —
ltaE (Escherichia coli) P75823 ✗ — —
SHM1 P37292 ✓ ✓ ✓
SHM2 P37291 ✓ ✓ ✓
SHMT1 P34896 ✓ ✓ ✗
SHMT2 P34897 ✓ ✓ ✗

Details

Glycine formation and glycine-serine interconversionMetabolic Pathwayglycine_serine_interconversion
glycine biosynthetic processGO:0006545

NEW module from five YeastPathways frames (PWY3O-261, GLYSYN-PWY, GLYSYN-THR-PWY, GLYSYN-ALA-PWY, PWY3O-230), each of which is a single reaction or a combination of the same reactions. They are alternative routes into one glycine/serine pool, so they are modelled as an optional variant set of serine-independent glycine routes (threonine aldolase, glyoxylate transamination) followed by the reversible SHMT step with cytosolic and mitochondrial isozyme variants. The phosphorylated serine pathway reactions of PWY3O-261 are in phosphorylated_serine_biosynthesis, which supplies serine to the SHMT step; the glycine cleavage system (glycine_cleavage_system) and the downstream folate one-carbon network (folate_one_carbon_interconversion) are separate. The human-specific serine_biosynthesis_one_carbon module overlaps the SHMT part. YeastCyc corrections: all four catalysts are correct and none is missing. PWY3O-230 lists only SHMT although its own comment names AGX1 as the first step; this module includes it. YeastCyc and its GO-CAM give no compartments; SHM1 is mitochondrial (PMID:8132653), SHM2 and GLY1 are cytosolic, and the AGX1 compartment is unresolved. GO-CAM disagreements: YeastPathways_PWY3O-261 places SHM1 in cytosol, uses only the broad process GO:0009070 rather than GO:0006545 or GO:0006564, and has no causal edges. No PomBase GO-CAM is linked, so S. pombe exemplars are not added. No glycine-specific regulation (Bas1/Gcn4, glycine induction) is modelled as a part.

Connections

Part 1: glycine formation from L-threonine or glyoxylate (optional)
Serine-independent glycine formationMetabolic Pathwayglycine_formation_routes

Alternative glycine-forming reactions that do not consume serine. Their presence and importance differ between lineages and growth conditions; the part is optional because some organisms make glycine mainly by SHMT.

Variant set: Serine-independent glycine routes by substrate route (One Or More)
Threonine aldolase routeReactionthreonine_aldolase_route

Annotons

Low-specificity L-threonine aldolase
threonine_aldolase_activity
Participant: Family: low-specificity L-threonine aldolases
Family:
low-specificity L-threonine aldolasesPANTHER:PTHR48097:SF9
Representative Members: GLY1 (Saccharomyces cerevisiae)UniProtKB:P37303 ltaE (Escherichia coli)UniProtKB:P75823
Required Function:
threonine aldolase activityGO:0004793

Function

threonine aldolase activityGO:0004793
Substrates: L-threonine
Products: glycine acetaldehyde

Locations

cytosolGO:0005829

PLP-dependent aldol cleavage of L-threonine; also a threonine catabolic step, and the acetaldehyde can feed cytosolic acetyl-CoA.

Glyoxylate transamination routeReactionglyoxylate_transamination_route

In yeast this route depends on glyoxylate-cycle glyoxylate and is glucose-repressed. The S. cerevisiae enzyme has been detected in mitochondrial proteomes and in the cytosol, and the mammalian AGXT ortholog is peroxisomal, so no location is asserted.

Annotons

Alanine:glyoxylate aminotransferase
alanine_glyoxylate_aminotransferase_activity
Participant: Family: class-V aminotransferases (AGT clade)
Family:
class-V aminotransferases (AGT clade)PANTHER:PTHR21152 Broad family; AGX1 is in subfamily SF24 and human AGXT in SF40. The required GO:0008453 function restricts the role to alanine:glyoxylate aminotransferases.
Representative Members: AGX1 (Saccharomyces cerevisiae)UniProtKB:P43567 AGXT (human)UniProtKB:P21549
Required Function:
L-alanine:glyoxylate transaminase activityGO:0008453

Function

L-alanine:glyoxylate transaminase activityGO:0008453
Substrates: glyoxylate L-alanine
Products: glycine pyruvate

Transaminates glyoxylate to glycine; main glycine route on non-fermentable carbon sources in yeast.

Part 2: reversible glycine-serine interconversion
Serine hydroxymethyltransferaseReactionshmt_step

L-serine + tetrahydrofolate <=> glycine + 5,10-methylene-THF + H2O. In the forward direction SHMT is a glycine source; in reverse it makes serine from glycine formed in part 1. Eukaryotes often have separate cytosolic and mitochondrial isozymes; bacteria have one cytoplasmic GlyA.

Variant set: SHMT compartment isozymes by subcellular compartment (One Or More)
Cytosolic SHMTReactioncytosolic_shmt_variant

Annotons

Cytosolic serine hydroxymethyltransferase
cytosolic_shmt_activity
Participant: Family: serine hydroxymethyltransferases
Family:
serine hydroxymethyltransferasesPANTHER:PTHR11680
Representative Members: SHM2 (Saccharomyces cerevisiae)UniProtKB:P37291 SHMT1 (human)UniProtKB:P34896 glyA (Escherichia coli)UniProtKB:P0A825
Required Function:
glycine hydroxymethyltransferase activityGO:0004372

Function

glycine hydroxymethyltransferase activityGO:0004372
Substrates: L-serine tetrahydrofolate
Products: glycine 5,10-methylenetetrahydrofolate water

Locations

cytosolGO:0005829

Cytosolic glycine/serine interconversion and one-carbon loading of tetrahydrofolate.

Mitochondrial SHMTReactionmitochondrial_shmt_variant

Annotons

Mitochondrial serine hydroxymethyltransferase
mitochondrial_shmt_activity
Participant: Family: serine hydroxymethyltransferases
Family:
serine hydroxymethyltransferasesPANTHER:PTHR11680
Representative Members: SHM1 (Saccharomyces cerevisiae)UniProtKB:P37292 SHMT2 (human)UniProtKB:P34897
Required Function:
glycine hydroxymethyltransferase activityGO:0004372

Function

glycine hydroxymethyltransferase activityGO:0004372
Substrates: glycine 5,10-methylenetetrahydrofolate water
Products: L-serine tetrahydrofolate

Locations

mitochondrial matrixGO:0005759

Mitochondrial glycine/serine interconversion; mainly a one-carbon supplier, and the serine-forming isozyme when glycine is abundant.