id: P53790
gene_symbol: Slc5a1
aliases:
  - Sglt1
  - SGLT1
  - Na+/glucose cotransporter 1
  - Sodium/glucose cotransporter 1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:10116
  label: Rattus norvegicus
description: >-
  Sodium/glucose cotransporter 1 (SGLT1) is a high-affinity Na+-coupled symporter
  that actively transports D-glucose and D-galactose across the plasma membrane with
  2:1 Na+:glucose stoichiometry. SGLT1 is the primary transporter for dietary hexose
  absorption across the apical brush-border membrane of enterocytes in the small intestine.
  In kidney, it functions in the S3 segment of proximal tubules for glucose reabsorption,
  handling approximately 3% of filtered glucose. Additionally serves as a water channel
  enabling passive water transport. Located at the blood-brain barrier in endothelial
  cells.

existing_annotations:
# ============================================================================
# CELLULAR COMPONENT ANNOTATIONS
# ============================================================================

# --- Apical plasma membrane (4 annotations with different evidence) ---
  - term:
      id: GO:0016324
      label: apical plasma membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation based on phylogenetic inference. SGLT1 apical localization
        is well-established
        across mammals. Direct experimental evidence in rat shows SGLT1 at apical
        membrane in
        MDCK cells (PMID:11831390), blood-brain barrier endothelial cells (PMID:14986005),
        and kidney proximal tubule S3 segments (PMID:16204409).
      action: ACCEPT
      reason: >-
        Core localization for SGLT1 function. Phylogenetic inference is well-supported
        by multiple
        direct experimental studies in rat demonstrating apical membrane localization
        in intestinal
        epithelium, renal proximal tubules, and brain endothelial cells. The N-terminal
        domain
        determines apical targeting (PMID:11831390).
      supported_by:
        - reference_id: PMID:11831390
          supporting_text: "The products of N-terminal deletion clones up to the 19th
            amino acid were localized at the apical plasma membrane"
        - reference_id: PMID:14986005
          supporting_text: "Immunostaining suggested that SGLT1 is located in the
            luminal membrane of the endothelial cells"

        - reference_id: file:rat/Slc5a1/Slc5a1-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0016324
      label: apical plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: >-
        IEA annotation based on UniProtKB/Swiss-Prot subcellular location mapping.
        Redundant with IBA and IDA annotations for same term.
      action: ACCEPT
      reason: >-
        While redundant with IBA annotation, this IEA represents valid automated inference
        from UniProt subcellular location annotation. Duplicates are acceptable in
        GO as they
        represent independent evidence paths. Core localization is correct.

  - term:
      id: GO:0016324
      label: apical plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:14986005
    review:
      summary: >-
        Direct experimental evidence from immunohistochemistry in rat brain capillaries
        showing
        SGLT1 in luminal (apical) membrane of blood-brain barrier endothelial cells.
      action: ACCEPT
      reason: >-
        High-quality experimental evidence demonstrating apical localization in brain
        endothelial
        cells. The study showed immunoreactivity in intracerebral capillaries with
        staining
        in the luminal membrane.
      supported_by:
        - reference_id: PMID:14986005
          supporting_text: "Immunostaining suggested that SGLT1 is located in the
            luminal membrane of the endothelial cells and in intracellular vesicles"

  - term:
      id: GO:0016324
      label: apical plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:11831390
    review:
      summary: >-
        Direct experimental evidence from MDCK cell localization studies showing rat
        SGLT1
        localizes to apical plasma membrane. N-terminal deletion analysis identified
        apical
        targeting signals.
      action: ACCEPT
      reason: >-
        High-quality experimental evidence. Study used rat SGLT1 expressed in MDCK
        cells and
        demonstrated apical localization, with identification of the N-terminal targeting
        domain.
      supported_by:
        - reference_id: PMID:11831390
          supporting_text: "SGLT1, an isoform of Na+-dependent glucose cotransporters,
            is localized at the apical plasma membrane in the epithelial cells of
            the small intestine and the kidney"

  - term:
      id: GO:0016324
      label: apical plasma membrane
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation transferred from other mammalian species by RGD. Redundant
        with
        multiple direct experimental annotations (IDA) for rat SGLT1.
      action: ACCEPT
      reason: >-
        Valid ortholog transfer that is consistent with direct rat experimental evidence.
        Duplicates are acceptable as independent evidence paths.

