Pyruvate carboxylase is the mitochondrial matrix, biotin-dependent enzyme that catalyzes the ATP-dependent carboxylation of pyruvate to oxaloacetate (pyruvate + bicarbonate + ATP = oxaloacetate + ADP + phosphate + H+; EC 6.4.1.1). It is a homotetramer in which each subunit carries a biotin carboxylase (BC) domain, a carboxyltransferase (CT) domain and a biotinyl-carboxyl-carrier (BCCP) domain with biotin covalently attached to a C-terminal lysine (Lys-1144); catalysis proceeds in two steps, ATP-dependent carboxylation of the tethered biotin followed by transfer of the carboxyl group to pyruvate, and requires a Mn(2+) ion per subunit. The enzyme is allosterically activated by acetyl-CoA. Its product oxaloacetate is the central anaplerotic intermediate that replenishes the tricarboxylic acid cycle and the committed first substrate of gluconeogenesis from pyruvate/lactate; in a tissue-specific manner it also supplies carbon for lipogenesis, neurotransmitter synthesis and insulin secretion, with highest expression in liver and kidney. Loss of pyruvate carboxylase activity causes the autosomal recessive disorder pyruvate carboxylase deficiency, characterized by lactic acidosis, hypoglycemia and neurologic dysfunction.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004736 pyruvate carboxylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. Phylogenetically inferred pyruvate carboxylase activity, fully concordant with the experimentally determined catalytic activity of the human enzyme (EC 6.4.1.1) and with the conserved biotin-dependent carboxylase family. Reason: Represents the defining, experimentally validated catalytic function of the gene product and is supported by orthologs across the PANTHER family. Supporting Evidence: PMID:9585002 Pyruvate carboxylase (PC) is a biotinylated mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred mitochondrial localization, consistent with the experimentally established mitochondrial-matrix localization of human PC. Reason: Correct organelle. The more specific compartment (mitochondrial matrix) is captured by other annotations; this broader term is accurate and is retained. Supporting Evidence: PMID:9585002 Pyruvate carboxylase (PC) is a biotinylated mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate. |
| GO:0006094 gluconeogenesis | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process. Pyruvate carboxylase catalyzes the committed first step of gluconeogenesis from pyruvate/lactate, generating oxaloacetate. Reason: Well-established, phylogenetically conserved role; UniProt assigns the gluconeogenesis pathway on the basis of characterization of the human enzyme. Supporting Evidence: PMID:9585002 Children with inborn errors of PC metabolism have lactic acidosis, hypoglycemia, and mental retardation. Reactome:R-HSA-70501 Activation of PC by acetyl-CoA produced from lipolysis and leading to excess gluconeogenesis is the central mechanism of metabolic syndrome and diabetes |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MODIFY | Summary: Correct but uninformatively general parent term inferred from an InterPro domain mapping. The specific catalytic activity (pyruvate carboxylase activity, GO:0004736) is separately annotated. Reason: The essence (that PC is catalytic) is correct, but 'catalytic activity' is a root-level MF term that adds no information beyond the specific enzyme activity already annotated. Replace with the specific term. Proposed replacements: pyruvate carboxylase activity Supporting Evidence: PMID:9585002 Pyruvate carboxylase (PC) is a biotinylated mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate. |
| GO:0004736 pyruvate carboxylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of the specific catalytic activity via ARBA/InterPro/RHEA/EC mapping (EC 6.4.1.1, RHEA:20844). Concordant with experimental data. Reason: The EC/RHEA mapping to pyruvate carboxylase activity is correct and matches the UniProt catalytic activity annotation. Supporting Evidence: PMID:9585002 Pyruvate carboxylase (PC) is a biotinylated mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding by the biotin carboxylase (ATP-grasp) domain. PC uses ATP to carboxylate its tethered biotin in the first half-reaction. Reason: Supported by domain architecture (ATP-grasp domain, ATP-binding residues at 152/236/271) and by the ATP-dependent catalytic activity of the enzyme. Supporting Evidence: PMID:8048912 The translated amino acid sequence of 1178 residues contained consensus sequences for the covalent attachment for biotin, the binding of ATP and the binding of the substrate, pyruvate. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000120 | ACCEPT | Summary: Mitochondrial matrix localization, the canonical compartment for PC, assigned by ARBA/UniProt-SubCell mapping. Reason: Matches the experimentally determined subcellular location (mitochondrion matrix) in UniProt. Supporting Evidence: PMID:9585002 Pyruvate carboxylase (PC) is a biotinylated mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate. |
