Pyruvate fates — pyruvate dehydrogenase complex and pyruvate carboxylase

The two committed eukaryotic fates of pyruvate that feed the TCA cycle. (1) Oxidative decarboxylation by the mitochondrial pyruvate dehydrogenase complex (PDC) links glycolysis to the TCA cycle: pyruvate + CoA + NAD+ -> acetyl-CoA + CO2 + NADH. Pyruvate enters the matrix through the mitochondrial pyruvate carrier. The PDC is a giant mitochondrial-matrix multienzyme machine built on a 60-mer E2 (dihydrolipoyllysine-residue acetyltransferase) core, with the thiamine-diphosphate-dependent E1 decarboxylase (an alpha2-beta2 heterotetramer), the E3-binding structural subunit (protein X / E3BP) that anchors the dihydrolipoyl dehydrogenase E3, and E3 itself, which reoxidises the lipoyl arms and passes electrons to NAD+. The same subunit architecture is conserved from yeasts (PDA1, PDB1, LAT1, PDX1, LPD1) to animals (PDHA1, PDHB, DLAT, PDHX, DLD), and the E3 is shared with the 2-oxoglutarate and branched-chain 2-oxoacid dehydrogenases. PDC flux is switched off by phosphorylation of E1alpha by pyruvate dehydrogenase kinases and on by dephosphorylation by the phosphatases. (2) Carboxylation by the biotin-dependent pyruvate carboxylase (PC): pyruvate + HCO3- + ATP -> oxaloacetate, the principal anaplerotic reaction replenishing oxaloacetate and the committed first step of gluconeogenesis from pyruvate or lactate. PC is a mitochondrial-matrix enzyme in animals, where it is allosterically activated by acetyl-CoA, the PDC product, coordinating the two fates; in budding yeast the two PC isozymes are cytosolic, so the oxaloacetate they make must be imported into mitochondria to replenish the cycle. In humans, inherited defects cause severe lactic acidosis and neurological disease: PDHA1 (X-linked, the commonest), PDHB, DLAT and PDHX deficiencies cause pyruvate dehydrogenase complex deficiency (Leigh syndrome spectrum), PC deficiency causes lactic acidosis with hypoglycemia, and DLD deficiency (the shared E3) gives a combined phenotype.

