DPEP1

id: P16444
gene_symbol: DPEP1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'DPEP1 (dipeptidase 1, also called renal dipeptidase, microsomal dipeptidase,
  or dehydropeptidase-I) is a GPI-anchored, zinc-dependent metallohydrolase of the
  peptidase M19 family. It is a disulfide-linked homodimer in which each extracellular
  (alpha/beta)8 TIM-barrel domain carries a binuclear (dinuclear) Zn2+ active site
  bridged by a glutamate (Glu125). The mature protein is attached to the apical/luminal
  plasma membrane (brush-border microvillus membrane) of epithelia, most notably the
  proximal tubule of the kidney and the intestinal brush border. Enzymatically it hydrolyzes
  a broad range of dipeptides; physiologically important reactions include conversion
  of leukotriene D4 to leukotriene E4, hydrolysis of cystinyl-bis-glycine generated
  during extracellular glutathione catabolism, and hydrolysis (dehydropeptidase/beta-lactamase
  activity) of beta-lactam antibiotics such as the carbapenem imipenem, which underlies
  the clinical co-formulation of imipenem with the DPEP1 inhibitor cilastatin. Independently
  of its catalytic activity, DPEP1 also functions as a cell-surface adhesion receptor
  on inflamed lung and liver endothelium that mediates neutrophil recruitment from
  the bloodstream; a catalytically dead E141D mutant retains adhesion activity, demonstrating
  that the adhesion and peptidase functions are separable.'
existing_annotations:
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: DPEP1 is a GPI-anchored protein localized to the apical/brush-border
        plasma membrane of kidney proximal tubule and intestinal epithelia. The plasma
        membrane localization is well supported experimentally and by the phylogenetic
        (IBA) inference across the membrane dipeptidase family.
      action: ACCEPT
      reason: Plasma membrane localization is consistent with experimental evidence
        (crystallography of the membrane-bound enzyme, GPI-anchor identification at
        Ser-385) and is the correct cellular compartment for this brush-border ectoenzyme.
        The IBA annotation is at an appropriate level of generality; more specific
        apical/microvillus membrane terms are also annotated.
      supported_by:
        - reference_id: PMID:12144777
          supporting_text: 'Human renal dipeptidase is a membrane-bound glycoprotein
            hydrolyzing dipeptides ... it faces toward the microvillar membrane of
            a kidney tubule.'
  - term:
      id: GO:0016805
      label: dipeptidase activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Dipeptidase activity is the defining molecular function of DPEP1, established
        experimentally and supported by phylogenetic (IBA) inference across the M19
        membrane dipeptidase family. DPEP1 hydrolyzes a wide range of dipeptides.
      action: ACCEPT
      reason: This is the core molecular function. It is directly demonstrated for
        the human enzyme (catalytic activity on dipeptides and dipeptide substrates)
        and conserved across the family, making the IBA annotation reliable.
      supported_by:
        - reference_id: PMID:2303490
          supporting_text: Two cDNA clones corresponding to human microsomal dipeptidase
            (MDP, formerly referred to as dehydropeptidase-I or renal dipeptidase
        - reference_id: PMID:32325220
          supporting_text: 'no in vitro activity against a variety of dipeptides and
            biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine)'
  - term:
      id: GO:0006508
      label: proteolysis
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: DPEP1 is a peptide-bond hydrolase (dipeptidase) and so participates
        in proteolysis at the broadest level. This IEA term is a keyword-derived parent
        of the more specific and well-supported dipeptidase activity annotation.
      action: ACCEPT
      reason: Proteolysis is a correct but very general biological-process parent for
        a dipeptidase. It is consistent with the experimentally established hydrolytic
        activity of DPEP1 on dipeptides and is not misleading, although the more specific
        molecular function (dipeptidase activity) is more informative.
      supported_by:
        - reference_id: PMID:2303490
          supporting_text: Expression of immunologically cross-reactive and enzymatically
            active MDP was attained in COS cells transfected with the cDNA.
  - term:
      id: GO:0006629
      label: lipid metabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: This term derives from the UniProt 'Lipid metabolism' keyword, which
        is applied because DPEP1 hydrolyzes leukotriene D4 (an eicosanoid lipid) to
        leukotriene E4. The leukotriene-specific terms already annotated capture this
        activity far more precisely.
      action: MARK_AS_OVER_ANNOTATED
      reason: While DPEP1 does act on a lipid-derived substrate (LTD4), the generic
        'lipid metabolic process' over-generalizes its role; DPEP1 is not a broad lipid-metabolizing
        enzyme. The specific terms leukotriene D4 catabolic process and leukotriene
        metabolic process are the appropriate representations and are already present.
      supported_by:
        - reference_id: PMID:32325220
          supporting_text: 'no in vitro activity against a variety of dipeptides and
            biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine)'
  - term:
      id: GO:0008233
      label: peptidase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Peptidase activity is a broad molecular-function parent of the experimentally
        established dipeptidase/metallodipeptidase activity of DPEP1.
      action: ACCEPT
      reason: This keyword-derived IEA term is correct but general. It is fully consistent
        with the more specific dipeptidase activity, metallodipeptidase activity, and
        metalloexopeptidase activity annotations and is acceptable as a broader parent.
      supported_by:
        - reference_id: PMID:2303490
          supporting_text: Two cDNA clones corresponding to human microsomal dipeptidase
            (MDP, formerly referred to as dehydropeptidase-I or renal dipeptidase
  - term:
      id: GO:0008237
      label: metallopeptidase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: DPEP1 is a zinc metallopeptidase whose active site contains a binuclear
        Zn2+ center bridged by Glu125, directly established by crystallography. Metallopeptidase
        activity is therefore well supported.
      action: ACCEPT
      reason: This keyword-derived IEA term is correct and supported by structural evidence
        of a catalytic binuclear zinc center. It is a valid broader parent of the more
        specific metallodipeptidase activity term.
      supported_by:
        - reference_id: PMID:12144777
          supporting_text: The active site in each of the (alpha/beta)(8) barrel subunits
            of the homodimeric molecule is composed of binuclear zinc ions bridged
            by the Glu125 side-chain
  - term:
      id: GO:0008800
      label: beta-lactamase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: DPEP1 (renal dehydropeptidase-I) hydrolyzes the beta-lactam ring of carbapenem
        antibiotics such as imipenem; this is the basis for clinical co-administration
        with the inhibitor cilastatin. The IEA term duplicates well-supported IDA annotations.
      action: ACCEPT
      reason: Beta-lactamase activity (EC 3.5.2.6) is directly demonstrated for the
        purified human enzyme, with measured kinetics on imipenem and competitive inhibition
        by cilastatin. The electronic annotation is correct and corroborated by experimental
        evidence.
      supported_by:
        - reference_id: PMID:6334084
          supporting_text: beta-Lactamase activity of the purified human enzyme was
            demonstrated by measuring its activity against the two beta-lactam antibiotics,
            imipenem and SCH 29482.
