Generic gluconeogenesis module

A generic, taxon-neutral decomposition of gluconeogenesis: the synthesis of a hexose phosphate (and, in some lineages, free glucose) from three- and four-carbon precursors such as pyruvate, lactate, glycerol, amino-acid skeletons, or the malate and oxaloacetate made by the glyoxylate cycle from two-carbon substrates. Seven near-equilibrium reactions are shared with Embden-Meyerhof-Parnas glycolysis and run in reverse. The three effectively irreversible glycolytic steps are bypassed by dedicated enzymes. Pyruvate kinase is bypassed either in two steps through oxaloacetate (a pyruvate carboxylase or a malate dehydrogenase makes oxaloacetate, and a phosphoenolpyruvate carboxykinase decarboxylates and phosphorylates it) or in one step by a pyruvate dikinase. Phosphofructokinase is bypassed by fructose-1,6-bisphosphatase. Hexokinase is bypassed only where free glucose is released, by glucose-6-phosphatase. Organisms that keep the product as glucose 6-phosphate for storage polysaccharides and cell-wall glucans stop one step earlier. The module is written as function selectors grounded by representative enzyme families, so that it can represent bacterial, fungal, plant and animal implementations.

MODULE:generic_gluconeogenesisDRAFTABSTRACTMetabolic Pathwaymodules/gluconeogenesis.yaml
gluconeogenesisGO:0006094
GO:0006094
gluconeogenesis
The module is grounded in the GO biological process term for gluconeogenesis.
MetaCyc:GLUCONEO-PWY
gluconeogenesis pathway
MetaCyc represents gluconeogenesis as a conserved pathway with organism-specific enzyme variants.
YeastPathways:GLUCONEO-PWY-1
gluconeogenesis I
Source pathway for the S. cerevisiae realisation (11 reactions). Retained: PYC1/PYC2 (pyruvate carboxylase), MDH2 (cytosolic malate dehydrogenase), PCK1 (ATP-dependent PEPCK), ENO1/ENO2, GPM1, PGK1, TDH1-3, FBA1, FBP1 and PGI1. Corrections: TPI1 is missing from the frame although the triose-phosphate isomerase step is required to return glyceraldehyde 3-phosphate to the aldolase as dihydroxyacetone phosphate, so it is added here. The mitochondrial malic enzyme MAE1 (malate to pyruvate) and the mitochondrial (MDH1) and peroxisomal (MDH3) malate dehydrogenases are listed but are not gluconeogenic bypass steps. MAE1 makes pyruvate in the matrix, MDH1 is the TCA-cycle isozyme and MDH3 the glyoxylate-cycle isozyme, so they are left to those modules.
PMID:1898090
Electron microscopic localization of pyruvate carboxylase in rat liver and Saccharomyces cerevisiae by immunogold procedures.
Pyruvate carboxylase is mitochondrial in rat liver but cytosolic in budding yeast, which is the basis of the compartment variant set on the carboxylation step.
In contrast, in S. cerevisiae, pyruvate carboxylase was found exclusively in the cytosol.
PMID:2665820
Localization and kinetics of pyruvate-metabolizing enzymes in relation to aerobic alcoholic fermentation in Saccharomyces cerevisiae CBS 8066 and Candida utilis CBS 621.
Independent confirmation that yeast pyruvate carboxylase is cytosolic.
In contrast to the general situation in fungi, plants and animals, pyruvate carboxylase was found to be a cytosolic enzyme in both yeasts.
PMID:9123965
Pyruvate metabolism in Saccharomyces cerevisiae.
Review of the yeast pyruvate branch point, including anaplerotic carboxylation by pyruvate carboxylase.
the anaplerotic carboxylation of pyruvate to oxaloacetate, catalysed by pyruvate carboxylase
PMID:1986231
Isolation, nucleotide sequence analysis, and disruption of the MDH2 gene from Saccharomyces cerevisiae: evidence for three isozymes of yeast malate dehydrogenase.
MDH2 encodes the major non-mitochondrial malate dehydrogenase and is required for growth on C2 carbon sources, where gluconeogenesis is fed by glyoxylate-cycle malate.
Disruption of the MDH2 gene in a haploid yeast strain produced a mutant unable to grow on minimal medium with acetate or ethanol as a carbon source.
PMID:2689220
Isolation and characterization of the gene encoding phosphoenolpyruvate carboxykinase from Saccharomyces cerevisiae.
PCK1 encodes the single, glucose-repressed yeast PEPCK.
Only one copy of the gene was found per haploid yeast genome. An RNA of about 2 kb which hybridized with a DNA probe internal to the PCK1 gene was found only in cells growing in non-fermentable carbon sources.
PMID:3003364
Fructose bisphosphatase of Saccharomyces cerevisiae. Cloning, disruption and regulation of the FBP1 structural gene.
FBP1 is the single yeast fructose-1,6-bisphosphatase; the null mutant is a hexose auxotroph.
The fbp1 mutant strain is a hexose auxotroph, otherwise growing normally.
PMID:3905788
Differential expression of the three yeast glyceraldehyde-3-phosphate dehydrogenase genes.
The same three GAPDH isozymes act on glucose and ethanol, so the glycolytic enzymes also serve the gluconeogenic direction.
The relative proportions of expression of each gene is the same in cells grown in the presence of glucose or ethanol as carbon source
file:modules/emp_glycolysis.yaml
Generic Embden-Meyerhof-Parnas (EMP) glycolysis module
The catabolic counterpart. The reversible trunk below uses the same enzyme families and exemplars as the corresponding EMP steps, run in the gluconeogenic direction.
27Nodes
13Parts
6Variant Sets
13Variants
17Annotons
11Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