# --- Plasma membrane (2 annotations) ---
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation for plasma membrane localization. This is a parent term of
        apical plasma membrane (GO:0016324) which is the more specific correct localization.
      action: KEEP_AS_NON_CORE
      reason: >-
        While technically correct, this is less specific than apical plasma membrane.
        The more specific term GO:0016324 better captures SGLT1's polarized localization.
        Acceptable to retain as it captures the broader membrane context.

  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation transferred from mammalian orthologs. Less specific than apical
        plasma membrane annotations.
      action: KEEP_AS_NON_CORE
      reason: >-
        Valid but less specific than apical plasma membrane. The more specific term
        GO:0016324 is preferred for capturing SGLT1's polarized epithelial localization.

# --- Brush border membrane (2 IDA annotations) ---
  - term:
      id: GO:0031526
      label: brush border membrane
    evidence_type: IDA
    original_reference_id: PMID:14986005
    review:
      summary: >-
        Brush border membrane localization is well supported for intestinal SGLT1,
        but PMID:14986005 itself focuses on brain capillary localization. Accept the
        term based on direct intestinal apical membrane evidence from other sources.
      action: ACCEPT
      reason: >-
        The brush border membrane term is appropriate for intestinal SGLT1, even
        though PMID:14986005 is likely a misassigned reference. Experimental data
        from intestinal apical membrane preparations support this localization.
      supported_by:
        - reference_id: PMID:17272350
          supporting_text: Western blotting showed that in each case there was a
            significant decrease in apical GLUT2 level, but no change in SGLT1 level.

  - term:
      id: GO:0031526
      label: brush border membrane
    evidence_type: IDA
    original_reference_id: PMID:17272350
    review:
      summary: >-
        Direct experimental evidence showing SGLT1 at intestinal brush border membrane
        in
        rat jejunum. Western blotting confirmed SGLT1 presence in apical membrane
        preparations.
      action: ACCEPT
      reason: >-
        High-quality experimental evidence demonstrating SGLT1 at brush border membrane
        of rat intestinal epithelium. This is a core localization for intestinal glucose
        absorption.
      supported_by:
        - reference_id: PMID:17272350
          supporting_text: "Western blotting showed that in each case there was a
            significant decrease in apical GLUT2 level, but no change in SGLT1 level"

# --- Brush border (ISO) ---
  - term:
      id: GO:0005903
      label: brush border
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation for brush border localization. Brush border (GO:0005903) is
        the
        parent of brush border membrane (GO:0031526). The more specific membrane term
        is more accurate for a transmembrane transporter.
      action: MODIFY
      reason: >-
        For a transmembrane transporter, the more specific term brush border membrane
        (GO:0031526) is more appropriate than the general brush border term.
      proposed_replacement_terms:
        - id: GO:0031526
          label: brush border membrane

# --- Membrane (IEA) ---
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        Very general IEA annotation based on InterPro record mapping. SGLT1 has many
        more specific membrane annotations (apical plasma membrane, brush border membrane).
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        This is too general to be informative. SGLT1 has specific annotations to apical
        plasma membrane and brush border membrane that are much more informative.
        While technically correct, this adds no useful information.

# --- Organelle (IDA) ---
  - term:
      id: GO:0043226
      label: organelle
    evidence_type: IDA
    original_reference_id: PMID:14986005
    review:
      summary: >-
        The paper mentions intracellular vesicles containing SGLT1 in brain endothelial
        cells. However, 'organelle' is extremely vague and should be more specific.
      action: MODIFY
      reason: >-
        The paper specifically mentions intracellular vesicles, not generic organelles.
        A more specific term would be appropriate if we want to capture this localization.
      proposed_replacement_terms:
        - id: GO:0031410
          label: cytoplasmic vesicle
      supported_by:
        - reference_id: PMID:14986005
          supporting_text: "Immunostaining suggested that SGLT1 is located in the
            luminal membrane of the endothelial cells and in intracellular vesicles"