  - term:
      id: GO:0016324
      label: apical plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: DPEP1 is a GPI-anchored ectoenzyme localized to the apical (luminal/brush-border)
        plasma membrane of kidney proximal tubule and intestinal epithelial cells.
      action: ACCEPT
      reason: Apical plasma membrane is the correct and informative subcellular location,
        supported by direct evidence (apical staining in colon epithelium; brush-border
        membrane localization). This is more specific than the generic plasma membrane
        term and should be retained.
      supported_by:
        - reference_id: PMID:20824289
          supporting_text: DPEP1 protein was observed on the apical side of the cancer
            cells
  - term:
      id: GO:0016787
      label: hydrolase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Hydrolase activity is a very high-level molecular-function parent of
        the dipeptidase/metallopeptidase and beta-lactamase activities of DPEP1.
      action: ACCEPT
      reason: This keyword-derived term is correct but uninformative on its own. It
        is a valid ancestor of the specific catalytic functions and is acceptable as
        a broad parent.
      supported_by:
        - reference_id: PMID:12144777
          supporting_text: Human renal dipeptidase is a membrane-bound glycoprotein
            hydrolyzing dipeptides and is involved in hydrolytic metabolism of penem
            and carbapenem beta-lactam antibiotics.
  - term:
      id: GO:0016805
      label: dipeptidase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Dipeptidase activity is the defining molecular function of DPEP1 (EC
        3.4.13.19). This IEA term duplicates the well-supported IBA and IDA dipeptidase
        activity annotations.
      action: ACCEPT
      reason: This is the core molecular function, directly demonstrated for the human
        enzyme and consistent across automated, phylogenetic, and experimental annotations.
      supported_by:
        - reference_id: PMID:32325220
          supporting_text: 'no in vitro activity against a variety of dipeptides and
            biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine)'
  - term:
      id: GO:0031528
      label: microvillus membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: DPEP1 is GPI-anchored to the brush-border microvillus membrane of the
        kidney proximal tubule, with its active site facing the luminal microvillar
        surface as shown crystallographically.
      action: ACCEPT
      reason: Microvillus membrane is a correct and specific cellular-component annotation,
        supported by direct GPI-anchor/subcellular-location evidence and by the structural
        orientation of the active site toward the microvillar membrane.
      supported_by:
        - reference_id: PMID:12144777
          supporting_text: it faces toward the microvillar membrane of a kidney tubule
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: DPEP1 binds two catalytic Zn2+ ions per monomer. Metal ion binding is
        a correct but generic parent of the experimentally established zinc ion binding.
      action: ACCEPT
      reason: This keyword-derived IEA term is correct; the more specific and experimentally
        supported zinc ion binding term is also annotated. The binuclear zinc center
        is directly demonstrated by crystallography.
      supported_by:
        - reference_id: PMID:12144777
          supporting_text: The active site in each of the (alpha/beta)(8) barrel subunits
            of the homodimeric molecule is composed of binuclear zinc ions bridged
            by the Glu125 side-chain
  - term:
      id: GO:0070573
      label: metallodipeptidase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: Metallodipeptidase activity precisely describes DPEP1, a zinc-dependent
        dipeptidase. This InterPro-derived IEA term duplicates the experimentally supported
        IDA metallodipeptidase activity annotations.
      action: ACCEPT
      reason: This is an accurate and appropriately specific molecular-function term
        combining the metal-dependence and dipeptidase activity, both of which are
        directly established for the human enzyme.
      supported_by:
        - reference_id: PMID:12144777
          supporting_text: The active site in each of the (alpha/beta)(8) barrel subunits
            of the homodimeric molecule is composed of binuclear zinc ions bridged
            by the Glu125 side-chain
  - term:
      id: GO:0098552
      label: side of membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: This keyword-derived term reflects that DPEP1 is a GPI-anchored protein
        attached to the extracellular (luminal) leaflet of the plasma membrane rather
        than spanning it.
      action: ACCEPT
      reason: The term is a correct but generic cellular-component annotation consistent
        with the GPI-anchored, extracellular-facing topology of DPEP1. The more specific
        apical/microvillus membrane terms are more informative and are also annotated.
      supported_by:
        - reference_id: PMID:2303490
          supporting_text: supporting the previous observation which suggested that
            mature MDP is anchored to the membrane by covalently attached phosphatidylinositol
  - term:
      id: GO:1901749
      label: leukotriene D4 catabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: DPEP1 catalyzes the hydrolysis of leukotriene D4 to leukotriene E4 (cleaving
        the glycine), an established physiological reaction. This ARBA-derived IEA term
        duplicates the experimentally supported IDA annotation.
      action: ACCEPT
      reason: This is a specific, correct biological-process annotation directly supported
        by demonstrated LTD4-to-LTE4 conversion activity and corresponding UniProt catalytic
        activity records.
      supported_by:
        - reference_id: PMID:32325220
          supporting_text: 'no in vitro activity against a variety of dipeptides and
            biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine)'
  - term:
      id: GO:0006691
      label: leukotriene metabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Leukotriene metabolic process is a broader parent of the specific LTD4
        catabolic process. DPEP1 metabolizes leukotriene D4 to E4, so this orthology-transferred
        term is correct.
      action: ACCEPT
      reason: This term, transferred by orthology from mouse Dpep1, accurately captures
        DPEP1's role in leukotriene metabolism. It is a valid broader parent of the
        more specific leukotriene D4 catabolic process term that is also annotated.
      supported_by:
        - reference_id: PMID:32325220
          supporting_text: 'no in vitro activity against a variety of dipeptides and
            biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine)'
  - term:
      id: GO:0006751
      label: glutathione catabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: DPEP1 hydrolyzes cysteinylglycine/cystinyl-bis-glycine, the dipeptides
        generated downstream of gamma-glutamyltransferase during extracellular glutathione
        degradation, releasing cysteine and glycine. This contributes to the terminal
        step of glutathione catabolism.
      action: ACCEPT
      reason: Cysteinylglycine dipeptidase activity is a well-established role of membrane
        dipeptidases in glutathione catabolism, directly supported by demonstrated cystinyl-bis-glycine
        hydrolysis and the D304-dependence of this activity. The orthology transfer
        is appropriate.
      supported_by:
        - reference_id: PMID:32325220
          supporting_text: 'no in vitro activity against a variety of dipeptides and
            biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine)'
  - term:
      id: GO:0006954
      label: inflammatory response
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: DPEP1 acts as an adhesion receptor on inflamed lung and liver endothelium
        that mediates neutrophil recruitment from the bloodstream, a non-enzymatic function
        established in mouse and transferred here by orthology. This is consistent with
        a role in the inflammatory response.
      action: KEEP_AS_NON_CORE
      reason: The adhesion/inflammation role is genuine but distinct from the core enzymatic
        function of DPEP1 and represents one specific facet (neutrophil recruitment).
