SLC14A1

id: Q13336
gene_symbol: SLC14A1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  SLC14A1 encodes urea transporter 1 (UT-B), a facilitative urea transporter that forms the
  molecular basis of the Kidd (JK) blood group system. The protein functions as a homotrimer,
  with each subunit containing a membrane-spanning pore formed by 10 transmembrane helices.
  UT-B enables rapid, energy-independent equilibration of urea across cell membranes via a
  channel-like mechanism. It is abundantly expressed on erythrocytes where it protects red
  blood cells from osmotic stress during circulation through the hyperosmotic renal medulla,
  and on endothelial cells of the renal vasa recta where it contributes to the urinary
  concentrating mechanism. Recent structural studies (2023-2024) have resolved the human
  UT-B structure, revealing conserved urea recognition motifs and providing insight into
  selective inhibitor binding. Notably, at physiological expression levels, UT-B is a
  selective urea transporter and does NOT function as a water channel.
existing_annotations:
  - term:
      id: GO:0071918
      label: urea transmembrane transport
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        This IBA annotation correctly identifies urea transmembrane transport as a core
        biological process for SLC14A1. The phylogenetic inference is well-supported by
        extensive experimental evidence across the urea transporter family. Multiple
        publications demonstrate that SLC14A1/HUT11 mediates facilitated urea transport
        in erythrocytes and kidney [PMID:7989337, PMID:7797558, PMID:8997401, PMID:10514515].
      action: ACCEPT
      reason: >-
        Urea transmembrane transport is the primary and defining function of SLC14A1.
        The protein belongs to the urea transporter family (PANTHER PTHR10464) and all
        functional studies confirm this activity. The phylogenetic inference from IBA
        is strongly supported by direct experimental evidence in human cells.
      supported_by:
        - reference_id: PMID:7989337
          supporting_text: "Expression studies in Xenopus oocytes demonstrated that HUT11 mediates a facilitated urea transport that was inhibited, as described in mammalian erythrocytes, by very low concentrations of phloretin, p-chloromercuribenzene sulfonate, and urea analogues."
        - reference_id: PMID:7797558
          supporting_text: "Jk(a-b-) red cells lack the Kidd/urea transport protein and have a selective defect of the urea transport capacity"
        - reference_id: file:human/SLC14A1/SLC14A1-deep-research-falcon.md
          supporting_text: "UT-B is a facilitative channel specialized for urea. High-resolution structures of human UT-B and UT-A paralogs, together with cryo-EM across multiple states, reveal a conserved urea recognition motif and an H-bond transfer path that guides urea through the pore"

  - term:
      id: GO:0006833
      label: water transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: >-
        This annotation is problematic and should be removed. While SLC14A1 can facilitate
        water transport when overexpressed at unphysiological levels in oocytes, this is
        an artifact of overexpression. PMID:10514515 explicitly demonstrates that at
        physiological expression levels, the Kidd/urea transporter does NOT function as
        a water channel. The paper title states this conclusion directly.
      action: REMOVE
      reason: >-
        The annotation of water transport to SLC14A1 is incorrect under physiological
        conditions. PMID:10514515 definitively shows that water permeability is only
        observed at unphysiological overexpression levels. At plasma membrane expression
        levels close to those in red cells, HUT11A-mediated water transport was absent.
        Jk(a-b-) red cells that lack UT-B have normal water permeability (PMID:7797558),
        further confirming water transport is not a function of this protein.
      supported_by:
        - reference_id: PMID:10514515
          supporting_text: "at plasma membrane expression levels close to the level observed in the red cell membrane, HUT11A-mediated water transport and small solutes uptake were absent"
        - reference_id: PMID:10514515
          supporting_text: "These findings show that, at physiological expression levels, the HUT11A transporter confers urea permeability but not water permeability, and that the observed water permeability is a feature of the red cell urea transporter when expressed at unphysiological high levels."
        - reference_id: PMID:7797558
          supporting_text: "Jk(a-b-) red cells lack the Kidd/urea transport protein and have a selective defect of the urea transport capacity, but a normal water permeability"