# --- Basolateral plasma membrane (TAS) ---
  - term:
      id: GO:0016323
      label: basolateral plasma membrane
    evidence_type: TAS
    original_reference_id: PMID:14986005
    review:
      summary: >-
        Questionable annotation. PMID:14986005 specifically shows SGLT1 in the LUMINAL
        (apical) membrane of brain endothelial cells, not basolateral. This appears
        to
        be an error in annotation.
      action: REMOVE
      reason: >-
        The cited paper explicitly states SGLT1 is in the luminal membrane, which
        is the
        apical/blood-facing side of brain capillary endothelium, not basolateral.
        SGLT1
        is canonically an apical transporter; basolateral glucose exit is mediated
        by GLUT2.
      supported_by:
        - reference_id: PMID:14986005
          supporting_text: "Immunostaining suggested that SGLT1 is located in the
            luminal membrane of the endothelial cells"

# --- Cell-cell junction (IDA) ---
  - term:
      id: GO:0005911
      label: cell-cell junction
    evidence_type: IDA
    original_reference_id: PMID:17090404
    review:
      summary: >-
        Direct experimental evidence showing SGLT1 clusters at cell-cell junctions
        in
        arterial endothelium. High-density clusters found in proximity to cell-to-cell
        junctions.
      action: KEEP_AS_NON_CORE
      reason: >-
        Valid experimental finding in endothelial cells showing SGLT1 clustering near
        cell-cell junctions. This represents a secondary localization pattern in vascular
        endothelium, not the primary physiological localization in intestine/kidney.
      supported_by:
        - reference_id: PMID:17090404
          supporting_text: "Clusters of the glucose transporter isoforms were found
            at a high density in proximity to the cell-to-cell junctions"

# --- Early endosome (ISO) ---
  - term:
      id: GO:0005769
      label: early endosome
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation from mammalian orthologs. SGLT1 trafficking through endosomal
        compartments is plausible for membrane protein recycling.
      action: KEEP_AS_NON_CORE
      reason: >-
        Likely reflects trafficking/recycling rather than steady-state functional
        localization. Not a core localization but may be valid for protein turnover.

# --- Perinuclear region of cytoplasm (ISO) ---
  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation from orthologs. May reflect biosynthetic pathway localization
        (ER/Golgi) rather than functional localization.
      action: KEEP_AS_NON_CORE
      reason: >-
        Likely reflects biosynthetic pathway (ER/Golgi in perinuclear region) rather
        than functional localization. Not a core localization for SGLT1 function.

# ============================================================================
# MOLECULAR FUNCTION ANNOTATIONS
# ============================================================================

# --- D-glucose:sodium symporter activity (4 annotations) ---
  - term:
      id: GO:0005412
      label: D-glucose:sodium symporter activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Core molecular function of SGLT1 - IBA based on phylogenetic inference.
        This is the defining activity of the SGLT1 transporter family.
      action: ACCEPT
      reason: >-
        This is THE core molecular function of SGLT1. The transporter catalyzes
        2 Na+ : 1 D-glucose cotransport as established across all species.
        UniProt confirms this catalytic activity with Rhea reaction annotation.
      supported_by:
        - reference_id: PMID:15829715
          supporting_text: "the renal brush-border membrane Na+/glucose co-transporter-1
            (SGLT1) is a molecular target for Cd2+ toxicity"

  - term:
      id: GO:0005412
      label: D-glucose:sodium symporter activity
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation from mammalian orthologs. Consistent with direct rat evidence.
      action: ACCEPT
      reason: >-
        Core molecular function, well-supported by direct rat experimental evidence
        and consistent phylogenetic conservation.

  - term:
      id: GO:0005412
      label: D-glucose:sodium symporter activity
    evidence_type: IDA
    original_reference_id: PMID:15829715
    review:
      summary: >-
        Direct experimental evidence showing rat SGLT1 Na+/glucose cotransport activity.
        Study used methyl-D-glucopyranoside uptake assays in SGLT1-expressing cells.
      action: ACCEPT
      reason: >-
        High-quality direct experimental evidence demonstrating the core molecular
        function in rat SGLT1.
      supported_by:
        - reference_id: PMID:15829715
          supporting_text: "Cd2+ acted as a noncompetitive, partial inhibitor of methyl-D-glucopyranoside
            uptake in vesicles from COS-7 cells transiently expressing SGLT1"

  - term:
      id: GO:0005412
      label: D-glucose:sodium symporter activity
    evidence_type: TAS
    original_reference_id: PMID:11831390
    review:
      summary: >-
        TAS annotation from paper on SGLT1 apical localization. Paper discusses SGLT1
        as glucose transporter but main focus is localization not transport activity.
      action: ACCEPT
      reason: >-
        The paper refers to SGLT1's known function as Na+-dependent glucose cotransporter.
        While the experimental focus is localization, the stated function is accurate.
      supported_by:
        - reference_id: PMID:11831390
          supporting_text: "SGLT1, an isoform of Na+-dependent glucose cotransporters,
            is localized at the apical plasma membrane"