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

Leaf nodes lacking representative members

✓ representative grounding skipped for abstract module.

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.

  • pep_formation → reversible_glycolytic_trunk [NOT_CHECKED]
    Continuity on phosphoenolpyruvate; no CoA intermediate.
  • reversible_glycolytic_trunk → fructose_bisphosphatase_step [NOT_CHECKED]
    Continuity on fructose 1,6-bisphosphate; no CoA intermediate.
  • fructose_bisphosphatase_step → gng_pgi_step [NOT_CHECKED]
    Continuity on fructose 6-phosphate; no CoA intermediate.
  • gng_pgi_step → terminal_hexose_endpoint [NOT_CHECKED]
    Continuity on glucose 6-phosphate; no CoA intermediate.

Function consistency and core coverage

17 gene-function check(s) reflected in core functions · 0 conflict(s) · 0 evidence or coverage gap(s) (40 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
pyruvate_carboxylase_activity PC (human)
UniProtKB:P11498
Family Representative 		pyruvate carboxylase activity
GO:0004736 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cytosolic_pyruvate_carboxylase_activity PYC1 (S. cerevisiae)
UniProtKB:P11154
Family Representative 		pyruvate carboxylase activity
GO:0004736 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cytosolic_pyruvate_carboxylase_activity PYC2 (S. cerevisiae)
UniProtKB:P32327
Family Representative 		pyruvate carboxylase activity
GO:0004736 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cytosolic_mdh_activity MDH2 (S. cerevisiae)
UniProtKB:P22133
Family Representative 		L-malate dehydrogenase (NAD+) activity
GO:0030060 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gtp_pepck_activity ANY_WITH_FUNCTION
Gene 		phosphoenolpyruvate carboxykinase (GTP) activity
GO:0004613 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
atp_pepck_activity PCK1 (S. cerevisiae)
UniProtKB:P10963
Family Representative 		phosphoenolpyruvate carboxykinase (ATP) activity
GO:0004612 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
diphosphate_pepck_activity ANY_WITH_FUNCTION
Gene 		phosphoenolpyruvate carboxykinase (diphosphate) activity
GO:0030585 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
ppdk_activity ANY_WITH_FUNCTION
Gene 		pyruvate, phosphate dikinase activity
GO:0050242 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
pep_synthase_activity ppsA (Escherichia coli K-12)
UniProtKB:P23538
Family Representative 		pyruvate, water dikinase activity
GO:0008986 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gng_enolase_activity ENO1 (S. cerevisiae)
UniProtKB:P00924
Family Representative 		phosphopyruvate hydratase activity
GO:0004634 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gng_enolase_activity ENO2 (S. cerevisiae)
UniProtKB:P00925
Family Representative 		phosphopyruvate hydratase activity
GO:0004634 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gng_pgam_activity GPM1 (S. cerevisiae; dPGM)
UniProtKB:P00950
Family Representative 		phosphoglycerate mutase activity
GO:0004619 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gng_pgk_activity PGK1 (S. cerevisiae)
UniProtKB:P00560
Family Representative 		phosphoglycerate kinase activity
GO:0004618 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gng_gapdh_activity TDH3 (S. cerevisiae)
UniProtKB:P00359
Family Representative 		glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity
GO:0004365 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gng_gapdh_activity TDH2 (S. cerevisiae)
UniProtKB:P00358
Family Representative 		glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity
GO:0004365 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gng_gapdh_activity TDH1 (S. cerevisiae)
UniProtKB:P00360
Family Representative 		glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity
GO:0004365 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gng_tpi_activity TPI1 (S. cerevisiae)
UniProtKB:P00942
Family Representative 		triose-phosphate isomerase activity
GO:0004807 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gng_aldolase_activity FBA1 (S. cerevisiae; class II)
UniProtKB:P14540
Family Representative 		fructose-bisphosphate aldolase activity
GO:0004332 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fructose_bisphosphatase_activity FBP1 (S. cerevisiae)
UniProtKB:P09201
Family Representative 		fructose 1,6-bisphosphate 1-phosphatase activity