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Plasma membrane localization is well-supported by multiple experimental studies.
        SLC14A1 is a multi-pass membrane protein expressed on erythrocyte plasma membranes
        and endothelial cells of the renal vasa recta [PMID:7797558, PMID:10514515].
      action: ACCEPT
      reason: >-
        The IEA annotation is correct and corroborated by multiple IDA annotations from
        experimental studies. The protein has been localized to the plasma membrane by
        immunoprecipitation, immunoblotting, and functional studies in erythrocytes.
      supported_by:
        - reference_id: PMID:7797558
          supporting_text: "A rabbit antibody raised against the predicted NH2-terminal amino-acids of the HUT11 protein reacted on immunoblots with a 46-60-kDa component present in all human erythrocytes except those from Jk(a-b-) individuals."

  - term:
      id: GO:0015204
      label: urea transmembrane transporter activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Urea transmembrane transporter activity is the core molecular function of SLC14A1.
        This IEA annotation is strongly supported by direct experimental evidence from
        multiple publications demonstrating facilitated urea transport in Xenopus oocyte
        expression systems [PMID:7989337, PMID:8997401, PMID:10514515].
      action: ACCEPT
      reason: >-
        This is the defining molecular function of UT-B. The IEA is correct and reinforced
        by multiple IDA annotations in this same annotation set.
      supported_by:
        - reference_id: PMID:7989337
          supporting_text: "Expression studies in Xenopus oocytes demonstrated that HUT11 mediates a facilitated urea transport"
        - reference_id: PMID:8997401
          supporting_text: "Both proteins allow the rapid transfer of urea but not of water."

  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        The annotation to the generic 'membrane' term is correct but less informative than
        the plasma membrane annotation. SLC14A1 is a multi-pass membrane protein with 10
        predicted transmembrane helices.
      action: ACCEPT
      reason: >-
        While this is a very general term, it is not incorrect. SLC14A1 is indeed an integral
        membrane protein. The more specific plasma membrane annotations are also present,
        so this broader annotation provides general context from InterPro domain analysis.
      supported_by:
        - reference_id: file:human/SLC14A1/SLC14A1-uniprot.txt
          supporting_text: "Multi-pass membrane protein"

  - term:
      id: GO:0016323
      label: basolateral plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Basolateral plasma membrane localization is supported by sequence similarity to
        mouse UT-B, which has been shown to be restricted to the basolateral membrane in
        urothelium. This is consistent with the protein's role in kidney urea handling.
      action: ACCEPT
      reason: >-
        The basolateral localization is documented in UniProt based on similarity evidence
        (ISS) from mouse studies. This subcellular localization is important for the
        protein's physiological role in the kidney concentrating mechanism.
      supported_by:
        - reference_id: file:human/SLC14A1/SLC14A1-uniprot.txt
          supporting_text: "Basolateral cell membrane ... Restricted to the basolateral membrane in various portions of the urothelium."
        - reference_id: file:human/SLC14A1/SLC14A1-deep-research-falcon.md
          supporting_text: "UT-B is also expressed on endothelial cells of the renal vasa recta (descending limbs), contributing to the medullary urea handling necessary for the urine-concentrating mechanism."

  - term:
      id: GO:0071918
      label: urea transmembrane transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        This IEA annotation from InterPro correctly identifies urea transmembrane transport
        as a core biological process. It is a duplicate of the IBA annotation above but
        from a different evidence source.
      action: ACCEPT
      reason: >-
        The InterPro-derived annotation is correct and consistent with the IBA annotation
        and direct experimental evidence. Duplicates with different evidence codes are
        acceptable and provide independent support.
      supported_by:
        - reference_id: PMID:7989337
          supporting_text: "HUT11 mediates a facilitated urea transport"