| GO:0005829 cytosol | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Electronic (ARBA) cytosol assignment. PC is canonically a mitochondrial matrix enzyme; a cytosolic pool exists in specific contexts (the cytosolic hydride transfer complex in cancer/hypoxic cells) but this is not the primary localization. Reason: The dominant, functionally relevant localization of human PC is the mitochondrial matrix. A minor context-specific cytosolic pool is documented (the cytosolic hydride transfer complex), so the cytosol term is retained as non-core rather than as a core localization. Supporting Evidence: PMID:34547241 This hydride transfer complex (HTC) is assembled by malate dehydrogenase 1, malic enzyme 1, and cytosolic pyruvate carboxylase. |
| GO:0006094 gluconeogenesis | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of the gluconeogenesis pathway via InterPro/UniPathway (UPA00138). Concordant with experimental and phylogenetic annotations. Reason: Correct pathway assignment; duplicates the well-supported IBA and TAS gluconeogenesis annotations. Supporting Evidence: Reactome:R-HSA-70501 Activation of PC by acetyl-CoA produced from lipolysis and leading to excess gluconeogenesis is the central mechanism of metabolic syndrome and diabetes |
| GO:0009374 biotin binding | IEA GO_REF:0000117 | ACCEPT | Summary: Core cofactor function. PC covalently binds biotin at Lys-1144 in the biotinyl-carboxyl-carrier domain; the tethered biotin is the carboxyl carrier in catalysis. Reason: Strongly supported by sequence (biotin attachment consensus), by covalent biotinylation at Lys-1144, and by structural data on biotin in the active site. Supporting Evidence: PMID:18297087 A BCCP domain is located in the active site of the CT domain, providing the first molecular insights into how biotin participates in the carboxyltransfer reaction. |
| GO:0046872 metal ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: PC binds one Mn(2+) ion per subunit in the carboxyltransferase domain (coordinating residues 572/741-carbamate/771/773), required for catalysis. Reason: Supported by crystallography showing Mn(2+) coordination in the active site; 'metal ion binding' is a general but accurate term for the Mn(2+)/Mg(2+) requirement. Supporting Evidence: PMID:18297087 Crystal structures of human and Staphylococcus aureus pyruvate carboxylase and molecular insights into the carboxyltransfer reaction. |
| GO:0005515 protein binding | IPI PMID:23861867 Nonstructural 5A protein of hepatitis C virus interacts with... | REMOVE | Summary: IntAct-curated interaction with the hepatitis C virus NS5A protein (Q03463-PRO_0000278740). The bare 'protein binding' term is uninformative about PC's molecular function. Reason: The underlying host-pathogen interaction (NS5A binds the biotin carboxylase domain of PC) is real, but 'protein binding' conveys no functional information and the paper supports no more informative PC molecular function to substitute. Removal does not mean the interaction is false; it is a host-virus contact, not a function of PC. Supporting Evidence: PMID:23861867 NS5A interacted with PC through the N-terminal region of NS5A and the biotin carboxylase domain of PC. |
| GO:0005515 protein binding | IPI PMID:34547241 A hydride transfer complex reprograms NAD metabolism and byp... | REMOVE | Summary: IntAct-curated interaction with malic enzyme 1 (ME1, P48163), a partner in the cytosolic hydride transfer complex. The bare 'protein binding' term is uninformative. Reason: The interaction (PC as a component of the MDH1-ME1-PC hydride transfer complex) is genuine, but 'protein binding' provides no functional specificity. PC's own activity in that complex is already captured by pyruvate carboxylase activity, and its complex membership by the NAD+/NADP+ process annotations from the same paper. Removal does not mean the interaction is false. Supporting Evidence: PMID:34547241 This hydride transfer complex (HTC) is assembled by malate dehydrogenase 1, malic enzyme 1, and cytosolic pyruvate carboxylase. |
