Vitamin K-dependent gamma-carboxylase is an endoplasmic-reticulum membrane enzyme that converts protein-bound glutamate to gamma-carboxyglutamate while oxidizing vitamin K hydroquinone to vitamin K epoxide. Its membrane-associated catalytic machinery recognizes substrate propeptides and modifies glutamate-rich regions on the lumenal side of the endoplasmic reticulum. This modification enables calcium-dependent functions of coagulation proteins and other substrates, including osteocalcin and matrix Gla protein. Impaired GGCX activity can cause combined vitamin K-dependent coagulation-factor deficiency and connective-tissue phenotypes. Alternative splicing produces 758- and 701-residue proteins; the physiological activity of the shorter product remains unresolved.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: GGCX is active on the ER-lumen side of the membrane. Reason: The is_active_in assertion has positive human topology support: UniProt places Lys218 within luminal residues 217–251 and residues 378–758 in the lumen, with experimental structural evidence. Retain this as a non-core compartment facet of the membrane-anchored catalytic function, whose core location is the ER membrane. Mouse microsomal activity in PMID:17327402 alone does not establish sidedness. |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:10910912 A topological study of the human gamma-glutamyl carboxylase. | ACCEPT | Summary: The ER membrane is the principal location of GGCX. Reason: The authentic human topology abstract establishes a membrane-spanning protein with cytoplasmic N terminus and luminal C terminus. Modern human structural work independently supports the membrane organization. Preserve the original IDA claim without converting the historical lower-bound crossing model into a precise modern topology or a shorter-product assay. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The electronic ER-membrane assignment agrees with direct human evidence. Reason: GGCX is an integral ER-membrane enzyme, supported independently by human topology and structural studies. Its luminal catalytic regions do not imply release as a soluble enzyme. Preserve the original electronic source rather than substituting a guessed organelle or product-specific localization. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-159752 | ACCEPT | Summary: The protein S reaction uses ER-membrane GGCX. Reason: The actual catalyst resolves to human P38435 entity 159860, explicitly located in the ER membrane. Reaction-level compartments are not automatically assigned to every participant. Supporting Evidence: Reactome:R-HSA-159752 |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-159761 | ACCEPT | Summary: The factor VII reaction places GGCX in the ER membrane. Reason: The shared catalyst entity is explicitly ER-membrane P38435. The precursor substrate location is distinguished from the enzyme location; this repeated source context does not count as a new localization experiment. Supporting Evidence: Reactome:R-HSA-159761 |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-159795 | ACCEPT | Summary: The protein C event retains the established ER-membrane enzyme. Reason: The source connects its catalytic role to entity 159860 and the explicit ER-membrane compartment. No freely soluble lumen residence or GGCX isoform-specific localization is inferred. Supporting Evidence: Reactome:R-HSA-159795 |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-159803 | ACCEPT | Summary: GGCX is membrane-associated during factor IX carboxylation. Reason: The normal F9 reaction resolves to the human GGCX entity with ER-membrane location. The shared catalyst record supports this existing location rather than transferring the compartment of the soluble precursor to GGCX. Supporting Evidence: Reactome:R-HSA-159803 |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-159819 | ACCEPT | Summary: The factor X reaction uses GGCX at the ER membrane. Reason: The actual P38435 catalyst entity has ER-membrane compartment 5789. The event is a substrate-specific reuse of that localization record, not evidence for a different GGCX product. Supporting Evidence: Reactome:R-HSA-159819 |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-159826 | ACCEPT | Summary: The prothrombin reaction uses ER-membrane GGCX. Reason: The enzyme entity is explicitly in the ER membrane. Prothrombin secretion does not imply GGCX secretion or a plasma location. Supporting Evidence: Reactome:R-HSA-159826 |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-163820 | ACCEPT | Summary: Protein Z precursor carboxylation uses the ER-membrane catalyst. Reason: The PROZ event references the verified human GGCX entity and its ER-membrane compartment. Initiator-methionine removal in the 2–758 entity is not a novel splice product. Supporting Evidence: Reactome:R-HSA-163820 |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-6807214 | ACCEPT | Summary: Osteocalcin carboxylation uses ER-membrane GGCX. Reason: The BGLAP event resolves to the same membrane-bound human enzyme. It does not transfer osteocalcin secretion or endocrine distribution to GGCX. Supporting Evidence: Reactome:R-HSA-6807214 |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9673231 | ACCEPT | Summary: The failed F9 reaction retains ER-membrane GGCX. Reason: The defective-recognition model retains normal entity 159860 at the ER membrane. The failure is assigned to F9 propeptide variants and does not indicate GGCX loss, relocalization or a negative localization annotation. Supporting Evidence: Reactome:R-HSA-9673231 |