MODULE:pyruvate_metabolismDRAFTMetabolic Pathwaymodules/pyruvate_metabolism.yaml
pyruvate metabolic processGO:0006090
YeastPathways:PYRUVDEHYD-PWY
pyruvate decarboxylation to acetyl CoA (S. cerevisiae, SGD YeastPathways)
YeastCyc lists the E1 (PDA1, PDB1), E2 (LAT1) and E3 (LPD1) half-reactions; its comment describes protein X (PDX1) linking LAT1 to LPD1 but PDX1 is absent from the reaction gene lists and was added here.
PMID:9123965
Pyruvate metabolism in Saccharomyces cerevisiae.
Review of the three pyruvate branch-point reactions in S. cerevisiae: the pyruvate dehydrogenase complex, pyruvate decarboxylase (the PDH bypass, outside this module) and anaplerotic pyruvate carboxylase.
PMID:2007123
Disruption and mutagenesis of the Saccharomyces cerevisiae PDX1 gene encoding the protein X component of the pyruvate dehydrogenase complex.
Protein X (PDX1) binds and positions E3 on the E2 core; pdx1 complexes contain E1 and E2 but lack E3 and overall activity, establishing a structural rather than catalytic role.
PMID:2039506
Yeast pyruvate carboxylase: identification of two genes encoding isoenzymes.
S. cerevisiae has two pyruvate carboxylase genes, PYC1 (major) and PYC2 (10-20% residual activity in pyc1 nulls), and the residual isozyme is located exclusively in the cytoplasm.
PMID:1898090
Electron microscopic localization of pyruvate carboxylase in rat liver and Saccharomyces cerevisiae by immunogold procedures.
Immunogold labelling places pyruvate carboxylase in mitochondria in rat liver but exclusively in the cytosol in S. cerevisiae.
file:genes/yeast/PYC1/PYC1-ai-review.yaml
PYC1 gene review (S. cerevisiae)
The PYC1 review curates GO:0004736 pyruvate carboxylase activity in the cytosol as the core function of the major yeast isozyme.
file:genes/yeast/PYC2/PYC2-ai-review.yaml
PYC2 gene review (S. cerevisiae)
The PYC2 review curates GO:0004736 in the cytosol for the minor, functionally redundant isozyme.
GO:0006090
pyruvate metabolic process
The module is grounded in the GO pyruvate metabolic process (GO:0006090), covering the oxidative-decarboxylation (PDC) and carboxylation (PC) fates.
Reactome:R-HSA-70268
Pyruvate metabolism
Reaction stoichiometries follow the human Reactome pyruvate-metabolism reactions R-HSA-9861559 (PDC synthesizes acetyl-CoA from pyruvate) and R-HSA-70501 (PC carboxylates pyruvate to oxaloacetate).
file:human/PDHA1/PDHA1-ai-review.yaml
PDHA1 gene review (human)
The PDC E1-alpha grounding (UniProtKB:P08559, GO:0004739 pyruvate dehydrogenase (acetyl-transferring) activity, GO:0045254 complex) matches the completed human PDHA1 review.
file:human/PDHB/PDHB-ai-review.yaml
PDHB gene review (human)
The PDC E1-beta grounding (UniProtKB:P11177, GO:0004739, GO:0045254) matches the completed human PDHB review.
file:human/DLAT/DLAT-ai-review.yaml
DLAT gene review (human)
The PDC E2 core grounding (UniProtKB:P10515, GO:0004742 dihydrolipoyllysine- residue acetyltransferase activity, GO:0045254) matches the completed human DLAT review.
file:human/PDHX/PDHX-ai-review.yaml
PDHX gene review (human)
The E3-binding structural subunit grounding (UniProtKB:O00330, GO:0030674 protein-macromolecule adaptor activity, GO:0045254) matches the completed human PDHX review (a non-catalytic scaffold anchoring DLD).
file:human/DLD/DLD-ai-review.yaml
DLD gene review (human)
The shared E3 grounding (UniProtKB:P09622, GO:0004148 dihydrolipoyl dehydrogenase (NADH) activity) matches the completed human DLD review.
file:human/PC/PC-ai-review.yaml
PC gene review (human)
The pyruvate carboxylase grounding (UniProtKB:P11498, GO:0004736 pyruvate carboxylase activity) matches the completed human PC review.
5Nodes
2Parts
1Variant Sets
2Variants
7Annotons
1Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:pyruvate_metabolism 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.