        The term is correct and supported by the Cell 2019 study (separable from catalysis,
        as shown by the catalytically dead E141D mutant retaining neutrophil binding),
        but is best treated as non-core relative to its dipeptidase activity.
      supported_by:
        - reference_id: file:human/DPEP1/DPEP1-deep-research-falcon.md
          supporting_text: the non-enzymatic role of DPEP1 as an adhesion receptor for
            neutrophil recruitment to lung and liver endothelium
  - term:
      id: GO:0016999
      label: antibiotic metabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: DPEP1 hydrolyzes beta-lactam antibiotics (carbapenems such as imipenem),
        which falls under antibiotic metabolic process. This orthology-transferred term
        duplicates well-supported IDA annotations.
      action: ACCEPT
      reason: The term correctly reflects DPEP1's dehydropeptidase/beta-lactamase activity
        toward carbapenem antibiotics, which is directly demonstrated and clinically
        relevant (basis for imipenem-cilastatin co-formulation).
      supported_by:
        - reference_id: PMID:6334084
          supporting_text: beta-Lactamase activity of the purified human enzyme was
            demonstrated by measuring its activity against the two beta-lactam antibiotics,
            imipenem and SCH 29482.
  - term:
      id: GO:0030593
      label: neutrophil chemotaxis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: This orthology-transferred term reflects DPEP1's role as an endothelial
        adhesion receptor mediating neutrophil recruitment to inflamed lung and liver.
        Mechanistically the function is neutrophil adhesion/recruitment rather than
        classical chemotaxis (directed migration along a chemical gradient).
      action: MODIFY
      reason: The established function is DPEP1-mediated neutrophil adhesion to endothelium
        during recruitment, not chemotaxis per se; the original Cell 2019 study describes
        DPEP1 as an adhesion receptor. A more accurate term is neutrophil extravasation,
        capturing the role of DPEP1 on the endothelial side in capturing neutrophils
        leaving the bloodstream.
      proposed_replacement_terms:
        - id: GO:0072672
          label: neutrophil extravasation
      supported_by:
        - reference_id: file:human/DPEP1/DPEP1-deep-research-falcon.md
          supporting_text: DPEP1 as an adhesion receptor for neutrophil recruitment
            to lung and liver endothelium remains a major recent conceptual advance
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16189514
    review:
      summary: This is a generic protein binding annotation derived from a proteome-scale
        yeast two-hybrid interactome screen (interactor KIFBP/Q96EK5). The reported
        partner is an intracellular kinesin-binding protein, biologically implausible
        as a physiological partner of a GPI-anchored extracellular ectoenzyme.
      action: REMOVE
      reason: GO:0005515 protein binding is uninformative for curation and the supporting
        evidence comes from a single high-throughput interactome screen with no orthogonal
        validation and a topologically implausible (cytoplasmic) partner. It does not
        define a specific molecular function for DPEP1.
      supported_by:
        - reference_id: PMID:16189514
          supporting_text: Towards a proteome-scale map of the human protein-protein
            interaction network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25416956
    review:
      summary: Generic protein binding annotation from a proteome-scale interactome
        screen (interactor APPBP2/Q92624, an intracellular adaptor). No specific molecular
        function is established for DPEP1.
      action: REMOVE
      reason: GO:0005515 protein binding is uninformative and rests on a single high-throughput
        interactome dataset with a topologically implausible cytoplasmic partner for
        a GPI-anchored ectoenzyme. It should not be retained as a curated molecular
        function.
      supported_by:
        - reference_id: PMID:25416956
          supporting_text: A proteome-scale map of the human interactome network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: Generic protein binding annotation from a proteome-scale interactome
        screen (interactor ACADS/P16219, a mitochondrial acyl-CoA dehydrogenase). No
        specific molecular function is established for DPEP1.
      action: REMOVE
      reason: GO:0005515 protein binding is uninformative and the supporting evidence
        is a single high-throughput interactome dataset with a mitochondrial partner
        that cannot physiologically contact a GPI-anchored extracellular ectoenzyme.
        It does not warrant a curated molecular-function annotation.
      supported_by:
        - reference_id: PMID:28514442
          supporting_text: Architecture of the human interactome defines protein communities
            and disease networks.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: Generic protein binding annotation from a proteome-scale interactome
        screen (interactor ACADS/P16219, mitochondrial). No specific molecular function
        is established for DPEP1.
      action: REMOVE
      reason: GO:0005515 protein binding is uninformative and the supporting high-throughput
        interactome dataset reports a topologically implausible mitochondrial partner.
        It should not be retained as a curated molecular function.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: Dual proteome-scale networks reveal cell-specific remodeling
            of the human interactome.
  - term:
      id: GO:0030054
      label: cell junction
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: This cellular-component term derives from Human Protein Atlas immunofluorescence.
        DPEP1 is a GPI-anchored brush-border/apical membrane protein; a cell-junction
        signal may reflect apical/lateral membrane localization in epithelial cells
        but is not the characteristic functional site.
      action: KEEP_AS_NON_CORE
      reason: The HPA immunofluorescence signal is plausible for an apical-membrane
        epithelial protein but cell junction is not the established functional location
        of DPEP1; apical/microvillus/plasma membrane terms better describe its core
        site. Retain as non-core context.
      supported_by:
        - reference_id: PMID:20824289
          supporting_text: DPEP1 protein was observed on the apical side of the cancer
            cells
  - term:
      id: GO:0008800
      label: beta-lactamase activity
    evidence_type: IDA
    original_reference_id: PMID:32325220
    review:
      summary: In this comparative structural/biochemical study, DPEP1 (unlike the degenerate
        DPEP3) shows activity against imipenem, confirming its beta-lactamase activity.
      action: ACCEPT
      reason: DPEP1 beta-lactamase activity is directly supported here, where DPEP3
        is shown to lack activity against imipenem (and other substrates) that DPEP1/DPEP2
        possess. This corroborates the long-established carbapenem-hydrolyzing dehydropeptidase
        activity of DPEP1.