  - term:
      id: GO:0005372
      label: water transmembrane transporter activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        This annotation is incorrect and should be removed. PMID:10514515 directly
        demonstrates that at physiological expression levels, SLC14A1 does NOT have
        water transmembrane transporter activity. The paper title explicitly states:
        "At physiological expression levels the Kidd blood group/urea transporter
        protein is not a water channel."
      action: REMOVE
      reason: >-
        Water transport activity is an artifact of overexpression in Xenopus oocytes.
        At physiological levels, the protein is selective for urea and does not
        transport water. This IEA annotation is propagated from Ensembl orthologs
        but contradicts direct experimental evidence on the human protein.
      supported_by:
        - reference_id: PMID:10514515
          supporting_text: "at physiological expression levels, the HUT11A transporter confers urea permeability but not water permeability"
        - reference_id: PMID:8997401
          supporting_text: "Both proteins allow the rapid transfer of urea but not of water."
        - reference_id: PMID:7989337
          supporting_text: "No unidirectional movements of charged molecules, glycerol, or water were associated with HUT11 expression in oocytes."

  - term:
      id: GO:0015837
      label: amine transport
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-549127
    review:
      summary: >-
        This annotation appears to be a misannotation. The Reactome pathway R-HSA-549127
        is "SLC-mediated transport of organic cations" which involves OCT1-3 (SLC22 family),
        not SLC14A1. SLC14A1 is a urea transporter, not an organic cation or amine
        transporter. There is no experimental evidence that SLC14A1 transports amines.
      action: REMOVE
      reason: >-
        This annotation is incorrect. The Reactome pathway referenced concerns organic
        cation transporters of the SLC22 family. SLC14A1 belongs to the SLC14 urea
        transporter family and has not been shown to transport amines. The Reactome
        pathway summary explicitly describes OCT1-3 members, not urea transporters.
      supported_by:
        - reference_id: Reactome:R-HSA-549127
          supporting_text: "The organic cation transporters comprise three SLC22 members, OCT1-3. They can transport a wide range of organic cations including weak bases."

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        Plasma membrane localization based on immunofluorescence data. This is consistent
        with UT-B being an erythrocyte membrane protein and kidney endothelial membrane protein.
      action: ACCEPT
      reason: >-
        IDA from immunofluorescence is appropriate evidence for plasma membrane localization.
        Multiple experimental studies confirm this localization.
      supported_by:
        - reference_id: PMID:7797558
          supporting_text: "The anti-Jk3 antibody also immunoprecipitated a protein material of 46-60 kDa from all red cell membranes"

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:10514515
    review:
      summary: >-
        This publication demonstrates plasma membrane localization through functional
        expression studies in Xenopus oocytes and by comparison to red cell membrane
        expression levels. The study shows that at physiological plasma membrane
        expression levels, the protein functions as a selective urea transporter.
      action: ACCEPT
      reason: >-
        PMID:10514515 provides direct evidence for plasma membrane localization through
        expression studies and comparison to native red cell membrane levels.
      supported_by:
        - reference_id: PMID:10514515
          supporting_text: "at plasma membrane expression levels close to the level observed in the red cell membrane"

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:7797558
    review:
      summary: >-
        This landmark paper identifies SLC14A1 (HUT11) as the Kidd blood group antigen
        carrier and demonstrates its presence on red cell membranes through
        immunoprecipitation and immunoblotting experiments.
      action: ACCEPT
      reason: >-
        The paper provides direct evidence through antibody-based detection of the protein
        on erythrocyte membranes. Anti-Jk3 antibody immunoprecipitates a 46-60 kDa protein
        from red cell membranes, and anti-HUT11 antibody detects the same component.
      supported_by:
        - reference_id: PMID:7797558
          supporting_text: "The anti-Jk3 antibody also immunoprecipitated a protein material of 46-60 kDa from all red cell membranes, except those from Jk(a-b-) cells."
        - reference_id: PMID:7797558
          supporting_text: "A rabbit antibody raised against the predicted NH2-terminal amino-acids of the HUT11 protein reacted on immunoblots with a 46-60-kDa component present in all human erythrocytes except those from Jk(a-b-) individuals."

