FLVCR1

Summary: A FLVCR fragment binds hemopexin in the reported biochemical assay.

Reason: Actual PMID:20610401 original Methods/Results and Fig7 caption support hemopexin binding to a GST-tagged FLVCR fragment spanning residues 132–201, with GST-alone and competition controls. The original Methods and Results specify 132–201, whereas the Discussion gives 132–301 and that conflicting range is retained in the normal cache; the construct sequence has not been independently resolved. The protein reagent was purified rabbit apohemopexin; human FLVCR expression is explicit in rat NRK cell experiments, while the binding-fragment insert species is not separately stated. Preserve the original human HPX accession and retain contextual binding with this species/fragment scope. This is not a purified full-length human-human affinity or proof of a complete transport mechanism.

Summary: The GRID2IP source-pair assertion remains unresolved against the below-threshold measurements.

Reason: Exact IntAct records identify the GRID2IP-FLVCR1 peptide/domain assays, but every tested GRID2IP domain in the actual original SupplementaryDataset1 has normalized DAPF binding intensity below the authors' 0.05 detection threshold and composite pKd coded zero. Thus the source does not independently quantify a positive association for this protein pair. Keep the original assertion UNDECIDED pending curator/source reconciliation. Below threshold is not proof of noninteraction and does not justify REMOVE; IntAct negative=false and its malformed kd:1.0x10(molar) parameter are not substitutes for measured positive binding.

Summary: The MPDZ source-pair assertion remains unresolved against the below-threshold measurements.

Reason: Exact IntAct records identify the MPDZ-FLVCR1 peptide/domain assays, but every tested MPDZ domain in the actual original SupplementaryDataset1 has normalized DAPF binding intensity below the authors' 0.05 detection threshold and composite pKd coded zero. Thus the source does not independently quantify a positive association for this protein pair. Keep the original assertion UNDECIDED pending curator/source reconciliation. Below threshold is not proof of noninteraction and does not justify REMOVE; IntAct negative=false and its malformed kd:1.0x10(molar) parameter are not substitutes for measured positive binding.

Summary: The FLVCR1 terminal peptide binds a tested DLG4 PDZ domain.

Reason: Original PMID:36115835 SupplementaryDataset1 directly reports above-threshold DAPF holdup binding for at least one DLG4 PDZ domain to the FLVCR1 C-terminal ten-residue peptide. MODIFY to GO:0030165 PDZ domain binding because the assay directly tests binding to the named PDZ domain, an evidence-backed specific class for the same interaction. Human protein sequences and isolated tagged domains/biotinylated peptides were tested in vitro, not full-length endogenous protein complexes. These are single measurements converted using an estimated peptide concentration, without FLVCR1-specific FP replication; do not transfer the partner function or infer physiological transport regulation.

Proposed replacements: PDZ domain binding

Summary: The APBA1 source-pair assertion remains unresolved against the below-threshold measurements.

Reason: Exact IntAct records identify the APBA1-FLVCR1 peptide/domain assays, but every tested APBA1 domain in the actual original SupplementaryDataset1 has normalized DAPF binding intensity below the authors' 0.05 detection threshold and composite pKd coded zero. Thus the source does not independently quantify a positive association for this protein pair. Keep the original assertion UNDECIDED pending curator/source reconciliation. Below threshold is not proof of noninteraction and does not justify REMOVE; IntAct negative=false and its malformed kd:1.0x10(molar) parameter are not substitutes for measured positive binding.

Summary: The TJP1 source-pair assertion remains unresolved against the below-threshold measurements.

Reason: Exact IntAct records identify the TJP1-FLVCR1 peptide/domain assays, but every tested TJP1 domain in the actual original SupplementaryDataset1 has normalized DAPF binding intensity below the authors' 0.05 detection threshold and composite pKd coded zero. Thus the source does not independently quantify a positive association for this protein pair. Keep the original assertion UNDECIDED pending curator/source reconciliation. Below threshold is not proof of noninteraction and does not justify REMOVE; IntAct negative=false and its malformed kd:1.0x10(molar) parameter are not substitutes for measured positive binding.

Summary: The IL16 source-pair assertion remains unresolved against the below-threshold measurements.

Reason: Exact IntAct records identify the IL16-FLVCR1 peptide/domain assays, but every tested IL16 domain in the actual original SupplementaryDataset1 has normalized DAPF binding intensity below the authors' 0.05 detection threshold and composite pKd coded zero. Thus the source does not independently quantify a positive association for this protein pair. Keep the original assertion UNDECIDED pending curator/source reconciliation. Below threshold is not proof of noninteraction and does not justify REMOVE; IntAct negative=false and its malformed kd:1.0x10(molar) parameter are not substitutes for measured positive binding.