      supported_by:
        - reference_id: PMID:32325220
          supporting_text: 'no in vitro activity against a variety of dipeptides and
            biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine)'
  - term:
      id: GO:0016805
      label: dipeptidase activity
    evidence_type: IDA
    original_reference_id: PMID:32325220
    review:
      summary: DPEP1 hydrolyzes dipeptides and biological dipeptide substrates (including
        cystinyl-bis-glycine), confirmed in this comparative study where active DPEP1/DPEP2
        contrast with the inactive DPEP3.
      action: ACCEPT
      reason: Dipeptidase activity is the core molecular function of DPEP1, directly
        supported here, with the active-site determinants (His and Asp residues, binuclear
        zinc) shown to be intact in DPEP1 but degenerate in DPEP3.
      supported_by:
        - reference_id: PMID:32325220
          supporting_text: 'no in vitro activity against a variety of dipeptides and
            biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine)'
  - term:
      id: GO:1901749
      label: leukotriene D4 catabolic process
    evidence_type: IDA
    original_reference_id: PMID:32325220
    review:
      summary: DPEP1 acts on leukotriene D4 (among its biological substrates), converting
        LTD4 to LTE4, in contrast to the inactive DPEP3.
      action: ACCEPT
      reason: This biological-process annotation is directly supported by demonstrated
        activity of DPEP1 against leukotriene D4 in the comparative substrate panel,
        consistent with the established LTD4-to-LTE4 conversion reaction.
      supported_by:
        - reference_id: PMID:32325220
          supporting_text: 'no in vitro activity against a variety of dipeptides and
            biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine)'
  - term:
      id: GO:0006751
      label: glutathione catabolic process
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: DPEP1 hydrolyzes cysteinylglycine (cystinyl-bis-glycine), the dipeptide
        product of extracellular glutathione breakdown, completing glutathione catabolism
        at the apical membrane. This ISS annotation (by similarity to mouse Dpep1) is
        corroborated by direct human enzyme substrate data.
      action: ACCEPT
      reason: The role in glutathione catabolism is well supported by demonstrated cystinyl-bis-glycine
        hydrolysis (D304-dependent) and is consistent across the membrane dipeptidase
        family. This ISS row duplicates the orthology-based IEA glutathione catabolic
        process annotation.
      supported_by:
        - reference_id: PMID:32325220
          supporting_text: 'no in vitro activity against a variety of dipeptides and
            biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine)'
  - term:
      id: GO:0016999
      label: antibiotic metabolic process
    evidence_type: IDA
    original_reference_id: PMID:6334084
    review:
      summary: Purified human renal dipeptidase hydrolyzes the beta-lactam antibiotics
        imipenem and SCH 29482 at rates capable of inactivating them in the kidney,
        directly placing DPEP1 in antibiotic metabolism.
      action: ACCEPT
      reason: Directly supported by enzymatic measurements on beta-lactam antibiotics;
        this is the experimental basis for the antibiotic metabolic process annotation
        and for the clinical imipenem-cilastatin co-formulation.
      supported_by:
        - reference_id: PMID:6334084
          supporting_text: beta-Lactamase activity of the purified human enzyme was
            demonstrated by measuring its activity against the two beta-lactam antibiotics,
            imipenem and SCH 29482.
  - term:
      id: GO:0008270
      label: zinc ion binding
    evidence_type: IDA
    original_reference_id: PMID:12144777
    review:
      summary: The crystal structure shows DPEP1 binds two zinc ions per active site,
        forming the binuclear catalytic center bridged by Glu125.
      action: ACCEPT
      reason: Zinc ion binding is directly and structurally demonstrated and is essential
        for catalysis. This is a core, well-supported molecular-function annotation.
      supported_by:
        - reference_id: PMID:12144777
          supporting_text: The active site in each of the (alpha/beta)(8) barrel subunits
            of the homodimeric molecule is composed of binuclear zinc ions bridged
            by the Glu125 side-chain
  - term:
      id: GO:0008800
      label: beta-lactamase activity
    evidence_type: IDA
    original_reference_id: PMID:6334084
    review:
      summary: Purified human renal dipeptidase has beta-lactamase activity, hydrolyzing
        imipenem and SCH 29482 with cilastatin acting as a reversible competitive inhibitor.
      action: ACCEPT
      reason: This is the original direct experimental demonstration of DPEP1 beta-lactamase
        (dehydropeptidase) activity, including kinetics and cilastatin inhibition. A
        core, well-supported molecular function.
      supported_by:
        - reference_id: PMID:6334084
          supporting_text: The beta-lactamase inhibitor, cilastatin, demonstrated reversible
            competitive inhibition of the peptidase-catalyzed hydrolysis of both antibiotics
            with the same Ki of 0.7 microM.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:11487543
    review:
      summary: DPEP1 was detected by high-throughput proteomics in exosome-like vesicles
        secreted by intestinal epithelial cells. As a GPI-anchored brush-border protein,
        DPEP1 is commonly recovered in exosomes/membrane vesicles shed from apical surfaces.
      action: KEEP_AS_NON_CORE
      reason: The exosome localization is a real but secondary finding from high-throughput
        proteomics; it reflects vesicle shedding of an apical membrane protein rather
        than the functional site of DPEP1 (brush-border/microvillus membrane). Retain
        as non-core.
      supported_by:
        - reference_id: PMID:11487543
          supporting_text: Intestinal epithelial cells secrete exosome-like vesicles.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:23533145
    review:
      summary: DPEP1 was identified by high-throughput proteomics in urinary/prostatic-secretion
        exosomes, consistent with shedding of this GPI-anchored apical membrane protein
        into extracellular vesicles.
      action: KEEP_AS_NON_CORE
      reason: This high-throughput exosome detection reflects vesicle shedding rather
        than the functional brush-border location of DPEP1; keep as non-core localization
        context.
      supported_by:
        - reference_id: PMID:23533145
          supporting_text: In-depth proteomic analyses of exosomes isolated from expressed
            prostatic secretions in urine.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:19056867
    review:
      summary: DPEP1 was detected by large-scale proteomics in urinary exosomes, consistent
        with shedding of the GPI-anchored apical brush-border protein from kidney epithelia.
      action: KEEP_AS_NON_CORE
      reason: High-throughput urinary exosome proteomics localization is secondary to
        DPEP1's functional brush-border membrane site; keep as non-core context.
      supported_by:
        - reference_id: PMID:19056867
          supporting_text: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:12144777
    review:
      summary: DPEP1 is a membrane-bound enzyme whose active site faces the microvillar
        (apical plasma) membrane of the kidney tubule, as shown by its crystal structure.