| GO:0007596 blood coagulation | TAS PMID:9845520 A missense mutation in gamma-glutamyl carboxylase gene cause... | KEEP AS NON CORE | Summary: Coagulation is a physiological consequence of GGCX-dependent precursor maturation. Reason: The human family and expressed-mutant study links reduced GGCX activity to deficiencies of vitamin K-dependent coagulation proteins. Retain this physiological role outside the catalytic core: GGCX modifies precursors in the ER, rather than executing the circulating protease cascade or fibrin polymerization. Procoagulant and anticoagulant substrates prevent assigning a single direction from the disease phenotype. |
| GO:0008488 gamma-glutamyl carboxylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Gamma-glutamyl carboxylase activity is the principal catalytic function. Reason: The actual AN0/PTN002651685 assertion lies on the verified human lineage and its experimental donor set includes human GGCX legitimately. Independent human enzyme assays support this activity (PMID:39880037). The target has no identified loss in the inspected lineage; donor count is not the basis for acceptance. |
| GO:0008488 gamma-glutamyl carboxylase activity | IDA PMID:17073445 Brønsted analysis reveals Lys218 as the carboxylase active s... | UNDECIDED | Summary: Osteocalcin input is supported; its neurotransmitter-suppression context remains unresolved. Reason: Curated UniProt FUNCTION evidence supports osteocalcin/BGLAP as a GGCX substrate, including the has_input P02818 atom. The experimentally supported statement cites PMID:17073445 and PMID:39880952. The unresolved component is whether this activity is part of negative regulation of neurotransmitter secretion (GO:0046929). Original Methods/Results for PMID:17073445 remain inaccessible, and the retained independent evidence does not establish that physiological relationship. UNDECIDED therefore applies to the full conjunction, while both catalytic activity and osteocalcin input are supported. |
| GO:0008488 gamma-glutamyl carboxylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The enzyme classification matches the established human catalytic activity. Reason: The electronic assignment agrees with direct human GGCX carboxylation assays. GGCX modifies peptidyl glutamate while converting reduced vitamin K; it is not assigned the separate vitamin K reductase reaction. The original electronic provenance is retained. Supporting Evidence: |
| GO:0008488 gamma-glutamyl carboxylase activity | TAS PMID:1749935 Cloning and expression of the cDNA for human gamma-glutamyl ... | ACCEPT | Summary: Human GGCX catalyzes gamma-carboxylation of protein substrates. Reason: The original cloning abstract reports increased carboxylase activity after expression of human GGCX. Modern direct human-enzyme work independently confirms the catalytic assignment. The historical abstract does not establish every construct or substrate detail, but this well-supported function does not depend on those missing details. |
| GO:0008488 gamma-glutamyl carboxylase activity | TAS Reactome:R-HSA-159752 | ACCEPT | Summary: GGCX catalyzes carboxylation of protein S. Reason: The actual PROS1 reaction assigns human P38435 to catalyst 159812 with gamma-glutamyl carboxylase activity. This is an enzyme role, distinct from the protein substrate. It uses the same catalyst object as the other curated substrate events. Supporting Evidence: Reactome:R-HSA-159752 |
| GO:0008488 gamma-glutamyl carboxylase activity | TAS Reactome:R-HSA-159761 | ACCEPT | Summary: GGCX catalyzes carboxylation of the factor VII precursor. Reason: The F7 event identifies the target through catalyst 159812 and human P38435. It supports the established catalytic function without implying that GGCX performs the downstream proteolytic activation of factor VII. Supporting Evidence: Reactome:R-HSA-159761 |
| GO:0008488 gamma-glutamyl carboxylase activity | TAS Reactome:R-HSA-159795 | ACCEPT | Summary: GGCX carboxylates the protein C precursor. Reason: The PROC event assigns the gamma-carboxylation step to the exact human GGCX catalyst. Modification of this anticoagulant substrate does not confer protein C protease activity on GGCX. Supporting Evidence: Reactome:R-HSA-159795 |
| GO:0008488 gamma-glutamyl carboxylase activity | TAS Reactome:R-HSA-159803 | ACCEPT | Summary: GGCX carboxylates the factor IX precursor. Reason: The normal F9 reaction explicitly connects the carboxylase activity to human P38435. GGCX performs the covalent modification, while propeptide removal and later coagulation proteolysis are distinct steps. Supporting Evidence: Reactome:R-HSA-159803 |