Summary: The FLVCR1 terminal peptide binds a tested SCRIB PDZ domain.

Reason: Original PMID:36115835 SupplementaryDataset1 directly reports above-threshold DAPF holdup binding for at least one SCRIB PDZ domain to the FLVCR1 C-terminal ten-residue peptide. MODIFY to GO:0030165 PDZ domain binding because the assay directly tests binding to the named PDZ domain, an evidence-backed specific class for the same interaction. Human protein sequences and isolated tagged domains/biotinylated peptides were tested in vitro, not full-length endogenous protein complexes. These are single measurements converted using an estimated peptide concentration, without FLVCR1-specific FP replication; do not transfer the partner function or infer physiological transport regulation.

Proposed replacements: PDZ domain binding

Summary: The DLG2 source-pair assertion remains unresolved against the below-threshold measurements.

Reason: Exact IntAct records identify the DLG2-FLVCR1 peptide/domain assays, but every tested DLG2 domain in the actual original SupplementaryDataset1 has normalized DAPF binding intensity below the authors' 0.05 detection threshold and composite pKd coded zero. Thus the source does not independently quantify a positive association for this protein pair. Keep the original assertion UNDECIDED pending curator/source reconciliation. Below threshold is not proof of noninteraction and does not justify REMOVE; IntAct negative=false and its malformed kd:1.0x10(molar) parameter are not substitutes for measured positive binding.

Summary: The FLVCR1 terminal peptide binds a tested PDZK1 PDZ domain.

Reason: Original PMID:36115835 SupplementaryDataset1 directly reports above-threshold DAPF holdup binding for at least one PDZK1 PDZ domain to the FLVCR1 C-terminal ten-residue peptide. MODIFY to GO:0030165 PDZ domain binding because the assay directly tests binding to the named PDZ domain, an evidence-backed specific class for the same interaction. Human protein sequences and isolated tagged domains/biotinylated peptides were tested in vitro, not full-length endogenous protein complexes. These are single measurements converted using an estimated peptide concentration, without FLVCR1-specific FP replication; do not transfer the partner function or infer physiological transport regulation.

Proposed replacements: PDZ domain binding

Summary: The FRMPD2 source-pair assertion remains unresolved against the below-threshold measurements.

Reason: Exact IntAct records identify the FRMPD2-FLVCR1 peptide/domain assays, but every tested FRMPD2 domain in the actual original SupplementaryDataset1 has normalized DAPF binding intensity below the authors' 0.05 detection threshold and composite pKd coded zero. Thus the source does not independently quantify a positive association for this protein pair. Keep the original assertion UNDECIDED pending curator/source reconciliation. Below threshold is not proof of noninteraction and does not justify REMOVE; IntAct negative=false and its malformed kd:1.0x10(molar) parameter are not substitutes for measured positive binding.

Summary: The FLVCR1 terminal peptide binds a tested MAGI2 PDZ domain.

Reason: Original PMID:36115835 SupplementaryDataset1 directly reports above-threshold DAPF holdup binding for at least one MAGI2 PDZ domain to the FLVCR1 C-terminal ten-residue peptide. MODIFY to GO:0030165 PDZ domain binding because the assay directly tests binding to the named PDZ domain, an evidence-backed specific class for the same interaction. Human protein sequences and isolated tagged domains/biotinylated peptides were tested in vitro, not full-length endogenous protein complexes. These are single measurements converted using an estimated peptide concentration, without FLVCR1-specific FP replication; do not transfer the partner function or infer physiological transport regulation.

Proposed replacements: PDZ domain binding

Summary: The FLVCR1 terminal peptide binds a tested NHERF4 PDZ domain.

Reason: Original PMID:36115835 SupplementaryDataset1 directly reports above-threshold DAPF holdup binding for at least one NHERF4 PDZ domain to the FLVCR1 C-terminal ten-residue peptide. MODIFY to GO:0030165 PDZ domain binding because the assay directly tests binding to the named PDZ domain, an evidence-backed specific class for the same interaction. Human protein sequences and isolated tagged domains/biotinylated peptides were tested in vitro, not full-length endogenous protein complexes. These are single measurements converted using an estimated peptide concentration, without FLVCR1-specific FP replication; do not transfer the partner function or infer physiological transport regulation.

Proposed replacements: PDZ domain binding

Summary: The LNX2 source-pair assertion remains unresolved against the below-threshold measurements.