GO:0042132 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gng_pgi_activity PGI1 (S. cerevisiae)
UniProtKB:P12709
Family Representative 		glucose-6-phosphate isomerase activity
GO:0004347 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
glucose_6_phosphatase_activity ANY_WITH_FUNCTION
Gene 		glucose-6-phosphatase activity
GO:0004346 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
pyruvate_carboxylase_activity biotin-dependent pyruvate carboxylase
PANTHER:PTHR43778
Family 		pyruvate carboxylase activity
GO:0004736 		Family Supported
Family review supports GO:0004736 FAMILY_WIDE. Asserted by pyruvate_metabolism, gluconeogenesis and bacterial_pyruvate_metabolism; accepted by every reviewed member.
cytosolic_pyruvate_carboxylase_activity biotin-dependent pyruvate carboxylase
PANTHER:PTHR43778
Family 		pyruvate carboxylase activity
GO:0004736 		Family Supported
Family review supports GO:0004736 FAMILY_WIDE. Asserted by pyruvate_metabolism, gluconeogenesis and bacterial_pyruvate_metabolism; accepted by every reviewed member.
cytosolic_mdh_activity malate dehydrogenase
PANTHER:PTHR11540
Family 		L-malate dehydrogenase (NAD+) activity
GO:0030060 		Family Supported
Family review supports GO:0030060 FAMILY_WIDE. Asserted by glyoxylate_cycle, malate_aspartate_shuttle, gluconeogenesis and peroxisomal_beta_oxidation (SF72); accepted by every reviewed isozyme.
atp_pepck_activity ATP-dependent PEP carboxykinase
PANTHER:PTHR30031
Family 		phosphoenolpyruvate carboxykinase (ATP) activity
GO:0004612 		Family Supported
Family review supports GO:0004612 FAMILY_WIDE. Asserted by gluconeogenesis; accepted by PCK1 and Methylorubrum PckA.
pep_synthase_activity phosphoenolpyruvate synthase
PANTHER:PTHR43030
Family 		pyruvate, water dikinase activity
GO:0008986 		Family Supported
Family review supports GO:0008986 FAMILY_WIDE. Asserted by gluconeogenesis and bacterial_pyruvate_metabolism modules; accepted by the E. coli and P. putida PpsA reviews; PAINT root node PTN000532546.
gng_enolase_activity enolase family
PANTHER:PTHR11902
Family 		phosphopyruvate hydratase activity
GO:0004634 		Family Supported
Family review supports GO:0004634 FAMILY_WIDE. The modules (emp_glycolysis, gluconeogenesis, glycolysis_payoff_phase) select the whole family for this activity, and PAINT puts it at the family root. Experimental seeds cover every major lineage and include yeast ERR2 and ERR3. ERR1 and ENO4 hold the activity by homology only. For ERR1 the active-site residues are intact, so neither is treated as an exception.
gng_pgam_activity phosphoglycerate mutase (dPGM and iPGM families)
PANTHER:PTHR11931:SF0
Family 		phosphoglycerate mutase activity
GO:0004619 		Family Supported
Family review supports GO:0004619 for PANTHER:PTHR11931:SF0. The active PGM subfamilies. The emp_glycolysis, gluconeogenesis and glycolysis_payoff_phase modules select the base family, which also takes in BPGM and GPM2/GPM3. SF11 (BPGM) is listed because BPGM has a genuine minor phosphoglycerate mutase activity (EC 5.4.2.11), kept as non-core in its review.
gng_pgam_activity phosphoglycerate mutase (dPGM and iPGM families)
PANTHER:PTHR11931:SF33
Family 		phosphoglycerate mutase activity
GO:0004619 		Family Supported
Family review supports GO:0004619 for PANTHER:PTHR11931:SF33. The active PGM subfamilies. The emp_glycolysis, gluconeogenesis and glycolysis_payoff_phase modules select the base family, which also takes in BPGM and GPM2/GPM3. SF11 (BPGM) is listed because BPGM has a genuine minor phosphoglycerate mutase activity (EC 5.4.2.11), kept as non-core in its review.
gng_pgam_activity phosphoglycerate mutase (dPGM and iPGM families)
PANTHER:PTHR11931:SF8
Family 		phosphoglycerate mutase activity
GO:0004619 		Family Supported
Family review supports GO:0004619 for PANTHER:PTHR11931:SF8. The active PGM subfamilies. The emp_glycolysis, gluconeogenesis and glycolysis_payoff_phase modules select the base family, which also takes in BPGM and GPM2/GPM3. SF11 (BPGM) is listed because BPGM has a genuine minor phosphoglycerate mutase activity (EC 5.4.2.11), kept as non-core in its review.
gng_pgam_activity phosphoglycerate mutase (dPGM and iPGM families)
PANTHER:PTHR11931:SF15
Family 		phosphoglycerate mutase activity
GO:0004619 		Family Supported