| GO:0042802 identical protein binding | IPI PMID:18297087 Crystal structures of human and Staphylococcus aureus pyruva... | KEEP AS NON CORE | Summary: Self-association reflecting the functional homotetramer of pyruvate carboxylase, established by crystallography. Reason: PC is an obligate homotetramer and self-interaction is a real, structurally characterized property. It supports the oligomeric organization needed for catalysis but is not itself the core molecular function. Supporting Evidence: PMID:18297087 A conserved tetrameric association is observed for both enzymes |
| GO:0042802 identical protein binding | IPI PMID:34547241 A hydride transfer complex reprograms NAD metabolism and byp... | KEEP AS NON CORE | Summary: Self-association (homotetramer) detected in the study of the cytosolic hydride transfer complex; consistent with the known homotetrameric assembly. Reason: Duplicate evidence for the biologically real homo-oligomerization of PC. Retained as supporting the tetrameric quaternary structure, not the core MF. Supporting Evidence: PMID:18297087 A conserved tetrameric association is observed for both enzymes |
| GO:0006094 gluconeogenesis | TAS Reactome:R-HSA-70501 | ACCEPT | Summary: Reactome-asserted role of PC in gluconeogenesis, based on the characterized enzymatic reaction (PC carboxylates pyruvate to oxaloacetate). Reason: Authoritative pathway assertion consistent with the committed-step role of PC in gluconeogenesis; duplicates the IBA/IEA gluconeogenesis annotations. Supporting Evidence: Reactome:R-HSA-70501 Activation of PC by acetyl-CoA produced from lipolysis and leading to excess gluconeogenesis is the central mechanism of metabolic syndrome and diabetes |
| GO:0004736 pyruvate carboxylase activity | EXP PMID:12437512 Expression and characterization of a human pyruvate carboxyl... | ACCEPT | Summary: Experimental characterization of human PC enzyme activity via a retroviral expression system, including PC enzyme activity assays on wild-type and the Ala610Thr disease variant. Reason: Direct experimental measurement of pyruvate carboxylase activity for the human enzyme; core molecular function. Supporting Evidence: PMID:12437512 We show, through immunoblot analysis, PC enzyme activity assays, reverse-transcription PCR and mitochondrial-import experiments, that this mutation is disease-causing |
| GO:0005737 cytoplasm | IDA PMID:34547241 A hydride transfer complex reprograms NAD metabolism and byp... | KEEP AS NON CORE | Summary: ComplexPortal/IDA cytoplasmic localization associated with the cytosolic hydride transfer complex (HTC). PC is canonically mitochondrial matrix; a cytosolic pool participates in the HTC in cancer/hypoxic cells. Reason: Real but context-specific (a minor cytosolic pool assembled into the MDH1-ME1-PC complex). Not the primary localization or core function; retained as non-core. Supporting Evidence: PMID:34547241 HTC is found in phase-separated bodies in the cytosol of cancer or hypoxic cells and can be assembled in vitro with recombinant proteins. |
| GO:0006739 NADP+ metabolic process | IDA PMID:34547241 A hydride transfer complex reprograms NAD metabolism and byp... | KEEP AS NON CORE | Summary: PC contributes to NADP+/NAD metabolism as a member of the cytosolic hydride transfer complex, which transfers reducing equivalents from NADH to NADP+. Reason: A genuine, experimentally supported role, but it is an emergent, context-specific function of the MDH1-ME1-PC complex in cancer/hypoxic cells rather than the core anaplerotic/gluconeogenic function of PC. Supporting Evidence: PMID:34547241 We report a multi-enzymatic complex that reprograms NAD metabolism by transferring reducing equivalents from NADH to NADP+. |
| GO:0019674 NAD+ metabolic process | IDA PMID:34547241 A hydride transfer complex reprograms NAD metabolism and byp... | KEEP AS NON CORE | Summary: PC as part of the hydride transfer complex participates in NAD metabolism (consuming NADH as reducing-equivalent donor). Reason: Same rationale as the NADP+ annotation; real but emergent and context-specific to the cytosolic HTC, not PC's core function. Supporting Evidence: PMID:34547241 We report a multi-enzymatic complex that reprograms NAD metabolism by transferring reducing equivalents from NADH to NADP+. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence-based (HPA) mitochondrial localization, consistent with the canonical mitochondrial-matrix localization of PC. Reason: Correct organelle localization corroborated by orthogonal evidence (UniProt subcellular location, MGI IDA, mitochondrial proteomics). Supporting Evidence: PMID:9585002 Pyruvate carboxylase (PC) is a biotinylated mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate. |