Reason: Exact IntAct records identify the LNX2-FLVCR1 peptide/domain assays, but every tested LNX2 domain in the actual original SupplementaryDataset1 has normalized DAPF binding intensity below the authors' 0.05 detection threshold and composite pKd coded zero. Thus the source does not independently quantify a positive association for this protein pair. Keep the original assertion UNDECIDED pending curator/source reconciliation. Below threshold is not proof of noninteraction and does not justify REMOVE; IntAct negative=false and its malformed kd:1.0x10(molar) parameter are not substitutes for measured positive binding.

Summary: The PATJ source-pair assertion remains unresolved against the below-threshold measurements.

Reason: Exact IntAct records identify the PATJ-FLVCR1 peptide/domain assays, but every tested PATJ domain in the actual original SupplementaryDataset1 has normalized DAPF binding intensity below the authors' 0.05 detection threshold and composite pKd coded zero. Thus the source does not independently quantify a positive association for this protein pair. Keep the original assertion UNDECIDED pending curator/source reconciliation. Below threshold is not proof of noninteraction and does not justify REMOVE; IntAct negative=false and its malformed kd:1.0x10(molar) parameter are not substitutes for measured positive binding.

Summary: The FLVCR1 terminal peptide binds a tested LNX1 PDZ domain.

Reason: Original PMID:36115835 SupplementaryDataset1 directly reports above-threshold DAPF holdup binding for at least one LNX1 PDZ domain to the FLVCR1 C-terminal ten-residue peptide. MODIFY to GO:0030165 PDZ domain binding because the assay directly tests binding to the named PDZ domain, an evidence-backed specific class for the same interaction. Human protein sequences and isolated tagged domains/biotinylated peptides were tested in vitro, not full-length endogenous protein complexes. These are single measurements converted using an estimated peptide concentration, without FLVCR1-specific FP replication; do not transfer the partner function or infer physiological transport regulation. LNX1_1 has normalized BI 0.05565566, only slightly above the 0.05 detection threshold; this is not evidence of robust or high-affinity binding.

Proposed replacements: PDZ domain binding

Summary: The FLVCR1 terminal peptide binds a tested DLG3 PDZ domain.

Reason: Original PMID:36115835 SupplementaryDataset1 directly reports above-threshold DAPF holdup binding for at least one DLG3 PDZ domain to the FLVCR1 C-terminal ten-residue peptide. MODIFY to GO:0030165 PDZ domain binding because the assay directly tests binding to the named PDZ domain, an evidence-backed specific class for the same interaction. Human protein sequences and isolated tagged domains/biotinylated peptides were tested in vitro, not full-length endogenous protein complexes. These are single measurements converted using an estimated peptide concentration, without FLVCR1-specific FP replication; do not transfer the partner function or infer physiological transport regulation.

Proposed replacements: PDZ domain binding

Summary: The MAGI1 source-pair assertion remains unresolved against the below-threshold measurements.

Reason: Exact IntAct records identify the MAGI1-FLVCR1 peptide/domain assays, but every tested MAGI1 domain in the actual original SupplementaryDataset1 has normalized DAPF binding intensity below the authors' 0.05 detection threshold and composite pKd coded zero. Thus the source does not independently quantify a positive association for this protein pair. Keep the original assertion UNDECIDED pending curator/source reconciliation. Below threshold is not proof of noninteraction and does not justify REMOVE; IntAct negative=false and its malformed kd:1.0x10(molar) parameter are not substitutes for measured positive binding.

Summary: The APBA2 source-pair assertion remains unresolved against the below-threshold measurements.

Reason: Exact IntAct records identify the APBA2-FLVCR1 peptide/domain assays, but every tested APBA2 domain in the actual original SupplementaryDataset1 has normalized DAPF binding intensity below the authors' 0.05 detection threshold and composite pKd coded zero. Thus the source does not independently quantify a positive association for this protein pair. Keep the original assertion UNDECIDED pending curator/source reconciliation. Below threshold is not proof of noninteraction and does not justify REMOVE; IntAct negative=false and its malformed kd:1.0x10(molar) parameter are not substitutes for measured positive binding.

Summary: The GRIP2 source-pair assertion remains unresolved against the below-threshold measurements.

Reason: Exact IntAct records identify the GRIP2-FLVCR1 peptide/domain assays, but every tested GRIP2 domain in the actual original SupplementaryDataset1 has normalized DAPF binding intensity below the authors' 0.05 detection threshold and composite pKd coded zero. Thus the source does not independently quantify a positive association for this protein pair. Keep the original assertion UNDECIDED pending curator/source reconciliation. Below threshold is not proof of noninteraction and does not justify REMOVE; IntAct negative=false and its malformed kd:1.0x10(molar) parameter are not substitutes for measured positive binding.