Family review supports GO:0004619 for PANTHER:PTHR11931:SF15. The active PGM subfamilies. The emp_glycolysis, gluconeogenesis and glycolysis_payoff_phase modules select the base family, which also takes in BPGM and GPM2/GPM3. SF11 (BPGM) is listed because BPGM has a genuine minor phosphoglycerate mutase activity (EC 5.4.2.11), kept as non-core in its review.
gng_pgam_activity phosphoglycerate mutase (dPGM and iPGM families)
PANTHER:PTHR11931:SF11
Family 		phosphoglycerate mutase activity
GO:0004619 		Family Supported
Family review supports GO:0004619 for PANTHER:PTHR11931:SF11. The active PGM subfamilies. The emp_glycolysis, gluconeogenesis and glycolysis_payoff_phase modules select the base family, which also takes in BPGM and GPM2/GPM3. SF11 (BPGM) is listed because BPGM has a genuine minor phosphoglycerate mutase activity (EC 5.4.2.11), kept as non-core in its review.
gng_pgam_activity phosphoglycerate mutase (dPGM and iPGM families)
PANTHER:PTHR31637
Family 		phosphoglycerate mutase activity
GO:0004619 		Family Supported
Family review supports GO:0004619 FAMILY_WIDE. The module selects this family (as a family_term of the PGAM step, beside dPGM PTHR11931) for phosphoglycerate mutase activity. That is the shared reaction of every characterized member, and PAINT places it at a node that covers all three subfamilies with seeds from each lineage. GO no longer has a separate term for the cofactor-independent mechanism, so the generic term is the correct one.
gng_pgk_activity phosphoglycerate kinase family
PANTHER:PTHR11406
Family 		phosphoglycerate kinase activity
GO:0004618 		Family Supported
Family review supports GO:0004618 FAMILY_WIDE. Asserted by emp_glycolysis, gluconeogenesis and glycolysis_payoff_phase; accepted by S. cerevisiae PGK1, S. pombe pgk1, human PGK1 and P. putida Pgk.
gng_gapdh_activity glyceraldehyde-3-phosphate dehydrogenase family
PANTHER:PTHR10836
Family 		glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity
GO:0004365 		Family Supported
Family review supports GO:0004365 FAMILY_WIDE. Asserted by emp_glycolysis, gluconeogenesis and glycolysis_payoff_phase; accepted by the S. cerevisiae, S. pombe, human and mouse reviews.
gng_tpi_activity triosephosphate isomerase family
PANTHER:PTHR21139
Family 		triose-phosphate isomerase activity
GO:0004807 		Family Supported
Family review supports GO:0004807 FAMILY_WIDE. Asserted by glycolysis_investment_phase, emp_glycolysis and gluconeogenesis; accepted by every reviewed member.
gng_aldolase_activity fructose-bisphosphate aldolase (class II and class I families)
PANTHER:PTHR30559
Family 		fructose-bisphosphate aldolase activity
GO:0004332 		Family Supported
Family review supports GO:0004332 FAMILY_WIDE. The modules (emp_glycolysis aldolase_activity, gluconeogenesis gng_aldolase_activity) assert this activity for PTHR30559 together with the class I family PTHR11627. Aldolase activity is the defining function of every characterized member and the PAINT root node PTN001254576 carries it with yeast, fission yeast and E. coli seeds. Both yeast gene reviews accept the inherited IBA.
gng_aldolase_activity fructose-bisphosphate aldolase (class II and class I families)
PANTHER:PTHR11627
Family 		fructose-bisphosphate aldolase activity
GO:0004332 		Family Supported
Family review supports GO:0004332 FAMILY_WIDE. The modules use PTHR11627 for the aldolase step (emp_glycolysis and gluconeogenesis, paired with the class II family PTHR30559; glycolysis_investment_phase with human ALDOA). The activity is ancestral to the family and depends on the Schiff-base lysine; every checked member except Drosophila Ald2 keeps it. Ald2 is listed as an exception, consistent with PAINT's IKR. The ALDOA, ALDOB and C. elegans aldo-1 gene reviews accept the inherited activity.
fructose_bisphosphatase_activity fructose-1,6-bisphosphatase (FBPase class I)
PANTHER:PTHR11556
Family 		fructose 1,6-bisphosphate 1-phosphatase activity
GO:0042132 		Family Supported
Family review supports GO:0042132 FAMILY_WIDE. Asserted by gluconeogenesis; accepted by S. cerevisiae FBP1 and P. putida Fbp. Plant SBPase prefers sedoheptulose bisphosphate.
gng_pgi_activity glucose-6-phosphate isomerase family
PANTHER:PTHR11469
Family 		glucose-6-phosphate isomerase activity
GO:0004347 		Family Supported
Family review supports GO:0004347 FAMILY_WIDE. The defining activity of every characterized member, and the activity all three modules attach to the family.