Function consistency and core coverage

16 gene-function check(s) reflected in core functions · 0 conflict(s) · 3 evidence or coverage gap(s) (36 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
pdha1_activity PDHA1 (human)
UniProtKB:P08559
Family Representative 		pyruvate dehydrogenase (acetyl-transferring) activity
GO:0004739 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pdha1_activity PDA1 (Saccharomyces cerevisiae)
UniProtKB:P16387
Family Representative 		pyruvate dehydrogenase (acetyl-transferring) activity
GO:0004739 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pdha1_activity pda1 (Schizosaccharomyces pombe)
UniProtKB:Q10489
Family Representative 		pyruvate dehydrogenase (acetyl-transferring) activity
GO:0004739 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
pdhb_activity PDHB (human)
UniProtKB:P11177
Family Representative 		pyruvate dehydrogenase (acetyl-transferring) activity
GO:0004739 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pdhb_activity PDB1 (Saccharomyces cerevisiae)
UniProtKB:P32473
Family Representative 		pyruvate dehydrogenase (acetyl-transferring) activity
GO:0004739 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pdhb_activity pdb1 (Schizosaccharomyces pombe)
UniProtKB:Q09171
Family Representative 		pyruvate dehydrogenase (acetyl-transferring) activity
GO:0004739 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
dlat_activity DLAT (human)
UniProtKB:P10515
Family Representative 		dihydrolipoyllysine-residue acetyltransferase activity
GO:0004742 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dlat_activity LAT1 (Saccharomyces cerevisiae)
UniProtKB:P12695
Family Representative 		dihydrolipoyllysine-residue acetyltransferase activity
GO:0004742 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dlat_activity lat1 (Schizosaccharomyces pombe)
UniProtKB:O59816
Family Representative 		dihydrolipoyllysine-residue acetyltransferase activity
GO:0004742 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pdhx_activity PDHX (human)
UniProtKB:O00330
Family Representative 		protein-macromolecule adaptor activity
GO:0030674 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pdhx_activity PDX1 (Saccharomyces cerevisiae)
UniProtKB:P16451
Family Representative 		protein-macromolecule adaptor activity
GO:0030674 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pdhx_activity pdx1 (Schizosaccharomyces pombe)
UniProtKB:O94709
Family Representative 		protein-macromolecule adaptor activity
GO:0030674 		Function Unreviewed
No retained annotation or core molecular function supports this GO assertion. Missing or broader evidence is a coverage gap, not proof the activity is absent.
dld_activity DLD (human)
UniProtKB:P09622
Family Representative 		dihydrolipoyl dehydrogenase (NADH) activity
GO:0004148 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dld_activity LPD1 (Saccharomyces cerevisiae)
UniProtKB:P09624
Family Representative 		dihydrolipoyl dehydrogenase (NADH) activity
GO:0004148 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dld_activity dld1 (Schizosaccharomyces pombe)
UniProtKB:O00087
Family Representative 		dihydrolipoyl dehydrogenase (NADH) activity
GO:0004148 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pc_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_pc_activity PYC1 (Saccharomyces 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_pc_activity PYC2 (Saccharomyces 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_pc_activity pyr1 (Schizosaccharomyces pombe)
UniProtKB:Q9UUE1
Family Representative 		pyruvate carboxylase activity
GO:0004736 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pdha1_activity Pyruvate dehydrogenase E1 alpha family (PDHA1)
PANTHER:PTHR11516