      action: ACCEPT
      reason: Plasma membrane localization is directly supported; more specific apical/microvillus
        membrane terms are also annotated. Correct cellular compartment for this GPI-anchored
        ectoenzyme.
      supported_by:
        - reference_id: PMID:12144777
          supporting_text: it faces toward the microvillar membrane of a kidney tubule
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-266012
    review:
      summary: Reactome places DPEP1 at the plasma membrane in the reaction converting
        LTD4 to LTE4. This is consistent with its GPI-anchored apical-membrane localization.
      action: ACCEPT
      reason: Plasma membrane is the correct location and is consistent with the experimentally
        established GPI-anchored brush-border localization. Duplicates other plasma
        membrane annotations.
      supported_by:
        - reference_id: PMID:12144777
          supporting_text: it faces toward the microvillar membrane of a kidney tubule
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5433067
    review:
      summary: Reactome places DPEP1 at the plasma membrane in a reaction hydrolyzing
        glycine from aflatoxin-glutathione conjugate detoxification intermediates, consistent
        with its apical-membrane localization.
      action: ACCEPT
      reason: Plasma membrane is the correct cellular component and consistent with
        the GPI-anchored brush-border localization. Duplicates other plasma membrane
        annotations.
      supported_by:
        - reference_id: PMID:12144777
          supporting_text: it faces toward the microvillar membrane of a kidney tubule
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: This ISS term (by similarity to rat Dpep1, P22412) reflects that the
        DPEP1 ectodomain and active site face the extracellular/luminal space, and
        a secretory (PI-PLC-cleaved/soluble) form can be released.
      action: KEEP_AS_NON_CORE
      reason: DPEP1 is primarily a membrane-anchored ectoenzyme acting at the apical
        membrane; while its catalytic domain is extracellular and a soluble form exists,
        plasma/apical/microvillus membrane terms better describe its functional site.
        Retain as non-core.
      supported_by:
        - reference_id: PMID:2303490
          supporting_text: supporting the previous observation which suggested that
            mature MDP is anchored to the membrane by covalently attached phosphatidylinositol
  - term:
      id: GO:0016999
      label: antibiotic metabolic process
    evidence_type: IDA
    original_reference_id: PMID:8737157
    review:
      summary: Human recombinant dehydropeptidase-I (DPEP1) was tested for hydrolytic
        stability of carbapenem and penem antibiotics, directly demonstrating its role
        in beta-lactam antibiotic metabolism.
      action: ACCEPT
      reason: This experimental study of DPEP1-mediated antibiotic hydrolysis directly
        supports the antibiotic metabolic process annotation; duplicates the other
        IDA antibiotic metabolism rows.
      supported_by:
        - reference_id: PMID:8737157
          supporting_text: Comparative stability of carbapenem and penem antibiotics
            to human recombinant dehydropeptidase-I.
  - term:
      id: GO:0034235
      label: GPI anchor binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: DPEP1 is itself a GPI-anchored protein, but 'GPI anchor binding' as a
        molecular function implies the protein binds GPI anchors of other molecules.
        This ISS annotation (from rat P22412) likely conflates being GPI-anchored with
        a GPI-anchor-binding activity.
      action: REMOVE
      reason: There is no experimental evidence that DPEP1 binds GPI anchors as a molecular
        function; the protein is post-translationally modified with a GPI anchor (captured
        by the GPI-anchor lipid-anchor feature and membrane localization), which is
        distinct from a GPI-anchor-binding activity. This ISS term is a likely mis-transfer
        and is not informative.
      supported_by:
        - reference_id: PMID:2303490
          supporting_text: supporting the previous observation which suggested that
            mature MDP is anchored to the membrane by covalently attached phosphatidylinositol
  - term:
      id: GO:0071277
      label: cellular response to calcium ion
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: This ISS annotation is transferred by sequence similarity from rat Dpep1
        (P22412). There is no human experimental support, and no clear mechanistic link
        between DPEP1's dipeptidase function and a cellular calcium response.
      action: REMOVE
      reason: The annotation rests solely on similarity to a rat ortholog with no demonstrated
        mechanism connecting DPEP1 to calcium-ion signaling. It is not supported by
        the human literature and risks over-annotation; should be removed pending direct
        evidence.
      supported_by:
        - reference_id: file:human/DPEP1/DPEP1-deep-research-falcon.md
          supporting_text: DPEP1 is a disulfide-linked homodimer whose extracellular
            domain adopts an (alpha/beta)8-barrel fold typical of membrane-bound dipeptidases
  - term:
      id: GO:0071732
      label: cellular response to nitric oxide
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: This ISS annotation is transferred by sequence similarity from rat Dpep1
        (P22412), with no human experimental support and no clear mechanistic basis
        linking DPEP1's enzymatic function to a nitric-oxide response.
      action: REMOVE
      reason: The annotation depends only on rat ortholog similarity and lacks any direct
        mechanistic or experimental support in human. It is a likely over-annotation
        and should be removed pending direct evidence.
      supported_by:
        - reference_id: file:human/DPEP1/DPEP1-deep-research-falcon.md
          supporting_text: DPEP1 is a disulfide-linked homodimer whose extracellular
            domain adopts an (alpha/beta)8-barrel fold typical of membrane-bound dipeptidases
  - term:
      id: GO:0070573
      label: metallodipeptidase activity
    evidence_type: IDA
    original_reference_id: PMID:12144777
    review:
      summary: The crystal structure shows DPEP1 is a zinc-dependent dipeptidase with
        a binuclear zinc active site recognizing dipeptide substrates (cilastatin occupies
        the dipeptide pocket).
      action: ACCEPT
      reason: Metallodipeptidase activity is precisely the molecular function of DPEP1
        and is directly supported by the structure showing a dipeptide-sized binuclear-zinc
        active site. Core function.
      supported_by:
        - reference_id: PMID:12144777
          supporting_text: A dipeptidyl moiety of the therapeutically used cilastatin
            inhibitor is fully accommodated in the active-site pocket, which is small
            enough for precise recognition of dipeptide substrates.
  - term:
      id: GO:0072340
      label: lactam catabolic process
    evidence_type: TAS
    original_reference_id: PMID:12144777
    review:
      summary: DPEP1 is involved in hydrolytic metabolism of penem and carbapenem beta-lactam
        (lactam) antibiotics, supporting a lactam catabolic process annotation.
      action: ACCEPT
      reason: Lactam catabolic process accurately captures DPEP1's beta-lactam ring
        hydrolysis activity and is well supported by the structural and enzymatic literature.
      supported_by:
        - reference_id: PMID:12144777
          supporting_text: Human renal dipeptidase is a membrane-bound glycoprotein
            hydrolyzing dipeptides and is involved in hydrolytic metabolism of penem
            and carbapenem beta-lactam antibiotics.