  - term:
      id: GO:0015204
      label: urea transmembrane transporter activity
    evidence_type: IDA
    original_reference_id: PMID:10514515
    review:
      summary: >-
        This paper demonstrates urea transport activity of the physiological HUT11A variant
        in Xenopus oocytes. Importantly, it shows that at physiological expression levels,
        the protein selectively transports urea (inhibited by phloretin) but not water.
      action: ACCEPT
      reason: >-
        Direct assay evidence demonstrating urea transport activity with pharmacological
        characterization including phloretin sensitivity at physiological expression levels.
      supported_by:
        - reference_id: PMID:10514515
          supporting_text: "at plasma membrane expression levels close to the level observed in the red cell membrane, HUT11A-mediated water transport and small solutes uptake were absent and the urea transport was poorly inhibited by p-chloromercuribenzene sulfonate, but strongly inhibited by phloretin."

  - term:
      id: GO:0015204
      label: urea transmembrane transporter activity
    evidence_type: IDA
    original_reference_id: PMID:7797558
    review:
      summary: >-
        This paper demonstrates that Jk(a-b-) red cells, which lack SLC14A1 protein, have
        a selective defect in urea transport capacity, providing genetic evidence that
        SLC14A1 is responsible for urea transport activity in erythrocytes.
      action: ACCEPT
      reason: >-
        Genetic loss-of-function evidence: Jk(null) individuals who lack SLC14A1 protein
        have defective urea transport, directly linking the protein to urea transport activity.
      supported_by:
        - reference_id: PMID:7797558
          supporting_text: "Jk(a-b-) red cells lack the Kidd/urea transport protein and have a selective defect of the urea transport capacity, but a normal water permeability"

  - term:
      id: GO:0015204
      label: urea transmembrane transporter activity
    evidence_type: IDA
    original_reference_id: PMID:7989337
    review:
      summary: >-
        This is the original cloning paper demonstrating facilitated urea transport activity
        of HUT11 (SLC14A1) when expressed in Xenopus oocytes. The activity was inhibited
        by classical urea transport inhibitors.
      action: ACCEPT
      reason: >-
        First direct demonstration of urea transport activity by heterologous expression.
        The transport showed characteristic pharmacological inhibition by phloretin and
        p-chloromercuribenzene sulfonate.
      supported_by:
        - reference_id: PMID:7989337
          supporting_text: "Expression studies in Xenopus oocytes demonstrated that HUT11 mediates a facilitated urea transport that was inhibited, as described in mammalian erythrocytes, by very low concentrations of phloretin, p-chloromercuribenzene sulfonate, and urea analogues."

  - term:
      id: GO:0015204
      label: urea transmembrane transporter activity
    evidence_type: IDA
    original_reference_id: PMID:8997401
    review:
      summary: >-
        This paper provides detailed pharmacological characterization of human UT-B (HUT11)
        comparing it to the kidney urea transporter HUT2. Both transporters mediate rapid
        urea transfer but not water transport, with distinct inhibitor sensitivity profiles.
      action: ACCEPT
      reason: >-
        Detailed functional characterization demonstrating urea transport activity with
        pharmacological profiling. The study explicitly notes that HUT11 allows rapid
        transfer of urea but not water.
      supported_by:
        - reference_id: PMID:8997401
          supporting_text: "Both proteins allow the rapid transfer of urea but not of water. Both are inhibited by phloretin, although with different half-maximal inhibitory concentrations (IC50; 75 microM, for HUT11 and 230 microM for HUT2)."
        - reference_id: PMID:8997401
          supporting_text: "We demonstrate that thiourea diffuses through HUT11 with a Michaelis constant (Km) of 40 mM, but not through HUT2."

  - term:
      id: GO:0016323
      label: basolateral plasma membrane
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Basolateral plasma membrane localization inferred from mouse ortholog data.
        This is consistent with the protein's role in kidney epithelial cells where
        basolateral localization is important for urea countercurrent exchange.
      action: ACCEPT
      reason: >-
        ISS from mouse ortholog is appropriate for subcellular localization. The basolateral
        localization is relevant to the protein's physiological function in kidney.
      supported_by:
        - reference_id: file:human/SLC14A1/SLC14A1-uniprot.txt
          supporting_text: "Basolateral cell membrane ... Restricted to the basolateral membrane in various portions of the urothelium."