| GO:0005759 mitochondrial matrix | EXP PMID:9585002 Molecular characterization of pyruvate carboxylase deficienc... | ACCEPT | Summary: Experimentally determined mitochondrial-matrix localization; this is the canonical compartment where PC is active. Reason: Direct experimental subcellular-location evidence for the specific compartment (matrix); core localization for the enzyme's function. Supporting Evidence: PMID:9585002 Pyruvate carboxylase (PC) is a biotinylated mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput mitochondrial proteomics places PC in the mitochondrion, consistent with the canonical localization. Reason: Corroborating high-confidence mitochondrial-proteome evidence for the established mitochondrial localization of PC. Supporting Evidence: PMID:9585002 Pyruvate carboxylase (PC) is a biotinylated mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate. |
| GO:0004736 pyruvate carboxylase activity | IMP PMID:9585002 Molecular characterization of pyruvate carboxylase deficienc... | ACCEPT | Summary: Pyruvate carboxylase activity inferred from the functional consequences of PC-deficiency mutations (patients with low PC activity, 2-25% of control), confirming the enzyme's activity in the human gene product. Reason: Loss-of-function mutations that reduce PC activity directly link the gene to pyruvate carboxylase activity; core molecular function. Supporting Evidence: PMID:9585002 the probands were found to have low PC activity (range, 2-25% of control) in blood lymphocytes and skin fibroblasts |
| GO:0005737 cytoplasm | IDA PMID:23861867 Nonstructural 5A protein of hepatitis C virus interacts with... | KEEP AS NON CORE | Summary: AgBase/IDA cytoplasmic localization from the HCV NS5A interaction study, which also documents mitochondrial colocalization of PC and NS5A. PC is canonically mitochondrial matrix. Reason: A cytoplasmic signal is reported, but the study emphasizes mitochondrial colocalization; cytoplasmic localization is not the primary compartment or a core function. Retained as non-core. Supporting Evidence: PMID:23861867 we verified that both PC and NS5A were colocalized in the mitochondria as determined by immunofluorescence assay |
| GO:0010629 negative regulation of gene expression | IMP PMID:23861867 Nonstructural 5A protein of hepatitis C virus interacts with... | MARK AS OVER ANNOTATED | Summary: This annotation derives from a host-pathogen study in which HCV NS5A downregulates the PC promoter. Here PC is the target of downregulation, not the effector; the process does not describe an intrinsic molecular function of PC. Reason: The experimental finding is that NS5A (and NS4B) down-regulate PC transcription; PC itself is not shown to negatively regulate gene expression. Attributing negative regulation of gene expression to PC as an actor is an over-annotation (PC is the regulated gene, not the regulator). Supporting Evidence: PMID:23861867 We also showed that the transcriptional activity of PC was downregulated in cells expressing NS5A, in HCV replicon cells, and in HCV infected cells |
| GO:0019074 viral RNA genome packaging | IMP PMID:23861867 Nonstructural 5A protein of hepatitis C virus interacts with... | MARK AS OVER ANNOTATED | Summary: Derived from the observation that silencing PC reduces production of infectious HCV particles in infected cells. This reflects an indirect metabolic dependency of the virus on host PC, not a direct role of PC in packaging the viral genome. Reason: The study shows PC is a host metabolic enzyme whose basal activity the virus depends on (silencing reduces infectious-particle production), but there is no evidence PC directly participates in packaging of the viral RNA genome. This is an over-interpretation of a metabolic-dependency phenotype. Supporting Evidence: PMID:23861867 silencing of PC reduced infectious particle production in HCV infected cells. This may explain that basal level of PC is also required for HCV propagation. |