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: PMID:20031578
    review:
      summary: The cited reference is a genome-wide association study linking a DPEP1
        locus variant to plasma homocysteine; it does not itself localize the DPEP1
        protein. Plasma membrane localization is nonetheless well established by independent
        direct evidence.
      action: ACCEPT
      reason: Plasma membrane is the correct location for DPEP1, although the cited GWAS
        is not the appropriate source of localization evidence. The annotation is retained
        because the location is strongly supported elsewhere (GPI-anchor, crystallography);
        the GWAS reference is weak provenance for this specific term.
      supported_by:
        - reference_id: PMID:12144777
          supporting_text: it faces toward the microvillar membrane of a kidney tubule
  - term:
      id: GO:0006749
      label: glutathione metabolic process
    evidence_type: TAS
    original_reference_id: PMID:20031578
    review:
      summary: DPEP1 participates in glutathione metabolism by hydrolyzing the cysteinylglycine
        dipeptide generated during extracellular glutathione breakdown. This broader
        glutathione metabolic process term is appropriate, although the cited GWAS reference
        only links the DPEP1 locus to plasma homocysteine and does not directly demonstrate
        the enzymatic step.
      action: ACCEPT
      reason: The glutathione metabolic process role is genuine (cysteinylglycine hydrolysis
        in GSH catabolism), and this term is a valid broader parent of glutathione
        catabolic process. The GWAS reference is weak provenance, but the term is corroborated
        by direct cystinyl-bis-glycine hydrolysis evidence.
      supported_by:
        - reference_id: PMID:32325220
          supporting_text: 'no in vitro activity against a variety of dipeptides and
            biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine)'
  - term:
      id: GO:0008270
      label: zinc ion binding
    evidence_type: IDA
    original_reference_id: PMID:19879002
    review:
      summary: This DFT mechanistic study models DPEP1 as a dinuclear zinc enzyme in
        which the two zinc ions coordinate substrate and the bridging hydroxide nucleophile,
        consistent with zinc ion binding.
      action: ACCEPT
      reason: Zinc ion binding is a core, well-supported molecular function of DPEP1.
        This computational study reinforces the structurally established binuclear zinc
        center. (Note the evidence code IDA is generous for a DFT study, but the underlying
        zinc-binding is directly established crystallographically.)
      supported_by:
        - reference_id: PMID:19879002
          supporting_text: The reaction mechanism of the dinuclear zinc enzyme human
            renal dipeptidase is investigated using hybrid density functional theory.
  - term:
      id: GO:0030336
      label: negative regulation of cell migration
    evidence_type: IMP
    original_reference_id: PMID:20824289
    review:
      summary: RNAi knockdown of DPEP1 in a colon cancer cell line increased invasive
        ability (without affecting proliferation or apoptosis), implying that DPEP1
        normally restrains cancer-cell invasion/migration.
      action: KEEP_AS_NON_CORE
      reason: The effect on invasiveness is an indirect, context-specific cancer-cell
        phenotype rather than a core molecular role of this dipeptidase, and the mechanism
        is unknown. It is supported by a single IMP study; keep as non-core.
      supported_by:
        - reference_id: PMID:20824289
          supporting_text: RNAi-mediated DPEP1 reduction in the colon cancer cell line
            did not result in cell proliferation or apoptosis, but was associated with
            an increased invasive ability.
  - term:
      id: GO:0045177
      label: apical part of cell
    evidence_type: IDA
    original_reference_id: PMID:20824289
    review:
      summary: Immunohistochemistry showed DPEP1 protein on the apical side of colon
        cancer cells, consistent with its apical-membrane localization in epithelia.
      action: ACCEPT
      reason: Apical localization is directly observed and consistent with the GPI-anchored
        brush-border/apical-membrane nature of DPEP1. Correct cellular-component annotation.
      supported_by:
        - reference_id: PMID:20824289
          supporting_text: DPEP1 protein was observed on the apical side of the cancer
            cells
  - term:
      id: GO:0050667
      label: homocysteine metabolic process
    evidence_type: IDA
    original_reference_id: PMID:20031578
    review:
      summary: The cited reference is a genome-wide association study reporting a statistical
        association between a DPEP1 locus SNP (rs1126464) and plasma homocysteine concentration.
        It provides no direct (IDA) demonstration that the DPEP1 protein metabolizes
        homocysteine; the link is genetic-epidemiological and the mechanism is unknown.
      action: REMOVE
      reason: A GWAS association of a locus with a plasma metabolite is not evidence
        that the gene product is enzymatically involved in homocysteine metabolism,
        and the IDA evidence code is inappropriate. DPEP1 has no demonstrated homocysteine-metabolizing
        activity; the association may be indirect (e.g., via cysteinylglycine/glutathione
        turnover). This over-interpreted annotation should be removed.
      supported_by:
        - reference_id: PMID:20031578
          supporting_text: we found novel associations with CPS1 (2q34; rs7422339;
            P=1.9 x 10(-11)), MUT (6p12.3; rs4267943; P=2.0 x 10(-9)), NOX4 (11q14.3;
            rs11018628; P=9.6 x 10(-12)), and DPEP1 (16q24.3; rs1126464; P=1.2 x 10(-12)).
  - term:
      id: GO:0070573
      label: metallodipeptidase activity
    evidence_type: IDA
    original_reference_id: PMID:19879002
    review:
      summary: This study models dipeptide hydrolysis by DPEP1 as a dinuclear zinc enzyme,
        supporting its metallodipeptidase activity.
      action: ACCEPT
      reason: Metallodipeptidase activity is the core molecular function of DPEP1. The
        computational mechanistic study reinforces the metal-dependent dipeptidase chemistry
        already established structurally and biochemically.
      supported_by:
        - reference_id: PMID:19879002
          supporting_text: This enzyme catalyzes the hydrolysis of dipeptides and beta-lactam
            antibiotics.