  - term:
      id: GO:0015204
      label: urea transmembrane transporter activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-444126
    review:
      summary: >-
        The Reactome pathway correctly describes HUT11 (SLC14A1) as an erythrocyte-specific
        urea transporter mediating rapid urea movement across cell membranes.
      action: ACCEPT
      reason: >-
        The Reactome pathway accurately captures the core molecular function of SLC14A1
        in urea transport, consistent with experimental evidence.
      supported_by:
        - reference_id: Reactome:R-HSA-444126
          supporting_text: "Carrier-mediated urea transport allows rapid urea movement across the cell membrane, which is particularly important in the process of urinary concentration and for rapid urea equilibrium in non-renal tissues. Two carriers exist in humans, HUT2 which is renal-specific (Olives B et al, 1996) and HUT11, which is erythrocyte-specific (Olives B et al, 1994)."

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:19865084
    review:
      summary: >-
        PMID:19865084 describes the crystal structure of a bacterial urea transporter
        homolog (Desulfovibrio vulgaris), not human SLC14A1 directly. While the structure
        provides insight into the UT family architecture, this IDA for plasma membrane
        should not cite this paper for human SLC14A1 localization.
      action: UNDECIDED
      reason: >-
        The citation appears misattributed. PMID:19865084 is about a bacterial homolog
        structure, not human SLC14A1 localization. However, the plasma membrane
        localization is well-supported by other references, so this may be an error
        in the original GO annotation citation.
      supported_by:
        - reference_id: PMID:19865084
          supporting_text: "Here we present the 2.3 A structure of a functional urea transporter from the bacterium Desulfovibrio vulgaris."

  - term:
      id: GO:0015265
      label: urea channel activity
    evidence_type: IDA
    original_reference_id: PMID:19865084
    review:
      summary: >-
        PMID:19865084 provides structural evidence that urea transporters operate via a
        channel-like mechanism with a continuous membrane-spanning pore. While this study
        is on a bacterial homolog, the findings established that UTs function as channels
        rather than carriers. Recent human UT-B structures (2023-2024) confirm the
        conserved channel architecture. GO:0015265 (urea channel activity) may be more
        mechanistically precise than GO:0015204 (urea transmembrane transporter activity).
      action: ACCEPT
      reason: >-
        The structural evidence demonstrates a channel-like mechanism for urea permeation.
        While the primary citation is for a bacterial homolog, the human UT-B structure
        confirms the same architecture. The annotation captures the mechanistic insight
        that UT-B functions as a channel rather than a carrier-type transporter.
      supported_by:
        - reference_id: PMID:19865084
          supporting_text: "These results establish that the urea transporter operates by a channel-like mechanism and reveal the physical and chemical basis of urea selectivity."
        - reference_id: file:human/SLC14A1/SLC14A1-deep-research-falcon.md
          supporting_text: "Human UTs are homotrimers; each subunit forms an independent pore with 10 transmembrane helices arranged with pseudo-C2 symmetry."

  - term:
      id: GO:0071918
      label: urea transmembrane transport
    evidence_type: IDA
    original_reference_id: PMID:19865084
    review:
      summary: >-
        Similar to the channel activity annotation above, this IDA cites the bacterial
        homolog structure paper. The paper provides mechanistic insight into urea
        permeation but is not direct evidence for human SLC14A1 function.
      action: UNDECIDED
      reason: >-
        While the structural insights are relevant to understanding the UT family
        mechanism, this citation is for a bacterial homolog rather than direct evidence
        on human SLC14A1. However, urea transmembrane transport is well-supported by
        other IDA citations.
      supported_by:
        - reference_id: PMID:19865084
          supporting_text: "The pore contains a constricted selectivity filter that can accommodate several dehydrated urea molecules in single file."