| GO:0019076 viral release from host cell | IMP PMID:23861867 Nonstructural 5A protein of hepatitis C virus interacts with... | MARK AS OVER ANNOTATED | Summary: Also derived from the PC-silencing/reduced-infectious-particle phenotype. This is an indirect host metabolic contribution to the HCV life cycle rather than a direct role of PC in viral release. Reason: The phenotype (reduced infectious-particle production on PC silencing) is a metabolic dependency of the virus on host lipogenesis/anaplerosis, not evidence that PC mediates viral egress. Over-annotation. Supporting Evidence: PMID:23861867 silencing of PC reduced infectious particle production in HCV infected cells. This may explain that basal level of PC is also required for HCV propagation. |
| GO:0044794 host-mediated activation of viral process | IMP PMID:23861867 Nonstructural 5A protein of hepatitis C virus interacts with... | MARK AS OVER ANNOTATED | Summary: Captures the general finding that host PC activity supports HCV propagation. This is a systemic host-pathogen metabolic effect, not a specific molecular function of PC. Reason: PC is a housekeeping metabolic enzyme co-opted by HCV; the paper frames PC as a host factor whose basal level is required for propagation. Annotating PC with a viral-process term over-states the specificity and directness of PC's involvement. Supporting Evidence: PMID:23861867 This may explain that basal level of PC is also required for HCV propagation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2993802 | KEEP AS NON CORE | Summary: Reactome-asserted cytosolic localization referring to the biotinylation of apo-PC by holocarboxylase synthetase (HLCS) prior to mitochondrial import; the mature enzyme functions in the matrix. Reason: Reflects a transient, maturation-stage cytosolic state (biotinylation before matrix translocation) documented by Reactome, not the enzyme's functional compartment. Retained as non-core rather than removed. Supporting Evidence: Reactome:R-HSA-3323111 Once biotinylated, three halocarboxylases (hCBXs) are localised to the mitochondrial matrix. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3323111 | KEEP AS NON CORE | Summary: Reactome cytosolic assignment for the pre-import step in which biotinylated carboxylases translocate to the mitochondrial matrix. Reason: Same maturation-pathway rationale; cytosolic localization is a transient pre-import state, not the functional compartment. Non-core. Supporting Evidence: Reactome:R-HSA-3323111 Cytosolic carboxylases translocate to mitochondrial matrix |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9035988 | KEEP AS NON CORE | Summary: Reactome cytosolic assignment for the defective-HLCS reaction (failure to biotinylate PC:Mn2+), again referring to the pre-import cytosolic state. Reason: Transient maturation-stage cytosolic localization, consistent with the other Reactome cytosol assertions; not the functional compartment. Non-core. Supporting Evidence: Reactome:R-HSA-3323111 Once biotinylated, three halocarboxylases (hCBXs) are localised to the mitochondrial matrix. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-3065959 | ACCEPT | Summary: Reactome-asserted mitochondrial-matrix localization (degradation of mitochondrial holocarboxylases). Consistent with the canonical matrix localization of PC. Reason: Correct functional compartment for PC, corroborated by experimental and electronic mitochondrial-matrix annotations. Supporting Evidence: Reactome:R-HSA-3323111 Once biotinylated, three halocarboxylases (hCBXs) are localised to the mitochondrial matrix. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-3323111 | ACCEPT | Summary: Reactome-asserted mitochondrial-matrix localization following translocation of biotinylated PC; the functional compartment of the enzyme. Reason: Matches the canonical, experimentally established mitochondrial-matrix localization of PC. Supporting Evidence: Reactome:R-HSA-3323111 Once biotinylated, three halocarboxylases (hCBXs) are localised to the mitochondrial matrix. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-70501 | ACCEPT | Summary: Reactome localizes the PC-catalyzed carboxylation of pyruvate to oxaloacetate to the mitochondrial matrix. Reason: The functional compartment where PC catalysis occurs; concordant with all other matrix annotations. Supporting Evidence: Reactome:R-HSA-70501 Mitochondrial pyruvate carboxylase (PC) catalyzes the irreversible reaction of pyruvate (PYR), bicarbonate (HCO3-), and ATP to form oxaloacetate |