  - term:
      id: GO:0072341
      label: modified amino acid binding
    evidence_type: IDA
    original_reference_id: PMID:20031578
    review:
      summary: This annotation is derived from a genome-wide association study of plasma
        homocysteine and the DPEP1 locus. The GWAS does not demonstrate that the DPEP1
        protein binds a modified amino acid; 'modified amino acid binding' is an inference
        not directly supported by the cited evidence.
      action: REMOVE
      reason: The IDA evidence code and the molecular function 'modified amino acid
        binding' are not supported by a GWAS association study, which contains no protein
        binding or biochemical assay for DPEP1. This over-interpreted annotation should
        be removed; DPEP1's substrate recognition is better captured by its dipeptidase/metallodipeptidase
        activity.
      supported_by:
        - reference_id: PMID:20031578
          supporting_text: we found novel associations with CPS1 (2q34; rs7422339;
            P=1.9 x 10(-11)), MUT (6p12.3; rs4267943; P=2.0 x 10(-9)), NOX4 (11q14.3;
            rs11018628; P=9.6 x 10(-12)), and DPEP1 (16q24.3; rs1126464; P=1.2 x 10(-12)).
  - term:
      id: GO:0050839
      label: cell adhesion molecule binding
    evidence_type: IDA
    original_reference_id: file:human/DPEP1/DPEP1-deep-research-falcon.md
    review:
      summary: Independently of its catalytic activity, DPEP1 acts as a cell-surface
        adhesion receptor on inflamed lung and liver endothelium that binds neutrophils,
        mediating their recruitment from the bloodstream. A catalytically dead E141D
        mutant retains this neutrophil-binding activity, and the LSALT peptide blocks
        it, establishing an adhesion function separable from peptidase activity.
      action: NEW
      reason: This molecular-function role (adhesion-receptor binding underlying neutrophil
        recruitment) is well established in the recent literature but is not represented
        in the curated GOA molecular-function set, which captures only the related biological
        processes (inflammatory response, neutrophil chemotaxis). Cell adhesion molecule
        binding is the closest existing GO molecular-function term; a dedicated neutrophil-adhesion-receptor
        term is also proposed.
      supported_by:
        - reference_id: file:human/DPEP1/DPEP1-deep-research-falcon.md
          supporting_text: A catalytically inert E141D DPEP1 mutant maintained neutrophil
            adhesion comparable to wild-type in cellular assays, while LSALT peptide
            binding to DPEP1 inhibited adhesion
  - term:
      id: GO:0008235
      label: metalloexopeptidase activity
    evidence_type: TAS
    original_reference_id: PMID:2303490
    review:
      summary: DPEP1 is a metallo-dependent exopeptidase (dipeptidase) cleaving the
        terminal peptide bond of dipeptides. Metalloexopeptidase activity is an accurate
        broader functional classification.
      action: ACCEPT
      reason: This term correctly classifies DPEP1 as a metal-dependent exopeptidase
        and is a valid broader parent of metallodipeptidase activity. Supported by the
        enzyme's established zinc-dependent dipeptidase chemistry.
      supported_by:
        - reference_id: PMID:2303490
          supporting_text: Two cDNA clones corresponding to human microsomal dipeptidase
            (MDP, formerly referred to as dehydropeptidase-I or renal dipeptidase
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, accompanied by conservative changes to GO 
      terms applied by UniProt.
    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:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods.
    findings: []
  - id: PMID:11487543
    title: Intestinal epithelial cells secrete exosome-like vesicles.
    findings: []
  - id: PMID:12144777
    title: Crystal structure of human renal dipeptidase involved in beta-lactam 
      hydrolysis.
    findings: []
  - id: PMID:16189514
    title: Towards a proteome-scale map of the human protein-protein interaction
      network.
    findings: []
  - id: PMID:19056867
    title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
    findings: []
  - id: PMID:19879002
    title: 'Dipeptide hydrolysis by the dinuclear zinc enzyme human renal dipeptidase:
      mechanistic insights from DFT calculations.'
    findings: []
  - id: PMID:20031578
    title: 'Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma homocysteine
      in a healthy population: a genome-wide evaluation of 13 974 participants in
      the Women''s Genome Health Study.'
    findings: []
  - id: PMID:20824289
    title: DPEP1, expressed in the early stages of colon carcinogenesis, affects
      cancer cell invasiveness.
    findings: []
  - id: PMID:2303490
    title: Primary structure of human microsomal dipeptidase deduced from 
      molecular cloning.
    findings: []
  - id: PMID:23533145
    title: In-depth proteomic analyses of exosomes isolated from expressed 
      prostatic secretions in urine.
    findings: []
  - id: PMID:25416956
    title: A proteome-scale map of the human interactome network.
    findings: []
  - id: PMID:28514442
    title: Architecture of the human interactome defines protein communities and
      disease networks.
    findings: []
  - id: PMID:32325220
    title: Structure of human DPEP3 in complex with the SC-003 antibody Fab 
      fragment reveals basis for lack of dipeptidase activity.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the 
      human interactome.
    findings: []
  - id: PMID:6334084
    title: Beta-lactamase activity of purified and partially characterized human
      renal dipeptidase.
    findings: []
  - id: PMID:8737157
    title: Comparative stability of carbapenem and penem antibiotics to human 
      recombinant dehydropeptidase-I.
    findings: []
  - id: Reactome:R-HSA-266012
    title: LTD4 is converted to LTE4 by DPEP1/2
    findings: []
  - id: Reactome:R-HSA-5433067
    title: DPEPs hydrolyse glycine from AFXBO-CG, AFNBO-CG
    findings: []
  - id: file:human/DPEP1/DPEP1-deep-research-falcon.md
    title: Deep research report on DPEP1
    findings:
      - statement: DPEP1 is a GPI-anchored binuclear-zinc membrane dipeptidase of the
          M19 family that hydrolyzes dipeptides, converts LTD4 to LTE4, hydrolyzes cysteinylglycine
          from glutathione catabolism, and hydrolyzes beta-lactam antibiotics.
        supporting_text: DPEP1 hydrolyzes dipeptides including glutathione catabolites
          (e.g., Cys-Gly), converts leukotriene D4 (LTD4) to LTE4, and hydrolyzes beta-lactam
          antibiotics such as thienamycin/imipenem; it is potently inhibited by cilastatin
      - statement: DPEP1 has a non-enzymatic function as an endothelial adhesion receptor
          for neutrophil recruitment, separable from its catalytic activity.
        supporting_text: A catalytically inert E141D DPEP1 mutant maintained neutrophil
          adhesion comparable to wild-type in cellular assays, while LSALT peptide binding
          to DPEP1 inhibited adhesion
core_functions:
  - description: DPEP1 is a GPI-anchored, zinc-dependent membrane dipeptidase (renal/microsomal
      dipeptidase, dehydropeptidase-I) that hydrolyzes a broad range of dipeptides
      at the apical/brush-border membrane of kidney and intestinal epithelia using
      a binuclear Zn2+ active site.
    molecular_function:
      id: GO:0070573
      label: metallodipeptidase activity
    directly_involved_in:
      - id: GO:0006508
        label: proteolysis
    locations:
      - id: GO:0016324
        label: apical plasma membrane
      - id: GO:0031528
        label: microvillus membrane
    supported_by:
      - reference_id: PMID:12144777
        supporting_text: A dipeptidyl moiety of the therapeutically used cilastatin
          inhibitor is fully accommodated in the active-site pocket, which is small
          enough for precise recognition of dipeptide substrates.