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-444126
    review:
      summary: >-
        The Reactome pathway describes urea transport across cell membranes, implicitly
        indicating plasma membrane localization for the transporter.
      action: ACCEPT
      reason: >-
        Consistent with extensive experimental evidence for plasma membrane localization.
        The Reactome description of rapid urea movement across cell membranes requires
        plasma membrane localization of the transporter.
      supported_by:
        - reference_id: Reactome:R-HSA-444126
          supporting_text: "Carrier-mediated urea transport allows rapid urea movement across the cell membrane"

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: PMID:7797558
    review:
      summary: >-
        The original paper identifying SLC14A1 as the Kidd blood group protein provides
        evidence for plasma membrane localization through immunoprecipitation from red
        cell membranes.
      action: ACCEPT
      reason: >-
        Consistent with the IDA annotations from the same paper. The protein was
        immunoprecipitated from red cell membranes by anti-Jk3 antibody.
      supported_by:
        - reference_id: PMID:7797558
          supporting_text: "The anti-Jk3 antibody also immunoprecipitated a protein material of 46-60 kDa from all red cell membranes"

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: PMID:7989337
    review:
      summary: >-
        The original cloning paper demonstrates expression studies showing functional
        urea transport, implying plasma membrane localization of the heterologously
        expressed protein.
      action: ACCEPT
      reason: >-
        The functional expression of urea transport activity requires plasma membrane
        localization of the expressed protein.
      supported_by:
        - reference_id: PMID:7989337
          supporting_text: "Expression studies in Xenopus oocytes demonstrated that HUT11 mediates a facilitated urea transport"

  - term:
      id: GO:0015840
      label: urea transport
    evidence_type: TAS
    original_reference_id: PMID:7989337
    review:
      summary: >-
        GO:0015840 (urea transport) is a broader term than GO:0071918 (urea transmembrane
        transport). Both are appropriate annotations for SLC14A1, with GO:0071918 being
        more specific to the transmembrane mechanism.
      action: ACCEPT
      reason: >-
        Urea transport is the core biological process for SLC14A1. This broader term
        encompasses the more specific urea transmembrane transport annotations.
      supported_by:
        - reference_id: PMID:7989337
          supporting_text: "These findings suggest that HUT11 is most likely responsible for the facilitated urea transport in human red blood cells."

references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with GO terms.
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity.
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.
    findings: []
  - id: GO_REF:0000108
    title: Automatic assignment of GO terms using logical inference, based on inter-ontology links.
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods.
    findings: []
  - id: PMID:10514515
    title: At physiological expression levels the Kidd blood group/urea transporter protein is not a water channel.
    findings:
      - statement: "At physiological expression levels, SLC14A1/HUT11A transports urea but NOT water. Water permeability only observed at unphysiological overexpression levels."
      - statement: "Identified HUT11A as the true physiological variant (389 aa vs 391 aa for original HUT11 clone)."
      - statement: "Phloretin strongly inhibits urea transport at physiological levels."
  - id: PMID:19865084
    title: Crystal structure of a bacterial homologue of the kidney urea transporter.
    findings:
      - statement: "Urea transporters form homotrimers with each subunit containing a continuous membrane-spanning pore."
      - statement: "Establishes that urea transporters operate by a channel-like mechanism, not a carrier mechanism."
      - statement: "Selectivity filter can accommodate dehydrated urea molecules in single file."
  - id: PMID:7797558
    title: Kidd blood group and urea transport function of human erythrocytes are carried by the same protein.
    findings:
      - statement: "SLC14A1/HUT11 is the molecular basis of the Kidd (JK) blood group system."
      - statement: "Jk(a-b-) red cells lack UT-B and have defective urea transport but normal water permeability."
      - statement: "Gene maps to chromosome 18q12-q21."
  - id: PMID:7989337
    title: Cloning and functional expression of a urea transporter from human bone marrow cells.
    findings:
      - statement: "First cloning of human erythrocyte urea transporter (HUT11)."
      - statement: "Encodes 43 kDa protein with 63% identity to rabbit UT2."
      - statement: "Mediates facilitated urea transport inhibited by phloretin and pCMBS."
      - statement: "No water transport observed in oocyte expression system."
  - id: PMID:8997401
    title: Functional differentiation of the human red blood cell and kidney urea transporters.
    findings:
      - statement: "Both HUT11 and HUT2 transport urea but not water."
      - statement: "Distinct pharmacological profiles: HUT11 more sensitive to phloretin and pCMBS than HUT2."
      - statement: "Thiourea is a substrate for HUT11 (Km 40 mM) but not HUT2."
  - id: Reactome:R-HSA-444126
    title: HUT2 and HUT11 mediate urea transport in kidney and erythrocytes respectively
    findings:
      - statement: "HUT11 (SLC14A1) is erythrocyte-specific urea transporter."
      - statement: "HUT2 (SLC14A2) is renal-specific urea transporter."
  - id: Reactome:R-HSA-549127
    title: SLC-mediated transport of organic cations
    findings:
      - statement: "This pathway describes OCT1-3 (SLC22 family), not SLC14A1."
  - id: file:human/SLC14A1/SLC14A1-deep-research-falcon.md
    title: Deep research report on SLC14A1
    findings:
      - statement: "Recent (2023-2024) human UT-B structures resolved by cryo-EM confirm homotrimeric architecture."
      - statement: "Conserved urea recognition motif and H-bond transfer path identified."
      - statement: "Selective inhibitors characterized with distinct binding modes."