| GO:0008488 gamma-glutamyl carboxylase activity | TAS Reactome:R-HSA-159819 | ACCEPT | Summary: GGCX carboxylates the factor X precursor. Reason: The F10 precursor event uses the verified GGCX catalyst and supports its direct gamma-carboxylase activity. The substrate coordinates describe the factor X chain, not a GGCX alternative product. Supporting Evidence: Reactome:R-HSA-159819 |
| GO:0008488 gamma-glutamyl carboxylase activity | TAS Reactome:R-HSA-159826 | ACCEPT | Summary: GGCX carboxylates prothrombin before secretion. Reason: The F2 event places human GGCX in the catalytic role for precursor gamma-carboxylation. It does not make GGCX the thrombin-generating protease or assign thrombin activity to it. Supporting Evidence: Reactome:R-HSA-159826 |
| GO:0008488 gamma-glutamyl carboxylase activity | TAS Reactome:R-HSA-163820 | ACCEPT | Summary: GGCX catalyzes protein Z precursor carboxylation. Reason: The PROZ event retains the same verified P38435 gamma-carboxylase catalyst. This is an additional substrate context for one established molecular function, not an independent enzyme class. Supporting Evidence: Reactome:R-HSA-163820 |
| GO:0008488 gamma-glutamyl carboxylase activity | TAS Reactome:R-HSA-6807214 | ACCEPT | Summary: GGCX catalyzes osteocalcin precursor carboxylation. Reason: The BGLAP reaction assigns human GGCX as the enzyme carrying out gamma-carboxylation. The event does not establish any particular downstream neurotransmitter, bone-development or testosterone endpoint. Supporting Evidence: Reactome:R-HSA-6807214 |
| GO:0008488 gamma-glutamyl carboxylase activity | TAS Reactome:R-HSA-9673231 | ACCEPT | Summary: The failed substrate reaction does not negate GGCX catalytic identity. Reason: This FailedReaction models F9 propeptide variants that impair recognition while retaining normal GGCX as catalyst 159812. It is not a successful-reaction experiment, but the enzyme identity and activity are independently established in human assays. Preserve the original positive polarity; no GGCX loss or NOT annotation is inferred. |
| GO:0016020 membrane | TAS PMID:1749935 Cloning and expression of the cDNA for human gamma-glutamyl ... | TOO GENERAL | Summary: Membrane is correct but less informative than the retained ER membrane location. Reason: The cloning study identifies a human membrane protein, and the specific ER-membrane annotation is independently supported. Current ontology is_a ancestry places GO:0005789 under GO:0016020, so the generic membrane row is redundant rather than incorrect. |
| GO:0017187 peptidyl-glutamic acid carboxylation | TAS Reactome:R-HSA-159740 | ACCEPT | Summary: GGCX directly performs peptidyl-glutamate carboxylation. Reason: The actual pathway assigns precursor gamma-carboxylation to GGCX. The protein performs the chemical step itself, so participation is supported independently of substrate necessity or knockout phenotype. This is the specific biological-process counterpart of its catalytic activity. |
| GO:0019842 vitamin binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Vitamin binding is a valid broad ligand-binding facet of catalysis. Reason: The AN0/PTN002651685 vitamin-binding assertion is inherited by the target and has a verified rat donor, which is sufficient in principle for a curated ancestral inference. Human GGCX binds vitamin K hydroquinone during catalysis (PMID:39880037). Retain this broad facet outside the more informative catalytic core; no unverified vitamin-specific term is substituted. |
| GO:0036211 protein modification process | TAS PMID:1749935 Cloning and expression of the cDNA for human gamma-glutamyl ... | TOO GENERAL | Summary: Protein modification is correct but redundant with the retained specific reaction. Reason: GGCX directly modifies protein-bound glutamate. The current is_a ancestry explicitly places the retained peptidyl-glutamic-acid carboxylation term GO:0017187 under protein modification GO:0036211. The broader term adds no useful specificity; this is not rejection of the original expression evidence. |
| GO:0042373 vitamin K metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Vitamin K conversion is directly coupled to GGCX catalysis. Reason: The Eumetazoa assertion at AN6/PTN000974017 is ancestral to human GGCX; its human self-donor is legitimate experimental grounding. GGCX performs vitamin K epoxidation during carboxylation (PMID:39880037), so it carries out a chemical step rather than merely depending on vitamin K availability. |
| GO:0042373 vitamin K metabolic process | IDA PMID:17073445 Brønsted analysis reveals Lys218 as the carboxylase active s... | ACCEPT | Summary: The cited chemistry supports direct participation in vitamin K metabolism. Reason: The accessible PMID:17073445 abstract reports vitamin K epoxidation and Lys218-dependent chemistry. This supports the stated metabolic process alongside direct human assays. No detailed proton-transfer mechanism or downstream physiological activity is inferred from that abstract. |
| GO:0042373 vitamin K metabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Vitamin K metabolism includes a chemical conversion directly performed by GGCX. Reason: The mouse-derived electronic assertion agrees with independent human evidence for vitamin K epoxidation during carboxylation. GGCX performs this chemical step rather than merely depending on a vitamin cofactor; the original donor and evidence code remain unchanged. Supporting Evidence: |