# --- Galactose:sodium symporter activity (2 annotations) ---
  - term:
      id: GO:0015371
      label: galactose:sodium symporter activity
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation for galactose transport. SGLT1 transports both D-glucose and
        D-galactose with similar affinity - this is well-established in the literature.
      action: ACCEPT
      reason: >-
        Core molecular function. SGLT1 transports D-galactose as well as D-glucose,
        both with high affinity. UniProt catalytic activity annotation confirms this.
        PMID:16204409 used galactose uptake to measure SGLT1 activity.
      supported_by:
        - reference_id: PMID:16204409
          supporting_text: "The phlorizin-sensitive uptake of d-[(3)H]galactose in
            BBM vesicles"

  - term:
      id: GO:0015371
      label: galactose:sodium symporter activity
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation based on sequence similarity. Consistent with ISO annotation
        and UniProt functional annotation.
      action: ACCEPT
      reason: >-
        Core molecular function. Galactose transport by SGLT1 is well-established
        and conserved across species.

# --- Water transmembrane transporter activity (2 annotations) ---
  - term:
      id: GO:0005372
      label: water transmembrane transporter activity
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation for water transport. SGLT1 functions as a water channel with
        high water conductivity comparable to aquaporins, enabling passive water transport.
      action: ACCEPT
      reason: >-
        Core molecular function. UniProt describes SGLT1 as having high water conductivity
        comparable to aquaporins, enabling passive water transport in response to
        osmotic
        gradients created during sugar/Na+ uptake.

  - term:
      id: GO:0005372
      label: water transmembrane transporter activity
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation from orthologs for water transport activity.
      action: ACCEPT
      reason: >-
        Core molecular function. Water transport by SGLT1 is well-documented and
        important for transepithelial water permeability in intestine.

# --- D-glucose transmembrane transporter activity (ISO) ---
  - term:
      id: GO:0055056
      label: D-glucose transmembrane transporter activity
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation for general glucose transporter activity. This is less specific
        than D-glucose:sodium symporter activity which captures the coupling mechanism.
      action: KEEP_AS_NON_CORE
      reason: >-
        While correct, this is less informative than D-glucose:sodium symporter activity
        (GO:0005412) which specifies the sodium-coupling mechanism that defines SGLT1.

# --- Alpha-glucoside transmembrane transporter activity (ISO) ---
  - term:
      id: GO:0015151
      label: alpha-glucoside transmembrane transporter activity
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation for alpha-glucoside transport. SGLT1 transports glucose (an
        alpha-glucoside in its cyclic form), but this term is typically used for
        disaccharide transport (e.g., maltose, sucrose). May be an over-annotation.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        SGLT1 transports monosaccharides (glucose, galactose), not alpha-glucosides
        like maltose or sucrose. The more accurate term is D-glucose:sodium symporter
        activity. This term implies transport of glycosides/disaccharides which is
        not the primary function.

# --- Symporter activity (IEA) ---
  - term:
      id: GO:0015293
      label: symporter activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        IEA annotation from UniProtKB keyword mapping. Very general term.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Too general. The specific term D-glucose:sodium symporter activity (GO:0005412)
        is much more informative and captures the actual substrate specificity.

# --- Transmembrane transporter activity (IEA) ---
  - term:
      id: GO:0022857
      label: transmembrane transporter activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        Very general IEA annotation from InterPro mapping.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Far too general to be informative. Specific molecular function annotations
        (D-glucose:sodium symporter activity) provide the relevant information.

# --- Monoatomic cation transmembrane transporter activity (IEA) ---
  - term:
      id: GO:0008324
      label: monoatomic cation transmembrane transporter activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: >-
        IEA from ARBA machine learning. SGLT1 uses Na+ gradient to drive glucose transport
        but is not primarily a cation transporter - it is a sugar transporter.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Misleading annotation. While SGLT1 translocates Na+ ions, it is primarily
        a
        sugar transporter that uses the Na+ gradient as driving force. The sodium
        transport is coupled to/incidental to the primary glucose transport function.