Summary: The FLVCR1 terminal peptide binds a tested WHRN PDZ domain.

Reason: Original PMID:36115835 SupplementaryDataset1 directly reports above-threshold DAPF holdup binding for at least one WHRN PDZ domain to the FLVCR1 C-terminal ten-residue peptide. MODIFY to GO:0030165 PDZ domain binding because the assay directly tests binding to the named PDZ domain, an evidence-backed specific class for the same interaction. Human protein sequences and isolated tagged domains/biotinylated peptides were tested in vitro, not full-length endogenous protein complexes. These are single measurements converted using an estimated peptide concentration, without FLVCR1-specific FP replication; do not transfer the partner function or infer physiological transport regulation.

Proposed replacements: PDZ domain binding

Summary: The GRIP1 source-pair assertion remains unresolved against the below-threshold measurements.

Reason: Exact IntAct records identify the GRIP1-FLVCR1 peptide/domain assays, but every tested GRIP1 domain in the actual original SupplementaryDataset1 has normalized DAPF binding intensity below the authors' 0.05 detection threshold and composite pKd coded zero. Thus the source does not independently quantify a positive association for this protein pair. Keep the original assertion UNDECIDED pending curator/source reconciliation. Below threshold is not proof of noninteraction and does not justify REMOVE; IntAct negative=false and its malformed kd:1.0x10(molar) parameter are not substitutes for measured positive binding.

Summary: The short-product-associated mitochondrial pool supports the inherited localization.

Reason: The mitochondrial-location IBD at PTN002589204 is on the target path. Actual endogenous human mitochondrial-fraction immunoblotting and complementary tagged murine-product localization support the short-product-associated location. Retain this distinct mitochondrial role without transferring it to all full-length plasma-membrane transport or inferring the inner mitochondrial membrane from the ancestral annotation.

Summary: Endogenous human fractionation supports mitochondrial association of the short product.

Reason: The primary study detects an endogenous human C-terminal-reactive band of the short-product size in purified mitochondrial fractions with compartment controls. Tagged localization corroborates the result but uses murine constructs. Retain mitochondrial association with explicit product/antibody scope; no inner-versus-outer membrane or experimentally mapped targeting-peptide cleavage follows from these data.

Summary: Mitochondrial membrane is supported; the inner bilayer is not experimentally resolved.

Reason: Mitochondrial association of the short product is supported by fractionation, endogenous human protein detection and tagged-product localization, but the inspected primary Methods do not distinguish the inner from the outer mitochondrial membrane. The suggested inner-membrane biosynthetic complex is a hypothesis. Generalize the electronic location to GO:0031966 mitochondrial membrane, an official ancestor of GO:0005743, preserving the original term and source context. GO:0031966 is already retained in this review with PMID:23187127 and GO_REF:0000044; this replacement preserves the original source context at the supported granularity and adds no new gene-level location or core function.

Proposed replacements: mitochondrial membrane

Summary: Generalize the reaction model location to the supported mitochondrial membrane.

Reason: Official R-HSA-9661408 assigns the inner membrane but cites only PMID:23187127; its own summary says mitochondrial membrane. The primary study supports mitochondrial localization and a membrane protein, while an inner-membrane complex is proposed rather than resolved experimentally. Replace with GO:0031966 mitochondrial membrane to preserve supported localization without importing an untested topological specificity from the pathway model. GO:0031966 is already retained in this review with PMID:23187127 and GO_REF:0000044; this replacement preserves the original source context at the supported granularity and adds no new gene-level location or core function.

Proposed replacements: mitochondrial membrane

Summary: Human-protein cellular export and independent imaging support the plasma-membrane pool.

Reason: Actual PMID:15369674 expresses human FLVCR in rat NRK cells and tests cell-associated export, with separate human K562 experiments. Its original surface-location assertion is independently corroborated by later human FLVCR1a membrane imaging. Retain the plasma-membrane pool without confusing the species of the protein and expression host.

Summary: Independent target imaging supports the full-length plasma-membrane pool.

Reason: The authentic PMID:22483575 abstract reports disease-variant trafficking and stability defects, although detailed localization Methods remain inaccessible. Independent actual human full-length FLVCR1 imaging and direct transport studies support the plasma membrane as the principal location for the long product. Preserve this IDA context without inventing the original host-cell or microscopy details.