| GO:0046929 negative regulation of neurotransmitter secretion | IDA PMID:17073445 Brønsted analysis reveals Lys218 as the carboxylase active s... | UNDECIDED | Summary: The direct reference does not yet resolve this neurotransmitter-regulation claim. Reason: PMID:17073445 is authentic and its abstract supports enzyme chemistry, but the full original was not recovered. The specific negative-regulation-of-neurotransmitter-secretion experiment cannot be verified from the available text. Retain uncertainty rather than alleging wrong-gene attribution or converting an abstract omission into a negative result. Supporting Evidence: |
| GO:0046929 negative regulation of neurotransmitter secretion | IEA GO_REF:0000107 | UNDECIDED | Summary: The mouse-derived neurotransmitter-secretion claim needs its specific experiment. Reason: The mouse IMP donor cites PMID:25264202. Its authentic abstract does not resolve neurotransmitter release, and full Methods/Results remain inaccessible. Insulin secretion is a different endpoint. This source limit does not refute the curated mouse experiment; reciprocal transfers do not erase its experimental provenance. Supporting Evidence: |
| GO:0051604 protein maturation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Carboxylation contributes directly to protein maturation. Reason: The mouse source measures loss of GGCX-dependent peptide carboxylation after disruption, and human studies independently establish the chemistry. GGCX performs a covalent modification that enables substrate-protein function; it is not merely consumed by the maturation process. Retain this broad consequence outside the more specific catalytic core. |
| GO:1903011 negative regulation of bone development | IEA GO_REF:0000107 | UNDECIDED | Summary: The exact bone-development effect cannot be adjudicated from the available source. Reason: The mouse IMP donor cites PMID:25264202. Full Methods/Results remain inaccessible, and the authentic abstract does not resolve the directional bone-development claim. This is unresolved evidence, not a negative biological finding. Supporting Evidence: |
| GO:2000225 negative regulation of testosterone biosynthetic process | IEA GO_REF:0000107 | UNDECIDED | Summary: The directional testosterone-biosynthesis endpoint remains unverified. Reason: The mouse IMP donor cites PMID:25264202, but full Methods/Results remain inaccessible and the authentic abstract does not resolve testosterone biosynthesis. Preserve uncertainty about this specific endpoint without denying possible endocrine effects. Supporting Evidence: |
| GO:0008488 gamma-glutamyl carboxylase activity | IDA PMID:17073445 Brønsted analysis reveals Lys218 as the carboxylase active s... | ACCEPT | Summary: The carboxylase assertion and vitamin K input/output context are supported. Reason: The cited abstract supports vitamin K epoxidation chemistry, corroborated by direct human enzyme assays. The activity is linked here to vitamin K metabolism with phyllohydroquinone input and 2,3-epoxyphylloquinone output. This chemical context is supported independently of the unresolved neurotransmitter-suppression context. |
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Download this section (compressed HTML)Q: Which original experiment in PMID:17073445 supports the negative regulation of neurotransmitter secretion claim and its osteocalcin-input extension, separately from the directly measured catalytic chemistry?
Suggested experts: GO annotation curators, Original study authors
Q: Which original experiments support the mouse-derived neurotransmitter-secretion, bone-development and testosterone-biosynthesis annotations? PMID:25264202 is currently available only as an authentic abstract.
Suggested experts: Bone-endocrine biology specialists, GO annotation curators
Q: Does the sequence-verified 701-residue splice product retain membrane insertion and coupled carboxylation/epoxidation activity, and where is it expressed relative to the 758-residue product?
Suggested experts: Vitamin K enzymology specialists, Transcript and protein isoform curators
Q: How are successive glutamate residues positioned for modification, and which proposed proton-transfer and bicarbonate-dependent steps are directly supported beyond structural models and mutational effects?
Suggested experts: GGCX structural enzymologists
Experiment: Compare sequence-verified 758- and 701-residue human products at matched abundance, measuring endoplasmic-reticulum membrane topology, protein-substrate carboxylation and vitamin K epoxide production separately.
Hypothesis: The amino-terminal deletion changes membrane organization or coupling efficiency without necessarily eliminating every catalytic readout.
Experiment: Measure carboxylation of defined individual substrate residues together with vitamin K epoxide formation during controlled substrate-loading and release experiments.
Hypothesis: Substrate recognition and modification order can be distinguished from an epoxidation-only proxy for productive carboxylation.
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