# ============================================================================
# BIOLOGICAL PROCESS ANNOTATIONS
# ============================================================================

# --- Intestinal D-glucose absorption (3 annotations) ---
  - term:
      id: GO:0001951
      label: intestinal D-glucose absorption
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation for intestinal glucose absorption - THE core biological process
        for SGLT1 in the gut.
      action: ACCEPT
      reason: >-
        Core biological process. SGLT1 is the primary transporter for dietary glucose
        absorption across enterocyte brush border membrane.
      supported_by:
        - reference_id: PMID:17272350
          supporting_text: "We have proposed a model of intestinal glucose absorption
            in which transport by SGLT1 induces rapid insertion and activation of
            GLUT2"

  - term:
      id: GO:0001951
      label: intestinal D-glucose absorption
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation from orthologs. Consistent with direct rat evidence.
      action: ACCEPT
      reason: >-
        Core biological process, well-supported by rat experimental evidence.

  - term:
      id: GO:0001951
      label: intestinal D-glucose absorption
    evidence_type: TAS
    original_reference_id: PMID:15829715
    review:
      summary: >-
        TAS annotation. The paper's main focus is cadmium inhibition of SGLT1, but
        mentions intestinal glucose absorption as established SGLT1 function.
      action: ACCEPT
      reason: >-
        Core biological process. While paper focuses on cadmium effects, it references
        SGLT1's role in intestinal glucose absorption.

# --- Renal D-glucose absorption (3 annotations) ---
      supported_by:
        - reference_id: PMID:15829715
          supporting_text: 2005 Apr 13. The endogenous CXXC motif governs the 
            cadmium sensitivity of the renal Na+/glucose co-transporter.
  - term:
      id: GO:0035623
      label: renal D-glucose absorption
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation for renal glucose reabsorption. SGLT1 handles glucose reabsorption
        in S3 segment of proximal tubule (minor fraction, ~3% of total).
      action: ACCEPT
      reason: >-
        Core biological process. PMID:16204409 directly demonstrates SGLT1 in rat
        kidney
        S3 proximal tubule segments with functional glucose transport activity.
      supported_by:
        - reference_id: PMID:16204409
          supporting_text: "SGLT1 (SLC5A1) mediates a part of glucose and galactose
            reabsorption in the mammalian proximal tubule"
        - reference_id: PMID:16204409
          supporting_text: "the expression of SGLT1 is represented by a 75-kDa protein
            localized largely in the PT S3 segments"

  - term:
      id: GO:0035623
      label: renal D-glucose absorption
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation from sequence similarity. Consistent with direct rat evidence.
      action: ACCEPT
      reason: >-
        Core biological process, well-supported by direct rat experimental evidence.

  - term:
      id: GO:0035623
      label: renal D-glucose absorption
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation from orthologs. Consistent with IBA and direct rat evidence.
      action: ACCEPT
      reason: >-
        Core biological process with strong experimental support in rat.

# --- D-glucose import across plasma membrane (2 annotations) ---
  - term:
      id: GO:0098708
      label: D-glucose import across plasma membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation for glucose import. Accurate description of SGLT1's transport
        direction (import into cell).
      action: ACCEPT
      reason: >-
        Core biological process. SGLT1 imports glucose from lumen into epithelial
        cells.
        This is a fundamental aspect of its transport function.

  - term:
      id: GO:0098708
      label: D-glucose import across plasma membrane
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation from orthologs. Consistent with IBA annotation.
      action: ACCEPT
      reason: >-
        Core biological process describing the import direction of SGLT1-mediated
        glucose transport.

# --- D-glucose transmembrane transport (2 annotations) ---
  - term:
      id: GO:1904659
      label: D-glucose transmembrane transport
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation for glucose transmembrane transport.
      action: ACCEPT
      reason: >-
        Core biological process. This is the primary transport function of SGLT1.