Gene-review completeness (17/17 grounded genes reviewed)

16 complete review(s) · 15 with deep research · 0 missing review · 2 reviewed but lacking deep research

Gene Review Complete Deep research
ENO1 P00924 ✓ ✓ ✓
ENO2 P00925 ✓ ✓ ✓
FBA1 P14540 ✓ ✓ ✓
FBP1 P09201 ✓ ✓ ✓
GPM1 P00950 ✓ ✓ ✓
MDH2 P22133 ✓ 26/27 ✓
PC P11498 ✓ ✓ ✗
PCK1 P10963 ✓ ✓ ✓
PGI1 P12709 ✓ ✓ ✓
PGK1 P00560 ✓ ✓ ✓
ppsA P23538 ✓ ✓ ✗
PYC1 P11154 ✓ ✓ ✓
PYC2 P32327 ✓ ✓ ✓
TDH1 P00360 ✓ ✓ ✓
TDH2 P00358 ✓ ✓ ✓
TDH3 P00359 ✓ ✓ ✓
TPI1 P00942 ✓ ✓ ✓

Details

Context
cytosolGO:0005829
Generic gluconeogenesisMetabolic Pathwaygeneric_gluconeogenesis
gluconeogenesisGO:0006094
Context
cytosolGO:0005829

Scope. The module starts at pyruvate or at cytosolic C4 acids and ends at glucose 6-phosphate or free glucose. The pathways that supply its precursors (glyoxylate cycle, lactate oxidation, amino-acid catabolism, glycerol kinase and glycerol-3-phosphate dehydrogenase) and the pathways that consume glucose 6-phosphate (trehalose, glycogen, glucan synthesis) are separate modules. Regulators such as fructose-2,6-bisphosphate metabolism and catabolite inactivation of FBPase and PEPCK are not included. Yeast realisation (YeastPathways GLUCONEO-PWY-1). Cytosolic pyruvate carboxylase PYC1/PYC2 or cytosolic MDH2 makes the oxaloacetate, the ATP-type PCK1 makes phosphoenolpyruvate, the glycolytic trunk enzymes (ENO1/ENO2, GPM1, PGK1, TDH1-3, TPI1, FBA1) run in reverse, and FBP1 and PGI1 complete the route to glucose 6-phosphate. MDH2 rather than PYC is the oxaloacetate source on ethanol or acetate. Corrections relative to YeastCyc and its GO-CAM: TPI1 is added, because the frame and GO-CAM omit the triose-phosphate isomerase step. MAE1, MDH1 and MDH3 are not counted as members. The GO-CAM types the mitochondrial NAD-malic enzyme MAE1 twice, as GO:0008948 oxaloacetate decarboxylase activity (1.1.1.39-RXN) and as GO:0030060 L-malate dehydrogenase (NAD+) activity (activity 6690711d00001655). Neither is the malic-enzyme activity, and the reaction runs in the anaplerotic/pyruvate-supplying direction, not as a gluconeogenic step. The GO-CAM correctly places PYC1/PYC2 in the cytosol. Structure. Compared with the earlier sketch, the pyruvate kinase bypass is now a variant set (two steps through oxaloacetate, or one step by a dikinase). Oxaloacetate supply has a carbon-source variant set (pyruvate carboxylation or malate oxidation), and pyruvate carboxylase has a compartment variant set. The reversible trunk is expanded into its six reactions, and the glucose-6-phosphate isomerase step, which was missing, has been added. Terminal glucose-6-phosphatase and the GTP- and diphosphate-dependent PEPCKs and PPDK stay as ungrounded function selectors; concrete human grounding is in gluconeogenesis_human.

Connections

Part 1: phosphoenolpyruvate formation (pyruvate kinase bypass)
Pyruvate or C4 acids to phosphoenolpyruvateMetabolic Pathwaypep_formation

The first irreversible bypass. Most eukaryotes go through oxaloacetate. Many bacteria, plants and protists can also phosphorylate pyruvate directly with a dikinase.

Variant set: Pyruvate kinase bypass routes by route variant (One Or More)
Two-step bypass through oxaloacetateMetabolic Pathwayoxaloacetate_route

Connections

Oxaloacetate from either source is the PEPCK substrate.
Part 1: oxaloacetate formation
Pyruvate or malate to oxaloacetateReactionoxaloacetate_supply

Oxaloacetate comes from carboxylation of pyruvate (from lactate, alanine or pyruvate itself) or from oxidation of malate (from the glyoxylate cycle when cells grow on acetate, ethanol or fatty acids). The two are alternatives that depend on the carbon source.