Summary: The full-length product underlies the plasma-membrane transport role.

Reason: Actual PMID:37100056 describes paired FLAG-tagged a/b localization Methods with plasma-membrane and citrate-synthase markers; the inspected Results attribute the shorter mitochondrial isoform to prior work and report rescue of phosphocholine by the full-length plasma-membrane product. Supplementary imaging was not independently audited here. Independent human FLVCR1a membrane imaging in PMID:38778100 supports this core location without assigning all natural products to it.

Summary: Human FLVCR1a imaging supports plasma-membrane localization.

Reason: Actual PMID:38778100 expresses human full-length FLVCR1a in HEK293 cells and uses membrane-marker/antibody imaging alongside uptake assays. This establishes the plasma-membrane pool underlying the transporter activity. No mitochondrial-product localization or universal endogenous tissue distribution is inferred from overexpression.

Summary: The electronic mapping agrees with the principal full-length plasma-membrane pool.

Reason: The UniProt/ARBA plasma-membrane mapping agrees with actual human full-length FLVCR1 imaging, cellular transport and reconstituted membrane activity. Retain this principal long-product location. Preserve the original electronic provenance without extrapolating it to the short mitochondrial product.

Summary: The reaction model places the full-length product at its supported plasma-membrane location.

Reason: Official Reactome R-HSA-917892 models FLVCR1-1 at the plasma membrane for cellular heme export, citing original cellular evidence. The same location is independently established in modern human FLVCR1a transport studies. Retain the location without treating pathway placement as independent proof of transport mechanism or assigning it to every product.

Summary: Heme handling and feedback do not establish an identified heme-synthetic step by FLVCR1.

Reason: GO:0006783 concerns formation of heme from precursors. The inspected evidence places FLVCR1 in completed-heme handling and shows coupled changes in biosynthetic flux or transcript abundance; it does not identify a synthetic reaction, scaffold or cofactor step supplied by FLVCR1. The proposed association with the inner-membrane biosynthetic complex remains hypothetical. Thus a direct biosynthetic-process attribution is broader than the established transport/homeostatic role, even though heme synthesis is affected.

Summary: Pathway placement does not establish that FLVCR1 performs heme synthesis.

Reason: The exact Reactome pathway summary describes the enzymes and precursor conversions that form heme. FLVCR1 is modelled as exporting finished heme, and the 2012 primary study supports coupling to heme handling and feedback rather than an identified synthetic step performed by FLVCR1. Pathway membership alone does not settle direct participation in heme formation. Preserve the source context but mark the biosynthetic-process attribution as overextended, not the observed effect on heme metabolism as false.

Summary: A verified target-path ancestral assertion supports contextual mitochondrial transport.

Reason: The mitochondrial-transport IBD at PTN002589204 (Euteleostomi) is on the exact target path and is legitimately grounded in target experiments. The primary study links the short human transcript to mitochondrial heme handling and recovers endogenous human protein in mitochondrial fractions. Retain this distinct mitochondrial physiological role with product and assay limits; self-donation and a short donor list are not circularity or weakness.

Summary: The short-product-associated mitochondrial pool contributes to compartmental heme handling.

Reason: PMID:23187127 supports product-dependent mitochondrial heme handling: human short-transcript depletion increases mitochondrial heme, and endogenous human protein is recovered in mitochondrial fractions. Retain the contextual mitochondrial-transport role. The heme-content assay is not purified transport, and overexpressed a/b constructs were murine despite human host cells. This does not establish a universal mitochondrial role for the full-length plasma-membrane product.

Summary: Heme handling contributes to iron homeostasis without establishing free-iron transport.

Reason: The official iron-homeostasis pathway includes iron carried within heme. Actual cellular heme export and product-dependent heme compartmentalization support contextual participation in handling intracellular heme-associated iron. Retain this homeostatic role without asserting direct free-iron-ion transport, a measured iron-binding mechanism, or universal control of every cellular iron pool.

Summary: Transport supplies choline and ethanolamine precursors to the Kennedy pathway.

Reason: Final PMID:38693265 links substrate-selective precursor transport to labeled phosphocholine and phosphoethanolamine production in knockout/rescue/mutant cells. FLVCR1 itself performs the experimentally linked precursor-entry step: transport of choline and ethanolamine into the cellular pathway, consistent with the original curator part_of GO:0008654 extensions on both substrate-transporter assertions. This is positive pathway participation through substrate delivery, whereas the heme-biosynthesis assertions concern export or redistribution of already completed heme and feedback on its synthesis, without an identified heme-forming step performed by FLVCR1. Retain the existing phospholipid-pathway association as contextual; the evidence does not establish that this is the only or obligatorily committed route of precursor entry. Downstream enzymes perform phosphorylation and lipid assembly. These particular assays do not directly measure mature phosphatidylcholine/phosphatidylethanolamine synthesis, and no biosynthetic catalytic activity is assigned to FLVCR1.