      - reference_id: PMID:2303490
        supporting_text: Two cDNA clones corresponding to human microsomal dipeptidase
          (MDP, formerly referred to as dehydropeptidase-I or renal dipeptidase
  - description: DPEP1 converts leukotriene D4 to leukotriene E4 by hydrolytic removal
      of glycine, contributing to leukotriene metabolism at the cell surface.
    molecular_function:
      id: GO:0016805
      label: dipeptidase activity
    directly_involved_in:
      - id: GO:1901749
        label: leukotriene D4 catabolic process
    locations:
      - id: GO:0016324
        label: apical plasma membrane
    supported_by:
      - reference_id: PMID:32325220
        supporting_text: 'no in vitro activity against a variety of dipeptides and
          biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine)'
  - description: DPEP1 hydrolyzes cysteinylglycine (cystinyl-bis-glycine) generated
      during extracellular glutathione degradation, completing glutathione catabolism
      at the luminal membrane.
    molecular_function:
      id: GO:0016805
      label: dipeptidase activity
    directly_involved_in:
      - id: GO:0006751
        label: glutathione catabolic process
    locations:
      - id: GO:0016324
        label: apical plasma membrane
    supported_by:
      - reference_id: PMID:32325220
        supporting_text: 'no in vitro activity against a variety of dipeptides and
          biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine)'
  - description: DPEP1 hydrolyzes the beta-lactam ring of carbapenem/penem antibiotics
      (e.g., imipenem) via its dehydropeptidase/beta-lactamase activity, the basis
      for clinical co-administration of imipenem with the DPEP1 inhibitor cilastatin.
    molecular_function:
      id: GO:0008800
      label: beta-lactamase activity
    directly_involved_in:
      - id: GO:0016999
        label: antibiotic metabolic process
    locations:
      - id: GO:0016324
        label: apical plasma membrane
    supported_by:
      - reference_id: PMID:6334084
        supporting_text: The beta-lactamase inhibitor, cilastatin, demonstrated reversible
          competitive inhibition of the peptidase-catalyzed hydrolysis of both antibiotics
          with the same Ki of 0.7 microM.
  - description: Independently of its catalytic activity, DPEP1 functions as a cell-surface
      adhesion receptor on inflamed lung and liver endothelium that captures neutrophils
      during their recruitment from the bloodstream; this adhesion function is retained
      by a catalytically dead E141D mutant.
    molecular_function:
      id: GO:0050839
      label: cell adhesion molecule binding
    directly_involved_in:
      - id: GO:0072672
        label: neutrophil extravasation
    locations:
      - id: GO:0005886
        label: plasma membrane
    supported_by:
      - reference_id: file:human/DPEP1/DPEP1-deep-research-falcon.md
        supporting_text: A catalytically inert E141D DPEP1 mutant maintained neutrophil
          adhesion comparable to wild-type in cellular assays, while LSALT peptide binding
          to DPEP1 inhibited adhesion
proposed_new_terms:
  - proposed_name: neutrophil adhesion receptor activity
    proposed_definition: An activity by which a cell-surface receptor on endothelium
      directly mediates adhesion/capture of neutrophils during their recruitment from
      the bloodstream, independent of any catalytic function.
    justification: DPEP1 exemplifies this activity; the existing cell adhesion molecule
      binding (GO:0050839) term partially captures it, but a dedicated neutrophil-adhesion-receptor
      molecular-function term would more precisely represent the DPEP1 adhesion role
      demonstrated by the catalytically dead E141D mutant retaining neutrophil binding.
    proposed_parent:
      id: GO:0050839
      label: cell adhesion molecule binding
    supported_by:
      - reference_id: file:human/DPEP1/DPEP1-deep-research-falcon.md
        supporting_text: DPEP1 as an adhesion receptor for neutrophil recruitment to
          lung and liver endothelium remains a major recent conceptual advance
suggested_questions:
  - question: Is DPEP1's adhesion-receptor function best represented by a generic cell
      adhesion molecule binding term, or does it warrant a dedicated neutrophil-adhesion
      molecular-function term, given that the activity is separable from catalysis (E141D
      mutant retains adhesion)?
    experts:
      - Choudhury SR
      - Senger DL
      - Kubes P
  - question: What is the mechanistic basis of the GWAS association between the DPEP1
      locus and plasma homocysteine, given that DPEP1 has no demonstrated homocysteine-metabolizing
      activity (possibly indirect via cysteinylglycine/glutathione turnover)?
    experts:
      - Paré G
      - Chasman DI
suggested_experiments:
  - hypothesis: DPEP1 contributes to renal/intestinal glutathione catabolism by hydrolyzing
      luminal cysteinylglycine, and loss of DPEP1 alters extracellular cysteine/glutathione
      flux.
    description: Measure cysteinylglycine, cysteine, and glutathione levels in apical/luminal
      fluids and tissue from DPEP1-knockout versus wild-type epithelial models, with
      and without cilastatin, using targeted LC-MS metabolomics.
    experiment_type: targeted metabolomics with genetic and pharmacological perturbation
  - hypothesis: The DPEP1 adhesion-receptor function and its dipeptidase activity are
      structurally and functionally separable, and the neutrophil-binding surface is
      distinct from the catalytic pocket.
    description: Map the neutrophil-binding epitope on DPEP1 by mutagenesis/peptide
      competition (e.g., LSALT peptide) and structural studies, and test whether catalytically
      dead mutants (E141D) retain neutrophil adhesion in flow-chamber and in vivo recruitment
      assays.
    experiment_type: structure-function and cell adhesion assay
  - hypothesis: The DPEP1 locus association with plasma homocysteine reflects an indirect
      metabolic link rather than direct homocysteine hydrolysis by DPEP1.
    description: Test whether purified DPEP1 has any activity on homocysteine-containing
      substrates in vitro, and whether DPEP1 perturbation changes homocysteine levels
      in cell/animal models, to distinguish direct enzymatic involvement from indirect
      (e.g., glutathione-pathway) effects.
    experiment_type: enzymatic assay and metabolic perturbation