Variant set: Oxaloacetate sources by carbon source / precursor (One Or More)
Pyruvate carboxylationReactionpyruvate_carboxylation_variant
Variant set: Pyruvate carboxylase compartment by compartment (Exactly One)
Mitochondrial pyruvate carboxylase (animals)Reactionmitochondrial_pc_variant

Annotons

Pyruvate carboxylase (mitochondrial)
pyruvate_carboxylase_activity
Participant: Family: biotin-dependent pyruvate carboxylase
Family:
biotin-dependent pyruvate carboxylasePANTHER:PTHR43778
Representative Members: PC (human)UniProtKB:P11498
Required Function:
pyruvate carboxylase activityGO:0004736

Function

pyruvate carboxylase activityGO:0004736
Substrates: pyruvate hydrogencarbonate ATP
Products: oxaloacetate ADP phosphate

Locations

mitochondrial matrixGO:0005759

Animal arrangement. The oxaloacetate leaves the matrix as malate or aspartate to reach cytosolic PEPCK, or is converted there by mitochondrial PEPCK.

Cytosolic pyruvate carboxylase (yeasts)Reactioncytosolic_pc_variant

Annotons

Pyruvate carboxylase (cytosolic)
cytosolic_pyruvate_carboxylase_activity
Participant: Family: biotin-dependent pyruvate carboxylase
Family:
biotin-dependent pyruvate carboxylasePANTHER:PTHR43778
Representative Members: PYC1 (S. cerevisiae)UniProtKB:P11154 PYC2 (S. cerevisiae)UniProtKB:P32327
Required Function:
pyruvate carboxylase activityGO:0004736

Function

pyruvate carboxylase activityGO:0004736
Substrates: pyruvate hydrogencarbonate ATP
Products: oxaloacetate ADP phosphate

Locations

cytosolGO:0005829

In budding yeast the enzyme is cytosolic (PMID:1898090, PMID:2665820), so the oxaloacetate is made next to PEPCK. The same enzymes are the anaplerotic supply of oxaloacetate during growth on glucose.

Cytosolic malate oxidationReactionmalate_oxidation_variant

Annotons

Cytosolic malate dehydrogenase
cytosolic_mdh_activity
Participant: Family: malate dehydrogenase
Family:
malate dehydrogenasePANTHER:PTHR11540
Representative Members: MDH2 (S. cerevisiae)UniProtKB:P22133
Required Function:
L-malate dehydrogenase (NAD+) activityGO:0030060

Function

L-malate dehydrogenase (NAD+) activityGO:0030060
Substrates: (S)-malate NAD(+)
Products: oxaloacetate NADH

Locations

cytosolGO:0005829

Converts malate exported from the glyoxylate cycle (or from mitochondria) into the oxaloacetate used by PEPCK. It is the entry route on C2 carbon sources. The reaction runs against its equilibrium and is pulled by PEPCK.

Part 2: oxaloacetate decarboxylation-phosphorylation
Oxaloacetate to phosphoenolpyruvateReactionoxaloacetate_to_phosphoenolpyruvate
Variant set: PEP carboxykinase energy donor variants by enzyme chemistry (Exactly One)
GTP-dependent PEP carboxykinase routeReactiongtp_pepck_variant

Annotons

GTP-dependent phosphoenolpyruvate carboxykinase
gtp_pepck_activity
Participant: Any With Function: phosphoenolpyruvate carboxykinase (GTP) activity
Required Function:
phosphoenolpyruvate carboxykinase (GTP) activityGO:0004613

Function

phosphoenolpyruvate carboxykinase (GTP) activityGO:0004613
Substrates: oxaloacetate GTP
Products: phosphoenolpyruvate GDP CO2

The animal enzyme (cytosolic and mitochondrial isoforms).

ATP-dependent PEP carboxykinase routeReactionatp_pepck_variant

Annotons

ATP-dependent phosphoenolpyruvate carboxykinase
atp_pepck_activity
Participant: Family: ATP-dependent PEP carboxykinase
Family:
ATP-dependent PEP carboxykinasePANTHER:PTHR30031
Representative Members: PCK1 (S. cerevisiae)UniProtKB:P10963
Required Function:
phosphoenolpyruvate carboxykinase (ATP) activityGO:0004612

Function

phosphoenolpyruvate carboxykinase (ATP) activityGO:0004612
Substrates: oxaloacetate ATP
Products: phosphoenolpyruvate ADP CO2

Locations

cytosolGO:0005829

The fungal, plant and many bacterial enzymes.

Diphosphate-dependent PEP carboxykinase routeReactiondiphosphate_pepck_variant

Annotons

Diphosphate-dependent phosphoenolpyruvate carboxykinase
diphosphate_pepck_activity
Participant: Any With Function: phosphoenolpyruvate carboxykinase (diphosphate) activity
Required Function:
phosphoenolpyruvate carboxykinase (diphosphate) activityGO:0030585

Function

phosphoenolpyruvate carboxykinase (diphosphate) activityGO:0030585
Substrates: oxaloacetate diphosphate
Products: phosphoenolpyruvate phosphate CO2
Direct phosphorylation of pyruvate by a dikinaseReactiondirect_dikinase_route

Pyruvate, phosphate dikinase (plants, some bacteria and protists) or phosphoenolpyruvate synthase (many bacteria and archaea) converts pyruvate to phosphoenolpyruvate in one step at the cost of two ATP phosphoanhydride bonds. Yeasts and animals do not have this route.