Summary: Human loss and complementation experiments support choline transport.

Reason: Actual PMID:37100056 human HEK293T/HeLa knockout and complementation experiments directly measure radiolabeled choline accumulation; FLVCR1 or SLC5A7 rescues the defect, while measured choline kinase activity is unchanged. The study distinguishes uptake from intracellular trapping and leaves other substrates possible. Subsequent purified-human-protein reconstitution in PMID:38693265 independently establishes direct transport.

Summary: Purified human FLVCR1 transports choline in reconstituted vesicles.

Reason: Final PMID:38693265 reconstitutes purified human FLVCR1 into lipid vesicles and measures choline uptake against protein-free controls, providing direct transporter evidence. Cellular rescue and substrate-site mutants corroborate the activity. Preserve the original phospholipid-biosynthesis part_of extension as pathway-entry context; the transporter imports precursor and does not acquire kinase or phospholipid-assembly activity.

Summary: Human FLVCR1a supports choline uptake coupled to downstream metabolic trapping.

Reason: Actual PMID:38778100 tests human full-length FLVCR1a in HEK293 cells, combining choline uptake, substrate-bound structure and mutagenesis. CHKA coexpression enhances measured accumulation through downstream utilization; FLVCR1 overexpression alone did not increase choline uptake in the tested condition. Retain the direct transporter function without reporting a universal affinity or assigning kinase activity to FLVCR1.

Summary: Independent human cellular and reconstituted assays establish choline transport despite the source-specific access gap.

Reason: The exact FLVCR1 assay in PMID:40972734 remains inaccessible: its authentic abstract describes a multi-transporter comparison but does not enumerate every target. Preserve the experimental curation because choline transport is independently established by human cellular and purified-protein assays in PMID:37100056/38693265/38778100. Do not transfer kinetic or inhibitor values reported for other SLCs to FLVCR1 or call the citation misattributed.

Summary: Human FLVCR1 variant assays corroborate choline transport.

Reason: Final PMID:39306721 publisher Methods/Results test human FLVCR1 and variants with CHKA in HEK293 cells and kinase-only mock controls. Whole-cell radiolabeled choline accumulation supports the existing activity, independently corroborated by purified-transporter work. This is a coupled uptake/trapping assay, not purified variant flux or a direct measure of disease severity.

Summary: A verified ancestral assertion and human-protein cellular assays support contextual heme transport.

Reason: The exact human target inherits this IBD from PTN000858905 (Eumetazoa), verified on the actual tree and original GAF. Human FLVCR expressed in rat cells supports radiolabeled-hemin washout and extracellular HPLC-detected heme, with independent acceptor-dependent cellular export studies. Retain this experimentally grounded heme capacity outside the principal choline/ethanolamine core; the work does not isolate purified full-length heme translocation. New choline evidence does not by itself contradict heme export.

Summary: Extracellular acceptors support FLVCR-dependent cellular heme export.

Reason: The original 2010 work measures acceptor-dependent cellular export and HPLC-detected endogenous heme in human-FLVCR-expressing rat cells. Macrophage and FLVCR-null mouse fibroblast experiments are separate models. It supports the reported heme-export capacity; it does not demonstrate purified full-length translocation or prove every element of the proposed histidine mechanism. Retain with this biochemical and cellular scope.

Summary: Variant export and trafficking findings support contextual heme transport with limited source access.

Reason: The verified abstract reports loss of fluorescent-heme-analog export for four FLVCR1 variants together with trafficking and stability defects. The full Methods remain inaccessible, so host species and unreported assay details are not asserted. Independent original 2004 and 2010 human-protein cellular export experiments support the same capacity. Retain it with explicit source-access limits rather than reject an experimental assertion from an incomplete article.

Summary: Cellular export assays support the electronic heme-transport assignment as a contextual capacity.

Reason: The ARBA assertion is consistent with target-specific human-protein cellular export assays using radiolabeled hemin and extracellular HPLC, independently supported by acceptor-dependent export. Retain this heme-related capacity with cellular-assay scope. The evidence does not establish heme as the exclusive substrate, and later choline uptake findings leave other physiological substrates possible.