  - term:
      id: GO:1904659
      label: D-glucose transmembrane transport
    evidence_type: TAS
    original_reference_id: PMID:11831390
    review:
      summary: >-
        TAS annotation. Paper focuses on localization but references SGLT1's glucose
        transport function.
      action: ACCEPT
      reason: >-
        Core biological process. While paper's experimental focus is localization,
        SGLT1's glucose transport function is accurately referenced.
      supported_by:
        - reference_id: PMID:11831390
          supporting_text: "SGLT1 glucose transporter...plays a pivotal role in the
            absorption and reabsorption of sugars"

# --- Galactose transmembrane transport (IEA) ---
  - term:
      id: GO:0015757
      label: galactose transmembrane transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: >-
        IEA annotation based on logical inference. SGLT1 transports galactose with
        similar affinity to glucose - this is experimentally demonstrated in rat.
      action: ACCEPT
      reason: >-
        Core biological process. Galactose transport by SGLT1 is well-established.
        PMID:16204409 used galactose uptake assays to measure rat SGLT1 activity.
      supported_by:
        - reference_id: PMID:16204409
          supporting_text: "SGLT1 (SLC5A1) mediates a part of glucose and galactose
            reabsorption in the mammalian proximal tubule"

# --- Intestinal absorption (2 annotations) ---
  - term:
      id: GO:0050892
      label: intestinal absorption
    evidence_type: TAS
    original_reference_id: PMID:16204409
    review:
      summary: >-
        TAS annotation. The paper primarily focuses on kidney, though it mentions
        intestinal absorption as SGLT1 function.
      action: ACCEPT
      reason: >-
        Core biological process. SGLT1's role in intestinal absorption is well-established.
      supported_by:
        - reference_id: PMID:16204409
          supporting_text: "SGLT1 (SLC5A1) mediates a part of glucose and galactose
            reabsorption in the mammalian proximal tubule"

  - term:
      id: GO:0050892
      label: intestinal absorption
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation from orthologs. Consistent with known SGLT1 function.
      action: ACCEPT
      reason: >-
        Core biological process for SGLT1 in the gut.

# --- Transepithelial water transport (ISO) ---
  - term:
      id: GO:0035377
      label: transepithelial water transport
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation for water transport function. SGLT1 acts as a water channel
        with high conductivity comparable to aquaporins.
      action: ACCEPT
      reason: >-
        Core biological process. SGLT1's water transport activity is important for
        intestinal water absorption coupled to glucose/Na+ uptake.

# --- Sodium ion import across plasma membrane (ISO) ---
  - term:
      id: GO:0098719
      label: sodium ion import across plasma membrane
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation for sodium import. SGLT1 couples 2 Na+ import per glucose.
      action: KEEP_AS_NON_CORE
      reason: >-
        While technically accurate (SGLT1 imports 2 Na+ per glucose), sodium transport
        is secondary to the primary function of glucose transport. The Na+ gradient
        drives glucose uptake rather than being the primary transported substrate.

# --- Sodium ion transport (IEA) ---
  - term:
      id: GO:0006814
      label: sodium ion transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        IEA annotation from UniProtKB keyword mapping.
      action: KEEP_AS_NON_CORE
      reason: >-
        While Na+ is cotransported with glucose, this annotation may give the misleading
        impression that SGLT1 is primarily a sodium transporter. The primary function
        is glucose transport using the Na+ gradient.

# --- Monoatomic ion transport (IEA) ---
  - term:
      id: GO:0006811
      label: monoatomic ion transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        Very general IEA annotation for ion transport.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Too general and misleading. SGLT1 is a sugar transporter that cotransports
        sodium, not primarily an ion transporter.

# --- Transmembrane transport (IEA) ---
  - term:
      id: GO:0055085
      label: transmembrane transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        Very general IEA annotation from InterPro mapping.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Far too general to be informative. Specific process annotations provide the
        relevant information about SGLT1 function.

# --- Transport across blood-brain barrier (ISO) ---
  - term:
      id: GO:0150104
      label: transport across blood-brain barrier
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation for BBB transport. Rat experimental evidence shows SGLT1
        in brain capillary endothelium with upregulation after ischemia.
      action: KEEP_AS_NON_CORE
      reason: >-
        Valid annotation supported by rat experimental evidence (PMID:14986005).
        Not a core function (intestine/kidney are primary sites) but represents
        an established secondary physiological role.
      supported_by:
        - reference_id: PMID:14986005
          supporting_text: "The data suggest that SGLT1 participates in transport
            of D-glucose across the blood-brain barrier"

# --- Chloride transmembrane transport (ISO) ---
  - term:
      id: GO:1902476
      label: chloride transmembrane transport
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    negated: true
    review:
      summary: >-
        ISO annotation for chloride transport. This is unexpected - SGLT1 is not
        known as a chloride transporter. May be an erroneous annotation.
      action: UNDECIDED
      reason: >-
        SGLT1 is a Na+/glucose symporter, not a chloride transporter. The basis for
        this annotation is unclear. Would need to trace the original evidence from
        the ortholog to evaluate. Marking as undecided pending clarification.