| GO:0005739 mitochondrion | IDA PMID:16729965 Novel localization of OCTN1, an organic cation/carnitine tra... | ACCEPT | Summary: MGI/IDA mitochondrial localization. The cited paper is primarily about the OCTN1 carnitine transporter but is used by MGI to support PC's mitochondrial localization; the assignment is consistent with the canonical localization of PC. Reason: Mitochondrial localization of PC is overwhelmingly supported by multiple independent lines of evidence; this IDA is consistent with that. Deferring to the curator on the specific supporting data (abstract-only cache). Supporting Evidence: PMID:9585002 Pyruvate carboxylase (PC) is a biotinylated mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate. |
| GO:0006107 oxaloacetate metabolic process | TAS Reactome:R-HSA-70501 | NEW | Summary: Proposed new annotation capturing PC's core anaplerotic role - the production of oxaloacetate, the central TCA-cycle intermediate, from pyruvate. GOA currently records gluconeogenesis but not the more general/direct oxaloacetate-production process that PC carries out. Reason: PC's immediate biological product is oxaloacetate, and its principal physiological role beyond gluconeogenesis is anaplerotic replenishment of TCA cycle oxaloacetate. The oxaloacetate metabolic process term directly reflects the enzyme's committed reaction and is not otherwise represented in GOA. Supporting Evidence: Reactome:R-HSA-70501 Mitochondrial pyruvate carboxylase (PC) catalyzes the irreversible reaction of pyruvate (PYR), bicarbonate (HCO3-), and ATP to form oxaloacetate PMID:9585002 Pyruvate carboxylase (PC) is a biotinylated mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate. |
| GO:0004736 pyruvate carboxylase activity | TAS PMID:7918683 Primary amino acid sequence and structure of human pyruvate ... | ACCEPT | Summary: Traceable statement of pyruvate carboxylase activity from the primary characterization of the human PC cDNA and sequence. Reason: Authoritative early characterization identifying the enzyme and its activity; supports the core molecular function. Supporting Evidence: PMID:7918683 a nuclear-encoded mitochondrial enzyme, catalyzes the conversion of pyruvate to oxaloacetate. |
| GO:0005524 ATP binding | TAS PMID:8048912 cDNA cloning of human kidney pyruvate carboxylase. | ACCEPT | Summary: Traceable statement of ATP binding based on identification of the ATP-binding consensus in the human PC sequence. Reason: Consistent with the ATP-grasp domain architecture and the ATP-dependent catalytic mechanism; supports the ATP-binding cofactor function. Supporting Evidence: PMID:8048912 The translated amino acid sequence of 1178 residues contained consensus sequences for the covalent attachment for biotin, the binding of ATP and the binding of the substrate, pyruvate. |
| GO:0009374 biotin binding | TAS PMID:8048912 cDNA cloning of human kidney pyruvate carboxylase. | ACCEPT | Summary: Traceable statement of biotin binding based on identification of the biotin covalent-attachment consensus in the human PC sequence. Reason: Concordant with covalent biotinylation at Lys-1144 and the enzyme's biotin-dependent mechanism; core cofactor function. Supporting Evidence: PMID:8048912 The translated amino acid sequence of 1178 residues contained consensus sequences for the covalent attachment for biotin, the binding of ATP and the binding of the substrate, pyruvate. |
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Download this section (compressed HTML)Q: Beyond the reported cytosolic hydride transfer complex, what fraction of cellular PC is cytosolic under normal physiology, and is there a functionally significant extra-mitochondrial pyruvate carboxylase pool?
Q: Does acetyl-CoA allosteric activation of human PC differ quantitatively across the gluconeogenic (liver/kidney) versus lipogenic (adipose/brain) tissue contexts?
Experiment: Kinetic characterization (kcat/Km, acetyl-CoA activation constant) of recombinant wild-type versus disease-variant human PC to quantify how deficiency mutations impair anaplerosis versus gluconeogenesis.
Experiment: Compartment-resolved metabolic flux analysis (e.g. 13C tracing) in liver-derived cells to distinguish PC's anaplerotic (TCA/oxaloacetate) from gluconeogenic flux contributions.
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