Summary: Human FLVCR expression increases measured cellular heme export.

Reason: The actual 2004 study expressed human FLVCR in rat NRK cells and measured ZnMP and radiolabeled-hemin washout plus extracellular heme by HPLC. K562 viral interference and antibody experiments provide corroboration. Thus this is more than a steady-state heme-content phenotype. Retain the measured cellular heme-export capacity, while distinguishing it from purified-transporter reconstitution and from evidence on the short mitochondrial product.

Summary: The Reactome event represents plasma-membrane export of heme.

Reason: The official R-HSA-917892 reaction describes plasma-membrane FLVCR1-1 exporting heme and cites the actual 2004 cellular-export study. That study provides radiolabeled-hemin and extracellular HPLC evidence. Retain the contextual heme activity. Other citations attached to the reaction were not independently assessed as supporting evidence.

Summary: The mitochondrial reaction model represents product-dependent heme handling.

Reason: Official R-HSA-9661408 models mitochondrial FLVCR1-2 heme export and cites PMID:23187127. Its primary evidence is mitochondrial localization plus product-dependent compartmental heme changes and erythroid phenotypes, not purified short-product transport. Retain the contextual heme-related activity with that limit; the reaction model supplies no independent demonstration of inner-membrane topology or transport stoichiometry.

Summary: Human FLVCR1a executes the choline-transport step.

Reason: Actual PMID:38778100 human FLVCR1a uptake and structural experiments establish transmembrane movement of choline, with downstream CHKA coexpression affecting net accumulation. The protein executes the transport step. Preserve the general choline-transport process without claiming an untested mitochondrial route, fixed physiological direction or invariant affinity across assay systems.

Summary: Choline transport is independently established while the exact comparative assay remains unverified.

Reason: The PMID:40972734 FLVCR1-specific comparison could not be recovered beyond authentic metadata/abstract, so its exact assay remains unverified. Retain the existing choline-transport assertion using independent human cellular and reconstituted transport evidence, without importing another transporter’s kinetics or treating an abstract that omits FLVCR1 as proof of misattribution.

Summary: Product-dependent heme distribution supports a contextual transport role.

Reason: The original study links selective human short-transcript depletion to mitochondrial heme accumulation and compares a-only with both-product depletion. These observations support a contextual heme-transport role, with experimental scope distinguished from direct reconstituted membrane translocation. Murine tagged constructs in human cells do not become human-protein experiments. Retain the phenotype-based transport annotation without making heme transport the sole established molecular function.

Summary: The broad inherited membrane location is covered by more specific retained compartments.

Reason: The membrane IBD at PTN000858822 is on the exact human target path and matches the original GAF. Its broad cellular location is sound, but independently retained plasma membrane and mitochondrial membrane describe the two product-associated pools more precisely; official plasma-membrane ancestry includes GO:0016020. Donor count and target self-evidence are not used to challenge the phylogenetic assertion.

Summary: The target inherits a supported heme-binding assertion, with fragment-assay limits retained.

Reason: The heme-binding IBD at PTN000858905 lies on the exact human target path; its FLVCR2 donor is not a reason to reject propagation. A FLVCR 132–201 GST fragment binds heme in PMID:20610401, but the inspected fragment Methods do not specify its insert species; this is corroborating biochemical evidence rather than a newly verified direct-human assay. The original Methods and Results specify 132–201, whereas the Discussion gives 132–301 and that conflicting range is retained in the normal cache; the construct sequence has not been independently resolved. Retain the considered phylogenetic binding assertion with that limit. Neither the fragment assay nor the IBD establishes binding by the 279-aa short natural product.

Summary: Substrate-specific activities already cover the generic transporter function.

Reason: The InterPro transmembrane-transporter assignment agrees with the protein architecture and direct assays. Retained choline and ethanolamine transmembrane transporter activities are official descendants of GO:0022857, so this generic activity is redundant rather than biologically false.

Summary: The verified ancestral assertion is consistent with target erythroid evidence.

Reason: The erythrocyte-differentiation IBD at PTN002589204 lies on the target path. The target itself has K562 depletion/hemoglobinization evidence, and mouse genetic models add organismal context. Retain the lineage-specific physiological role, distinguishing murine overexpression constructs, human endogenous depletion and mouse a-specific deletion rather than collapsing them into a single human isoform-rescue experiment.

Summary: FLVCR1 product-dependent heme handling contributes to erythroid maturation.