# --- Alpha-glucoside transport (ISO) ---
  - term:
      id: GO:0000017
      label: alpha-glucoside transport
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation for alpha-glucoside transport. SGLT1 transports monosaccharides,
        not glucosides (which typically refers to disaccharides).
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        SGLT1 transports D-glucose and D-galactose (monosaccharides), not alpha-glucosides
        like maltose or sucrose. This term is misleading for SGLT1's actual substrate
        specificity.

# --- Carbohydrate utilization (IDA) ---
  - term:
      id: GO:0009758
      label: carbohydrate utilization
    evidence_type: IDA
    original_reference_id: PMID:25592016
    review:
      summary: >-
        IDA annotation from study on dietary regulation of Sglt1 gene expression.
        The paper shows epigenetic regulation (H3K4 methylation) of Sglt1 in response
        to high-starch diet, not direct SGLT1 involvement in carbohydrate utilization.
      action: MODIFY
      reason: >-
        The paper demonstrates transcriptional regulation of Sglt1 by diet, not a
        direct
        role for SGLT1 protein in carbohydrate utilization. The appropriate process
        would be related to glucose absorption/transport, not utilization.
      proposed_replacement_terms:
        - id: GO:0001951
          label: intestinal D-glucose absorption
      supported_by:
        - reference_id: PMID:25592016
          supporting_text: "Feeding rats the high-starch/low-fat diet induced mono-,
            di-, and trimethylation of histone H3K4 on the promoter and transcribed
            regions of the Si and Sglt1 genes"

# --- Metanephros development (ISO) ---
  - term:
      id: GO:0001656
      label: metanephros development
    evidence_type: ISO
    original_reference_id: GO_REF:0000121
    review:
      summary: >-
        ISO annotation for kidney development. SGLT1 is a glucose transporter that
        is expressed during kidney development but is not known to have a developmental
        signaling role.
      action: UNDECIDED
      reason: >-
        The basis for this developmental annotation is unclear. SGLT1 may be expressed
        during kidney development but is primarily a glucose transporter, not a
        developmental regulator. Would need to evaluate the original ortholog evidence.