Family 		pyruvate dehydrogenase (acetyl-transferring) activity
GO:0004739 		Family Supported
Family review supports GO:0004739 FAMILY_WIDE. Asserted by pyruvate_metabolism; accepted by PDA1, pda1 and PDHA1. The acetoin-system AcoA subunits in SF60 (P. putida, B. subtilis, C. necator, Syntrophotalea) are member exceptions.
pdhb_activity Pyruvate dehydrogenase E1 beta / transketolase-like family (PDHB)
PANTHER:PTHR11624
Family 		pyruvate dehydrogenase (acetyl-transferring) activity
GO:0004739 		Family Supported
Family review supports GO:0004739 FAMILY_WIDE. Asserted by pyruvate_metabolism; accepted by PDB1, pdb1 and PDHB as a subunit of the E1 heterotetramer.
dlat_activity 2-oxoacid dehydrogenase E2 (dihydrolipoyl acyltransferase) family (DLAT)
PANTHER:PTHR23151:SF90
Family 		dihydrolipoyllysine-residue acetyltransferase activity
GO:0004742 		Family Supported
Family review supports GO:0004742 for PANTHER:PTHR23151:SF90. Catalytic E2 subfamilies, as pyruvate_metabolism asserts on the base family. Human PDHX in SF90 is a member exception.
dlat_activity 2-oxoacid dehydrogenase E2 (dihydrolipoyl acyltransferase) family (DLAT)
PANTHER:PTHR23151:SF89
Family 		dihydrolipoyllysine-residue acetyltransferase activity
GO:0004742 		Family Supported
Family review supports GO:0004742 for PANTHER:PTHR23151:SF89. Catalytic E2 subfamilies, as pyruvate_metabolism asserts on the base family. Human PDHX in SF90 is a member exception.
dlat_activity 2-oxoacid dehydrogenase E2 (dihydrolipoyl acyltransferase) family (DLAT)
PANTHER:PTHR23151:SF75
Family 		dihydrolipoyllysine-residue acetyltransferase activity
GO:0004742 		Family Supported
Family review supports GO:0004742 for PANTHER:PTHR23151:SF75. Catalytic E2 subfamilies, as pyruvate_metabolism asserts on the base family. Human PDHX in SF90 is a member exception.
dlat_activity 2-oxoacid dehydrogenase E2 (dihydrolipoyl acyltransferase) family (DLAT)
PANTHER:PTHR23151:SF83
Family 		dihydrolipoyllysine-residue acetyltransferase activity
GO:0004742 		Family Supported
Family review supports GO:0004742 for PANTHER:PTHR23151:SF83. Catalytic E2 subfamilies, as pyruvate_metabolism asserts on the base family. Human PDHX in SF90 is a member exception.
pdhx_activity 2-oxoacid dehydrogenase E3-binding-protein family (PDHX)
PANTHER:PTHR23151:SF82
Family 		protein-macromolecule adaptor activity
GO:0030674 		Family Supported
Family review supports GO:0030674 for PANTHER:PTHR23151:SF82. The E3BP adaptor role: fungal SF82 and human PDHX in SF90.
pdhx_activity 2-oxoacid dehydrogenase E3-binding-protein family (PDHX)
PANTHER:PTHR23151:SF90
Family 		protein-macromolecule adaptor activity
GO:0030674 		Family Supported
Family review supports GO:0030674 for PANTHER:PTHR23151:SF90. The E3BP adaptor role: fungal SF82 and human PDHX in SF90.
dld_activity Dihydrolipoyl dehydrogenase / pyridine-nucleotide-disulphide oxidoreductase family (DLD)
PANTHER:PTHR22912:SF151
Family 		dihydrolipoyl dehydrogenase (NADH) activity
GO:0004148 		Family Supported
Family review supports GO:0004148 for PANTHER:PTHR22912:SF151. The E3 subfamilies, not the divergent SthA transhydrogenase. SF219 is included on the basis of its independently mapped AcoL representative, the native sequence-based E3 assignment in PMID:10368162 and the conserved catalytic architecture. This extends chemistry scope, not a requirement that all E3 paralogs serve the same physiological complexes. No new PAINT node is inferred.
dld_activity Dihydrolipoyl dehydrogenase / pyridine-nucleotide-disulphide oxidoreductase family (DLD)
PANTHER:PTHR22912:SF160
Family 		dihydrolipoyl dehydrogenase (NADH) activity
GO:0004148 		Family Supported