Reason: K562 depletion comparisons, hemoglobinization readouts, murine-product overexpression and hemin rescue support an erythroid role. The comparison is not b-specific knockout/rescue in K562; the mouse a-specific knockout retains b. These source-specific endpoints warrant contextual retention, without treating differentiation as direct catalysis or inferring a single product-independent direction of effect.

Summary: Target-specific erythroid experiments support this contextual developmental role.

Reason: The electronic erythroid assertion has independent target-specific experimental support from K562 depletion/interference, differentiation readouts and product comparisons. Retain this contextual developmental role, without asserting that the transporter is itself a lineage-determining transcription factor or that both natural products have identical effects. Current molecular core assignment can emphasize transport while retaining this physiological annotation.

Summary: Experimental evidence supports mitochondrial membrane association with product-specific limits.

Reason: PMID:23187127 supports the membrane-protein short product in mitochondria through endogenous human fractionation and tagged murine-product localization. This broader membrane assignment is defensible even though the main Methods do not resolve inner versus outer membrane. Retain with assay and product scope, and distinguish mitochondrial heme-content effects from a direct short-product reconstituted transport measurement.

Summary: The broader mitochondrial-membrane assignment fits the short-product evidence.

Reason: The short natural product retains six predicted membrane-spanning segments and is associated with mitochondrial fractions, with endogenous human immunoblot and complementary tagged murine-product localization. The broader mitochondrial-membrane annotation is consistent with these observations. Retain as a distinct mitochondrial product role without assuming the inner bilayer, dimeric architecture, or cleavage of a predicted targeting peptide.

Summary: Human FLVCR1 supports ethanolamine uptake and precursor entry into phospholipid metabolism.

Reason: Final PMID:38693265 demonstrates cellular ethanolamine uptake by human FLVCR1 and substrate-selective mutagenesis, with isotope tracing into phosphoethanolamine. Q214A separates the ethanolamine requirement from choline transport. The choline proteoliposome result is not mislabeled as a purified ethanolamine flux experiment. Preserve the original pathway extension without claiming phosphorylation by FLVCR1 or mitochondrial-product transport.

Summary: FLVCR1a facilitates ethanolamine transport in the tested human cells.

Reason: Actual PMID:38778100 shows human FLVCR1a-mediated ethanolamine accumulation, enhanced by ETNK1 coexpression, together with an ethanolamine-bound structure and substrate-site mutagenesis. Ethanolamine washout supports reversible, gradient-dependent transport in the tested cells. Kinase-dependent trapping is an assay feature; the transporter itself is not ETNK1 and no short-product equivalence follows.

Summary: Human variant assays corroborate ethanolamine transport with kinase-dependent trapping.

Reason: Final PMID:39306721 tests human FLVCR1/variants with ETNK1 in HEK293 cells, measuring washed-cell radiolabeled ethanolamine accumulation against kinase-only controls. This supports the existing activity and agrees with independent structural/cellular evidence. The endpoint combines uptake and metabolic trapping; variant effects do not establish universal loss or natural mitochondrial-product transport.

Summary: Measured ethanolamine translocation supports the inferred transport process.

Reason: The GO_REF:0000108 inference from retained ethanolamine transmembrane transporter activity is coherent with directly measured human FLVCR1-dependent ethanolamine uptake and substrate-specific mutants. FLVCR1 performs the transport step. Preserve the electronic provenance and distinguish this plasma-membrane role from untested short-product transport.

Summary: Specific transport activities already entail the generic transmembrane-transport process.

Reason: Transmembrane transport is directly supported, but the retained substrate-specific molecular functions have this process in their official part_of ancestry, and corresponding choline/ethanolamine transport processes are retained. Mark the generic process as redundant. This uses an explicit cross-aspect part_of relation, not a false claim that the broader substrate transport terms themselves are transmembrane-transport descendants.

Summary: The target inherits an experimentally grounded cellular heme-export capacity.

Reason: The heme-export IBD at PTN000858905 is an actual positive ancestral assertion on the human target path. Human FLVCR cellular studies measure extracellular heme by HPLC and radiolabeled-hemin washout, not solely a secondary intracellular-content change. Retain this experimentally supported export role with cellular and acceptor context. Newer amine transport evidence does not demonstrate a target-specific loss of heme-associated export.

Summary: Human FLVCR increases extracellular heme in cellular export assays.

Reason: The cited paper demonstrates increased cellular heme export with human FLVCR in rat NRK cells, measured using radiolabeled hemin and extracellular HPLC, with separate human K562 interference/antibody evidence. Retain heme export as a contextual physiological capacity. It is not necessary to claim purified full-length translocation, exclusive heme substrate specificity or a short-product experiment to retain the observed process.