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:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping
    findings: []
  - id: GO_REF:0000108
    title: Automatic assignment of GO terms using logical inference, based on 
      inter-ontology links
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000121
    title: RGD ISO annotations to rat from other mammalian species
    findings: []
  - id: PMID:11831390
    title: The apical localization of SGLT1 glucose transporter is determined by
      the short amino acid sequence in its N-terminal domain.
    findings:
      - statement: N-terminal domain (first 19 amino acids) determines apical 
          localization in MDCK cells
        supporting_text: "The products of N-terminal deletion clones up to the 19th
          amino acid were localized at the apical plasma membrane, whereas the products
          of N-terminal 20- and 23-amino-acid deletion clones were localized along
          the entire plasma membrane."
      - statement: D28 mutations cause cytoplasmic retention
        supporting_text: "The products of D28N and D28G clones were localized in the
          cytoplasm, showing that the aspartic acid-28 may be essential for the delivery
          of SGLT1 to the plasma membrane."
  - id: PMID:14986005
    title: Localization of the Na+-D-glucose cotransporter SGLT1 in the 
      blood-brain barrier.
    findings:
      - statement: SGLT1 located in luminal membrane of brain capillary 
          endothelial cells
        supporting_text: "Immunostaining suggested that SGLT1 is located in the luminal
          membrane of the endothelial cells and in intracellular vesicles."
      - statement: Also found in intracellular vesicles
        supporting_text: "Immunostaining suggested that SGLT1 is located in the luminal
          membrane of the endothelial cells and in intracellular vesicles."
      - statement: SGLT1 mRNA upregulated after brain ischemia
        supporting_text: "1 day after a transient occlusion of the right middle cerebral
          artery, SGLT1 mRNA was detected in capillaries of both brain hemispheres."
  - id: PMID:15829715
    title: The endogenous CXXC motif governs the cadmium sensitivity of the 
      renal Na+/glucose co-transporter.
    findings:
      - statement: SGLT1 is a target for Cd2+ toxicity via CXXC motif
        supporting_text: "the renal brush-border membrane Na+/glucose co-transporter-1
          (SGLT1) is a molecular target for Cd2+ toxicity"
      - statement: Demonstrated Na+/glucose cotransport activity
        supporting_text: "Cd2+ acted as a noncompetitive, partial inhibitor of methyl-D-glucopyranoside
          uptake in vesicles from COS-7 cells transiently expressing SGLT1"
  - id: PMID:16204409
    title: Rat renal glucose transporter SGLT1 exhibits zonal distribution and 
      androgen-dependent gender differences.
    findings:
      - statement: SGLT1 localized to S3 segment of proximal tubule
        supporting_text: "the expression of SGLT1 is represented by a 75-kDa protein
          localized largely in the PT S3 segments"
      - statement: Gender differences in expression (female > male)
        supporting_text: "In tissue cryosections, the antibody strongly stained BBM
          of the S3 PT segments in the OS and medullary rays (F > M)"
      - statement: Androgen-dependent regulation
        supporting_text: "castration upregulated, whereas treatment of castrated rats
          with testosterone, but not with estradiol or progesterone, downregulated
          the 75-kDa protein"
  - id: PMID:17090404
    title: Asymmetric subcellular distribution of glucose transporters in the 
      endothelium of small contractile arteries.
    findings:
      - statement: SGLT1 present in vascular endothelium
        supporting_text: "We identified GLUT-1 to -5 and SGLT-1 in the endothelial
          cells of all three vascular beds."
      - statement: Clusters at cell-cell junctions
        supporting_text: "Clusters of the glucose transporter isoforms were found
          at a high density in proximity to the cell-to-cell junctions."
  - id: PMID:17272350
    title: 'Apical GLUT2 and Cav1.3: regulation of rat intestinal glucose and calcium
      absorption.'
    findings:
      - statement: SGLT1 at brush border membrane of jejunum
        supporting_text: "Western blotting showed that in each case there was a significant
          decrease in apical GLUT2 level, but no change in SGLT1 level."
      - statement: SGLT1 transport initiates GLUT2 insertion
        supporting_text: "We have proposed a model of intestinal glucose absorption
          in which transport by SGLT1 induces rapid insertion and activation of GLUT2
          in the apical membrane"
      - statement: SGLT1 component is phloretin-insensitive
        supporting_text: "the phloretin-insensitive SGLT1 component of glucose absorption"
  - id: PMID:25592016
    title: Induction of histone H3K4 methylation at the promoter, enhancer, and 
      transcribed regions of the Si and Sglt1 genes in rat jejunum in response 
      to a high-starch/low-fat diet.
    findings:
      - statement: Sglt1 gene expression induced by high-starch diet
        supporting_text: "induction of Si and Sglt1 gene expression in rat jejunum
          by a high-starch/low-fat diet intake is positively associated with histone
          H3K4 methylation"
      - statement: Epigenetic regulation via H3K4 methylation
        supporting_text: "Feeding rats the high-starch/low-fat diet induced mono-,
          di-, and trimethylation of histone H3K4 on the promoter and transcribed
          regions of the Si and Sglt1 genes"

  - id: file:rat/Slc5a1/Slc5a1-deep-research-falcon.md
    title: Deep research report on Slc5a1
    findings: []
core_functions:
  - description: >-
      Primary molecular function - electrogenic Na+-coupled D-glucose symporter with
      2:1 Na+:glucose stoichiometry
    molecular_function:
      id: GO:0005412
      label: D-glucose:sodium symporter activity
    directly_involved_in:
      - id: GO:0001951
        label: intestinal D-glucose absorption
      - id: GO:0035623
        label: renal D-glucose absorption
    locations:
      - id: GO:0016324
        label: apical plasma membrane
      - id: GO:0031526
        label: brush border membrane
  - description: >-
      Co-transports D-galactose with sodium using same mechanism as glucose transport
    molecular_function:
      id: GO:0015371
      label: galactose:sodium symporter activity
    directly_involved_in:
      - id: GO:0015757
        label: galactose transmembrane transport
    locations:
      - id: GO:0016324
        label: apical plasma membrane
  - description: >-
      Acts as water channel with high conductivity comparable to aquaporins
    molecular_function:
      id: GO:0005372
      label: water transmembrane transporter activity
    directly_involved_in:
      - id: GO:0035377
        label: transepithelial water transport
    locations:
      - id: GO:0016324
        label: apical plasma membrane