Family review supports GO:0004148 for PANTHER:PTHR22912:SF160. The E3 subfamilies, not the divergent SthA transhydrogenase. SF219 is included on the basis of its independently mapped AcoL representative, the native sequence-based E3 assignment in PMID:10368162 and the conserved catalytic architecture. This extends chemistry scope, not a requirement that all E3 paralogs serve the same physiological complexes. No new PAINT node is inferred.
dld_activity Dihydrolipoyl dehydrogenase / pyridine-nucleotide-disulphide oxidoreductase family (DLD)
PANTHER:PTHR22912:SF224
Family 		dihydrolipoyl dehydrogenase (NADH) activity
GO:0004148 		Family Supported
Family review supports GO:0004148 for PANTHER:PTHR22912:SF224. The E3 subfamilies, not the divergent SthA transhydrogenase. SF219 is included on the basis of its independently mapped AcoL representative, the native sequence-based E3 assignment in PMID:10368162 and the conserved catalytic architecture. This extends chemistry scope, not a requirement that all E3 paralogs serve the same physiological complexes. No new PAINT node is inferred.
dld_activity Dihydrolipoyl dehydrogenase / pyridine-nucleotide-disulphide oxidoreductase family (DLD)
PANTHER:PTHR22912:SF217
Family 		dihydrolipoyl dehydrogenase (NADH) activity
GO:0004148 		Family Supported
Family review supports GO:0004148 for PANTHER:PTHR22912:SF217. The E3 subfamilies, not the divergent SthA transhydrogenase. SF219 is included on the basis of its independently mapped AcoL representative, the native sequence-based E3 assignment in PMID:10368162 and the conserved catalytic architecture. This extends chemistry scope, not a requirement that all E3 paralogs serve the same physiological complexes. No new PAINT node is inferred.
dld_activity Dihydrolipoyl dehydrogenase / pyridine-nucleotide-disulphide oxidoreductase family (DLD)
PANTHER:PTHR22912:SF220
Family 		dihydrolipoyl dehydrogenase (NADH) activity
GO:0004148 		Family Supported
Family review supports GO:0004148 for PANTHER:PTHR22912:SF220. The E3 subfamilies, not the divergent SthA transhydrogenase. SF219 is included on the basis of its independently mapped AcoL representative, the native sequence-based E3 assignment in PMID:10368162 and the conserved catalytic architecture. This extends chemistry scope, not a requirement that all E3 paralogs serve the same physiological complexes. No new PAINT node is inferred.
dld_activity Dihydrolipoyl dehydrogenase / pyridine-nucleotide-disulphide oxidoreductase family (DLD)
PANTHER:PTHR22912:SF223
Family 		dihydrolipoyl dehydrogenase (NADH) activity
GO:0004148 		Family Supported
Family review supports GO:0004148 for PANTHER:PTHR22912:SF223. The E3 subfamilies, not the divergent SthA transhydrogenase. SF219 is included on the basis of its independently mapped AcoL representative, the native sequence-based E3 assignment in PMID:10368162 and the conserved catalytic architecture. This extends chemistry scope, not a requirement that all E3 paralogs serve the same physiological complexes. No new PAINT node is inferred.
dld_activity Dihydrolipoyl dehydrogenase / pyridine-nucleotide-disulphide oxidoreductase family (DLD)
PANTHER:PTHR22912:SF207
Family 		dihydrolipoyl dehydrogenase (NADH) activity
GO:0004148 		Family Supported
Family review supports GO:0004148 for PANTHER:PTHR22912:SF207. The E3 subfamilies, not the divergent SthA transhydrogenase. SF219 is included on the basis of its independently mapped AcoL representative, the native sequence-based E3 assignment in PMID:10368162 and the conserved catalytic architecture. This extends chemistry scope, not a requirement that all E3 paralogs serve the same physiological complexes. No new PAINT node is inferred.
pc_activity Pyruvate carboxylase family (PC)
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_pc_activity Pyruvate carboxylase family (PC)
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.