Variant set: Pyruvate dikinase types by enzyme chemistry (One Or More)
Pyruvate, phosphate dikinaseReactionppdk_variant

Annotons

Pyruvate, phosphate dikinase
ppdk_activity
Participant: Any With Function: pyruvate, phosphate dikinase activity
Required Function:
pyruvate, phosphate dikinase activityGO:0050242

Function

pyruvate, phosphate dikinase activityGO:0050242
Substrates: pyruvate ATP phosphate
Products: phosphoenolpyruvate AMP diphosphate
Phosphoenolpyruvate synthaseReactionpep_synthase_variant

Annotons

Phosphoenolpyruvate synthase (pyruvate, water dikinase)
pep_synthase_activity
Participant: Family: phosphoenolpyruvate synthase
Family:
phosphoenolpyruvate synthasePANTHER:PTHR43030
Representative Members: ppsA (Escherichia coli K-12)UniProtKB:P23538
Required Function:
pyruvate, water dikinase activityGO:0008986

Function

pyruvate, water dikinase activityGO:0008986
Substrates: pyruvate ATP H2O
Products: phosphoenolpyruvate AMP phosphate
Part 2: reversible glycolytic trunk
Phosphoenolpyruvate to fructose 1,6-bisphosphateMetabolic Pathwayreversible_glycolytic_trunk

The six near-equilibrium glycolytic reactions between phosphoenolpyruvate and fructose 1,6-bisphosphate, run in the gluconeogenic direction by the same enzymes that serve glycolysis. Reducing equivalents (NADH) are consumed at the GAPDH step and ATP at the PGK step. Glycerol-derived carbon enters at dihydroxyacetone phosphate, which is outside this module.

reversible glycolysis segment

Connections

gng_gapdh_step -> gng_tpi_step Provides Input For
gng_gapdh_step -> gng_aldolase_step Provides Input For
gng_tpi_step -> gng_aldolase_step Provides Input For
Part 1: hydration of phosphoenolpyruvate
Phosphoenolpyruvate to 2-phospho-D-glycerateReactiongng_enolase_step

Annotons

Enolase
gng_enolase_activity
Participant: Family: enolase family
Family:
enolase familyPANTHER:PTHR11902
Representative Members: ENO1 (S. cerevisiae)UniProtKB:P00924 ENO2 (S. cerevisiae)UniProtKB:P00925
Required Function:
phosphopyruvate hydratase activityGO:0004634

Function

phosphopyruvate hydratase activityGO:0004634
Substrates: phosphoenolpyruvate H2O
Products: 2-phospho-D-glycerate
Part 2: phosphoryl shift
2-phospho-D-glycerate to 3-phospho-D-glycerateReactiongng_pgam_step

Annotons

Phosphoglycerate mutase
gng_pgam_activity
Participant: Family: phosphoglycerate mutase (dPGM and iPGM families)
Family:
phosphoglycerate mutase (dPGM and iPGM families)
Representative Members: GPM1 (S. cerevisiae; dPGM)UniProtKB:P00950
Required Function:
phosphoglycerate mutase activityGO:0004619

Function

phosphoglycerate mutase activityGO:0004619
Substrates: 2-phospho-D-glycerate
Products: 3-phospho-D-glycerate
Part 3: ATP-dependent phosphorylation of 3-phosphoglycerate
3-phospho-D-glycerate + ATP to 1,3-bisphospho-D-glycerate + ADPReactiongng_pgk_step

Annotons

Phosphoglycerate kinase
gng_pgk_activity
Participant: Family: phosphoglycerate kinase family
Family:
phosphoglycerate kinase familyPANTHER:PTHR11406
Representative Members: PGK1 (S. cerevisiae)UniProtKB:P00560
Required Function:
phosphoglycerate kinase activityGO:0004618

Function

phosphoglycerate kinase activityGO:0004618
Substrates: 3-phospho-D-glycerate ATP
Products: 3-phospho-D-glyceroyl phosphate ADP
Part 4: reductive dephosphorylation to the aldehyde
1,3-bisphospho-D-glycerate + NADH to D-glyceraldehyde 3-phosphateReactiongng_gapdh_step

Annotons

Glyceraldehyde-3-phosphate dehydrogenase (phosphorylating)
gng_gapdh_activity
Participant: Family: glyceraldehyde-3-phosphate dehydrogenase family
Family:
glyceraldehyde-3-phosphate dehydrogenase familyPANTHER:PTHR10836
Representative Members: TDH3 (S. cerevisiae)UniProtKB:P00359 TDH2 (S. cerevisiae)UniProtKB:P00358 TDH1 (S. cerevisiae)UniProtKB:P00360
Required Function:
glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activityGO:0004365

Function

glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activityGO:0004365
Substrates: 3-phospho-D-glyceroyl phosphate NADH
Products: D-glyceraldehyde 3-phosphate NAD(+) phosphate

The same three isozymes contribute in the same proportions on glucose and on ethanol (PMID:3905788).