core_functions:
  - description: >-
      SLC14A1 mediates facilitated urea transport across erythrocyte and kidney endothelial
      cell membranes. Multiple IDA studies demonstrate urea transport activity in Xenopus
      oocyte expression systems with characteristic pharmacological inhibition by phloretin.
      Genetic evidence from Jk(null) individuals shows loss of urea transport capacity when
      protein is absent.
    molecular_function:
      id: GO:0015204
      label: urea transmembrane transporter activity
    directly_involved_in:
      - id: GO:0071918
        label: urea transmembrane transport
    locations:
      - id: GO:0005886
        label: plasma membrane
    supported_by:
      - reference_id: PMID:7989337
        supporting_text: "Expression studies in Xenopus oocytes demonstrated that HUT11 mediates a facilitated urea transport"
      - reference_id: PMID:7797558
        supporting_text: "Jk(a-b-) red cells lack the Kidd/urea transport protein and have a selective defect of the urea transport capacity"

  - description: >-
      Structural studies demonstrate that SLC14A1 operates via a channel-like mechanism
      with a continuous membrane-spanning pore, rather than alternating-access carrier
      mechanism. Human UT-B structures confirm conserved channel architecture with a
      selectivity filter for urea.
    molecular_function:
      id: GO:0015265
      label: urea channel activity
    directly_involved_in:
      - id: GO:0071918
        label: urea transmembrane transport
    locations:
      - id: GO:0005886
        label: plasma membrane
    supported_by:
      - reference_id: PMID:19865084
        supporting_text: "These results establish that the urea transporter operates by a channel-like mechanism"
      - reference_id: file:human/SLC14A1/SLC14A1-deep-research-falcon.md
        supporting_text: "Human UTs are homotrimers; each subunit forms an independent pore with 10 transmembrane helices"

proposed_new_terms: []

suggested_questions:
  - question: "What is the physiological significance of the Jk(a)/Jk(b) polymorphism (D280N) for urea transport kinetics? The D280N variant defines the major Kidd blood group antigens but the functional impact on transport activity is not well characterized."
  - question: "Is there tissue-specific regulation of SLC14A1 expression and does this affect local urea handling? Expression in brain, prostate, and bladder (per HPA) suggests potential non-classical functions beyond erythrocytes and kidney."

suggested_experiments:
  - description: "Compare urea transport kinetics between Jk(a) and Jk(b) variants in controlled expression systems. This would clarify whether the common D280N polymorphism affects function or is immunologically neutral."
  - description: "Investigate the reported tumor suppressor function of SLC14A1 in bladder and prostate cancer models. Recent studies suggest epigenetic silencing correlates with cancer progression; mechanistic basis is unclear."