Gene-review completeness (19/19 grounded genes reviewed)

19 complete review(s) · 8 with deep research · 0 missing review · 11 reviewed but lacking deep research

Gene Review Complete Deep research
DLAT P10515 ✓ ✓ ✗
DLD P09622 ✓ ✓ ✓
dld1 O00087 ✓ ✓ ✗
lat1 O59816 ✓ ✓ ✗
LAT1 P12695 ✓ ✓ ✓
LPD1 P09624 ✓ ✓ ✓
PC P11498 ✓ ✓ ✗
PDA1 P16387 ✓ ✓ ✓
pda1 Q10489 ✓ ✓ ✗
PDB1 P32473 ✓ ✓ ✓
pdb1 Q09171 ✓ ✓ ✗
PDHA1 P08559 ✓ ✓ ✗
PDHB P11177 ✓ ✓ ✗
PDHX O00330 ✓ ✓ ✗
PDX1 P16451 ✓ ✓ ✓
PYC1 P11154 ✓ ✓ ✓
PYC2 P32327 ✓ ✓ ✓
pyr1 Q9UUE1 ✓ ✓ ✗
SPCC1259.09c O94709 ✓ ✓ ✗

Details

Pyruvate dehydrogenase complex and pyruvate carboxylaseMetabolic Pathwaypyruvate_metabolism
pyruvate metabolic processGO:0006090

The two committed mitochondrial fates of pyruvate, grounded to the human enzymes of the pyruvate dehydrogenase complex — PDHA1 (UniProtKB:P08559) and PDHB (P11177) of E1 (GO:0004739, EC 1.2.4.1), the E2 core DLAT (P10515, GO:0004742, EC 2.3.1.12), the E3-binding structural subunit PDHX (O00330, GO:0030674) and the shared E3 DLD (P09622, GO:0004148, EC 1.8.1.4), assembled as GO:0045254 — and pyruvate carboxylase PC (P11498, GO:0004736, EC 6.4.1.1). GO molecular-function/cellular-component terms were taken from the human GOA records; Reactome reaction ids and titles were verified against the local reactome cache. Each step uses a PANTHER family selector (generic over paralogs and orthologs) plus a concrete human representative member; the PDC is modelled as a PROTEIN_COMPLEX node with its five subunit types. PDHX is deliberately grounded as a non-catalytic adaptor (its E2-type catalytic His is replaced by Ser); DLD is the shared E3 of multiple 2-oxoacid dehydrogenase complexes. Upstream, pyruvate comes from glycolysis (via the mitochondrial pyruvate carrier); downstream, PDC-derived acetyl-CoA and PC-derived oxaloacetate feed the TCA cycle, and PC also feeds gluconeogenesis. PDC activity is phospho-regulated by the PDK kinases / PDP phosphatases (not modelled here). ALIGN (YeastPathways project, 2026-10): S. cerevisiae (PDA1 P16387, PDB1 P32473, LAT1 P12695, PDX1 P16451, LPD1 P09624) and S. pombe (pda1, pdb1, lat1, pdx1, dld1) exemplars were added to each PDC subunit role; all fall in the same PANTHER families as the human subunits (PTHR11516, PTHR11624, PTHR23151, PTHR22912), checked against UniProt PANTHER cross-references. The pyruvate carboxylase step became an EXACTLY_ONE compartment variant set: mitochondrial-matrix PC in animals versus the cytosolic PYC1/PYC2 isozymes of S. cerevisiae (PMID:2039506, PMID:1898090) and S. pombe pyr1 (cytoplasmic by similarity), so the module-level "mitochondrial matrix" context, which previously claimed both enzymes, was removed and the title broadened; the slug is unchanged. The PDC-to-PC positive-regulation connection is animal-specific. YeastCyc corrections: PDX1 is named in the PYRUVDEHYD-PWY comment but absent from its reaction gene lists, and was added. Out of scope here: the yeast pyruvate dehydrogenase bypass (pyruvate decarboxylase, acetaldehyde dehydrogenase, acetyl-CoA synthetase; PMID:9123965), the mitochondrial pyruvate carrier, and PDC kinases/phosphatases (yeast PKP1/PKP2 and PTC5/PTC6). GO-CAM disagreements: the YeastPathways PYRUVDEHYD-PWY conversion places all PDC activities in the cytosol and omits PDX1. The PomBase model 67086be200000251 types pdx1 as GO:0005198 structural molecule activity rather than the adaptor activity used here, models pkp1/ptc5 regulation, and includes upstream pyruvate kinase and pyruvate import, CoA import, citrate synthase, lipoylation, alanine transaminase and 2-isopropylmalate synthase activities that lie outside this module; it has no pyruvate carboxylase.