Part 5: triose isomerisation
D-glyceraldehyde 3-phosphate to glycerone phosphateReactiongng_tpi_step

Half of the glyceraldehyde 3-phosphate must be isomerised to dihydroxyacetone phosphate to give the aldolase both of its substrates. This step is missing from the YeastPathways frame and its GO-CAM.

Annotons

Triose-phosphate isomerase
gng_tpi_activity
Participant: Family: triosephosphate isomerase family
Family:
triosephosphate isomerase familyPANTHER:PTHR21139
Representative Members: TPI1 (S. cerevisiae)UniProtKB:P00942
Required Function:
triose-phosphate isomerase activityGO:0004807

Function

triose-phosphate isomerase activityGO:0004807
Substrates: D-glyceraldehyde 3-phosphate
Products: glycerone phosphate
Part 6: aldol condensation
Glycerone phosphate + D-glyceraldehyde 3-phosphate to D-fructose 1,6-bisphosphateReactiongng_aldolase_step

Annotons

Fructose-bisphosphate aldolase
gng_aldolase_activity
Participant: Family: fructose-bisphosphate aldolase (class II and class I families)
Family:
fructose-bisphosphate aldolase (class II and class I families)PANTHER:PTHR30559
Representative Members: FBA1 (S. cerevisiae; class II)UniProtKB:P14540
Required Function:
fructose-bisphosphate aldolase activityGO:0004332

Function

fructose-bisphosphate aldolase activityGO:0004332
Substrates: glycerone phosphate D-glyceraldehyde 3-phosphate
Products: D-fructose 1,6-bisphosphate
Part 3: fructose 1,6-bisphosphate bypass
Fructose 1,6-bisphosphate to fructose 6-phosphateReactionfructose_bisphosphatase_step

Annotons

Fructose 1,6-bisphosphatase function
fructose_bisphosphatase_activity
Participant: Family: fructose-1,6-bisphosphatase (FBPase class I)
Family:
fructose-1,6-bisphosphatase (FBPase class I)PANTHER:PTHR11556
Representative Members: FBP1 (S. cerevisiae)UniProtKB:P09201
Required Function:
fructose 1,6-bisphosphate 1-phosphatase activityGO:0042132

Function

fructose 1,6-bisphosphate 1-phosphatase activityGO:0042132
Substrates: fructose 1,6-bisphosphate H2O
Products: fructose 6-phosphate phosphate

Locations

cytosolGO:0005829

The committed, irreversible bypass of phosphofructokinase. In eukaryotes it is inhibited by fructose 2,6-bisphosphate and AMP, reciprocally to PFK.

Part 4: hexose-phosphate isomerisation
D-fructose 6-phosphate to D-glucose 6-phosphateReactiongng_pgi_step

Annotons

Glucose-6-phosphate isomerase
gng_pgi_activity
Participant: Family: glucose-6-phosphate isomerase family
Family:
glucose-6-phosphate isomerase familyPANTHER:PTHR11469
Representative Members: PGI1 (S. cerevisiae)UniProtKB:P12709
Required Function:
glucose-6-phosphate isomerase activityGO:0004347

Function

glucose-6-phosphate isomerase activityGO:0004347
Substrates: D-fructose 6-phosphate
Products: D-glucose 6-phosphate

Locations

cytosolGO:0005829
Part 5: terminal glucose or glucose-6-phosphate endpoint
Terminal hexose endpointReactionterminal_hexose_endpoint
Variant set: Terminal product variants by physiological endpoint (Exactly One)
Glucose release endpointReactionglucose_release_variant

Annotons

Glucose-6-phosphatase function
glucose_6_phosphatase_activity
Participant: Any With Function: glucose-6-phosphatase activity
Required Function:
glucose-6-phosphatase activityGO:0004346

Function

glucose-6-phosphatase activityGO:0004346
Substrates: glucose 6-phosphate
Products: glucose

Animal liver and kidney, where free glucose is exported. The enzyme sits in the endoplasmic reticulum membrane with its active site in the lumen.

Glucose 6-phosphate endpointMetabolic Pathwayglucose_6_phosphate_endpoint_variant

Microbes and plant cells keep the product as glucose 6-phosphate and use it for storage carbohydrates (trehalose, glycogen, starch), cell-wall glucans, the pentose phosphate pathway and hexosamine synthesis. The yeast pathway ends here.

glucose 6-phosphate as terminal gluconeogenic product