Connections

pdc_step -> pc_step Positively Regulates
Acetyl-CoA produced by the PDC is the obligate allosteric activator of pyruvate carboxylase, coordinating the oxidative and anaplerotic fates of pyruvate (and, together, supplying acetyl-CoA + oxaloacetate for citrate synthesis / the TCA cycle). This direct coupling applies where PDC and PC share the mitochondrial matrix (animals); in yeasts PC is cytosolic and cannot sense matrix acetyl-CoA directly.
Part 1: oxidative decarboxylation to acetyl-CoA (glycolysis-to-TCA gateway)
pyruvate + CoA + NAD+ to acetyl-CoA + CO2 + NADH (pyruvate dehydrogenase complex)Protein Complexpdc_step

Annotons

PDHA1: PDC E1 alpha (TPP decarboxylase)
pdha1_activity
Participant: Family: Pyruvate dehydrogenase E1 alpha family (PDHA1)
Family:
Pyruvate dehydrogenase E1 alpha family (PDHA1)PANTHER:PTHR11516
Representative Members: PDHA1 (human)UniProtKB:P08559 PDA1 (Saccharomyces cerevisiae)UniProtKB:P16387 pda1 (Schizosaccharomyces pombe)UniProtKB:Q10489

Function

pyruvate dehydrogenase (acetyl-transferring) activityGO:0004739
Substrates: pyruvate thiamine diphosphate (cofactor)
Products: (hydroxyethyl-TPP intermediate) carbon dioxide

Locations

mitochondrial matrixGO:0005759

TPP-dependent decarboxylase; with PDHB forms the alpha2-beta2 E1 that decarboxylates pyruvate and reductively acetylates the E2 lipoyl arm. The phosphoregulated subunit (PDK off / PDP on). Human PDHA1 is X-linked and its deficiency is the commonest PDC deficiency.

PDHB: PDC E1 beta
pdhb_activity
Participant: Family: Pyruvate dehydrogenase E1 beta / transketolase-like family (PDHB)
Family:
Pyruvate dehydrogenase E1 beta / transketolase-like family (PDHB)PANTHER:PTHR11624
Representative Members: PDHB (human)UniProtKB:P11177 PDB1 (Saccharomyces cerevisiae)UniProtKB:P32473 pdb1 (Schizosaccharomyces pombe)UniProtKB:Q09171

Function

pyruvate dehydrogenase (acetyl-transferring) activityGO:0004739

Locations

mitochondrial matrixGO:0005759

Beta subunit of the E1 heterotetramer; completes the TPP-binding active site with E1 alpha. Human deficiency causes PDC (E1-beta) deficiency.

DLAT: PDC E2 (dihydrolipoyl acetyltransferase core)
dlat_activity
Participant: Family: 2-oxoacid dehydrogenase E2 (dihydrolipoyl acyltransferase) family (DLAT)
Family:
2-oxoacid dehydrogenase E2 (dihydrolipoyl acyltransferase) family (DLAT)
Representative Members: DLAT (human)UniProtKB:P10515 LAT1 (Saccharomyces cerevisiae)UniProtKB:P12695 lat1 (Schizosaccharomyces pombe)UniProtKB:O59816

Function

dihydrolipoyllysine-residue acetyltransferase activityGO:0004742
Substrates: S-acetyl-dihydrolipoyl intermediate coenzyme A
Products: acetyl-CoA

Locations

mitochondrial matrixGO:0005759

Lipoyl-bearing E2 subunit forming the 60-mer structural core of the PDC; transfers the acetyl group from the lipoyl arm to CoA, yielding acetyl-CoA. Human DLAT deficiency causes PDC (E2) deficiency; DLAT is also a primary biliary cholangitis autoantigen.

PDHX: PDC component X / E3-binding protein (structural)
pdhx_activity
Participant: Family: 2-oxoacid dehydrogenase E3-binding-protein family (PDHX)
Family:
2-oxoacid dehydrogenase E3-binding-protein family (PDHX)
Representative Members: PDHX (human)UniProtKB:O00330 PDX1 (Saccharomyces cerevisiae)UniProtKB:P16451 pdx1 (Schizosaccharomyces pombe)UniProtKB:O94709

Function

protein-macromolecule adaptor activityGO:0030674

Locations

mitochondrial matrixGO:0005759

Structural E3-binding subunit (component X): built into the E2 core, it binds and positions the shared E3 (DLD). Not a classic enzyme (catalytically dead). Human PDHX deficiency causes PDC (E3BP) deficiency.

DLD: shared E3 (dihydrolipoyl dehydrogenase)
dld_activity
Participant: Family: Dihydrolipoyl dehydrogenase / pyridine-nucleotide-disulphide oxidoreductase family (DLD)
Family:
Dihydrolipoyl dehydrogenase / pyridine-nucleotide-disulphide oxidoreductase family (DLD)
Representative Members: DLD (human)UniProtKB:P09622 LPD1 (Saccharomyces cerevisiae)UniProtKB:P09624 dld1 (Schizosaccharomyces pombe)UniProtKB:O00087

Function

dihydrolipoyl dehydrogenase (NADH) activityGO:0004148
Substrates: dihydrolipoyl-E2 (reduced lipoyl arm) NAD+
Products: lipoyl-E2 (reoxidised) NADH

Locations

mitochondrial matrixGO:0005759

FAD-dependent E3 that reoxidises the dihydrolipoyl arm, passing electrons to NAD+. The common E3 shared with the 2-oxoglutarate and branched-chain 2-oxoacid dehydrogenase complexes and the glycine cleavage system (see the BCAA catabolism module).

Part 2: anaplerotic / gluconeogenic carboxylation to oxaloacetate
pyruvate + HCO3- + ATP to oxaloacetate + ADP + PiReactionpc_step

Biotin-dependent carboxylation of pyruvate to oxaloacetate. The enzyme family is conserved, but its compartment differs by lineage.

Variant set: Pyruvate carboxylase compartment variants by compartment / lineage (Exactly One)
Mitochondrial-matrix pyruvate carboxylase (animals)Reactionmitochondrial_pc_variant

Annotons

PC: pyruvate carboxylase (biotin-dependent)
pc_activity
Participant: Family: Pyruvate carboxylase family (PC)
Family:
Pyruvate carboxylase family (PC)PANTHER:PTHR43778
Representative Members: PC (human)UniProtKB:P11498

Function

pyruvate carboxylase activityGO:0004736
Substrates: pyruvate hydrogencarbonate ATP biotin (covalent cofactor)
Products: oxaloacetate ADP phosphate

Locations

mitochondrial matrixGO:0005759

Biotin-dependent homotetramer; the principal anaplerotic reaction (replenishing TCA oxaloacetate) and the committed first step of gluconeogenesis from pyruvate/lactate. Allosterically activated by acetyl-CoA (the PDC product). Human deficiency causes pyruvate carboxylase deficiency (severe lactic acidosis, hypoglycemia).

Cytosolic pyruvate carboxylase (yeasts)Reactioncytosolic_pc_variant

Annotons

Cytosolic pyruvate carboxylase isozymes
cytosolic_pc_activity
Participant: Family: Pyruvate carboxylase family (PC)
Family:
Pyruvate carboxylase family (PC)PANTHER:PTHR43778
Representative Members: PYC1 (Saccharomyces cerevisiae)UniProtKB:P11154 PYC2 (Saccharomyces cerevisiae)UniProtKB:P32327 pyr1 (Schizosaccharomyces pombe)UniProtKB:Q9UUE1

Function

pyruvate carboxylase activityGO:0004736
Substrates: pyruvate hydrogencarbonate ATP biotin (covalent cofactor)
Products: oxaloacetate ADP phosphate

Locations

cytosolGO:0005829

Cytosolic anaplerotic carboxylation supplying oxaloacetate for aspartate-family amino acids, gluconeogenesis and, after import, the mitochondrial TCA cycle.