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.
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.
Parent term: cell adhesion molecule binding
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:12144777 Human renal dipeptidase is a membrane-bound glycoprotein hydrolyzing dipeptides ... it faces toward the microvillar membrane of a kidney tubule. |
| GO:0016805 dipeptidase activity | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:2303490 Two cDNA clones corresponding to human microsomal dipeptidase (MDP, formerly referred to as dehydropeptidase-I or renal dipeptidase PMID:32325220 no in vitro activity against a variety of dipeptides and biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine) |
| GO:0006508 proteolysis | IEA GO_REF:0000120 | ACCEPT | 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. 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. Supporting Evidence: PMID:2303490 Expression of immunologically cross-reactive and enzymatically active MDP was attained in COS cells transfected with the cDNA. |
| GO:0006629 lipid metabolic process | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:32325220 no in vitro activity against a variety of dipeptides and biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine) |
| GO:0008233 peptidase activity | IEA GO_REF:0000043 | ACCEPT | Summary: Peptidase activity is a broad molecular-function parent of the experimentally established dipeptidase/metallodipeptidase activity of DPEP1. 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. Supporting Evidence: PMID:2303490 Two cDNA clones corresponding to human microsomal dipeptidase (MDP, formerly referred to as dehydropeptidase-I or renal dipeptidase |
| GO:0008237 metallopeptidase activity | IEA GO_REF:0000043 | ACCEPT | 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. 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. Supporting Evidence: PMID:12144777 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 |
| GO:0008800 beta-lactamase activity | IEA GO_REF:0000120 | ACCEPT | 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. 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. Supporting Evidence: PMID:6334084 beta-Lactamase activity of the purified human enzyme was demonstrated by measuring its activity against the two beta-lactam antibiotics, imipenem and SCH 29482. |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: DPEP1 is a GPI-anchored ectoenzyme localized to the apical (luminal/brush-border) plasma membrane of kidney proximal tubule and intestinal epithelial cells. 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. Supporting Evidence: PMID:20824289 DPEP1 protein was observed on the apical side of the cancer cells |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | ACCEPT | Summary: Hydrolase activity is a very high-level molecular-function parent of the dipeptidase/metallopeptidase and beta-lactamase activities of DPEP1. 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. Supporting Evidence: PMID:12144777 Human renal dipeptidase is a membrane-bound glycoprotein hydrolyzing dipeptides and is involved in hydrolytic metabolism of penem and carbapenem beta-lactam antibiotics. |
| GO:0016805 dipeptidase activity | IEA GO_REF:0000120 | ACCEPT | 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. Reason: This is the core molecular function, directly demonstrated for the human enzyme and consistent across automated, phylogenetic, and experimental annotations. Supporting Evidence: PMID:32325220 no in vitro activity against a variety of dipeptides and biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine) |
| GO:0031528 microvillus membrane | IEA GO_REF:0000044 | ACCEPT | 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. 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. Supporting Evidence: PMID:12144777 it faces toward the microvillar membrane of a kidney tubule |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | 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. 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. Supporting Evidence: PMID:12144777 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 |
| GO:0070573 metallodipeptidase activity | IEA GO_REF:0000002 | ACCEPT | Summary: Metallodipeptidase activity precisely describes DPEP1, a zinc-dependent dipeptidase. This InterPro-derived IEA term duplicates the experimentally supported IDA metallodipeptidase activity annotations. 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. Supporting Evidence: PMID:12144777 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 |
| GO:0098552 side of membrane | IEA GO_REF:0000043 | ACCEPT | 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. 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. Supporting Evidence: PMID:2303490 supporting the previous observation which suggested that mature MDP is anchored to the membrane by covalently attached phosphatidylinositol |
| GO:1901749 leukotriene D4 catabolic process | IEA GO_REF:0000117 | ACCEPT | 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. Reason: This is a specific, correct biological-process annotation directly supported by demonstrated LTD4-to-LTE4 conversion activity and corresponding UniProt catalytic activity records. Supporting Evidence: PMID:32325220 no in vitro activity against a variety of dipeptides and biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine) |
| GO:0006691 leukotriene metabolic process | IEA GO_REF:0000107 | ACCEPT | 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. 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. Supporting Evidence: PMID:32325220 no in vitro activity against a variety of dipeptides and biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine) |
| GO:0006751 glutathione catabolic process | IEA GO_REF:0000107 | ACCEPT | 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. 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. Supporting Evidence: PMID:32325220 no in vitro activity against a variety of dipeptides and biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine) |
| GO:0006954 inflammatory response | IEA GO_REF:0000107 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/DPEP1/DPEP1-deep-research-falcon.md the non-enzymatic role of DPEP1 as an adhesion receptor for neutrophil recruitment to lung and liver endothelium |
| GO:0016999 antibiotic metabolic process | IEA GO_REF:0000107 | ACCEPT | 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. 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). Supporting Evidence: PMID:6334084 beta-Lactamase activity of the purified human enzyme was demonstrated by measuring its activity against the two beta-lactam antibiotics, imipenem and SCH 29482. |
| GO:0030593 neutrophil chemotaxis | IEA GO_REF:0000107 | MODIFY | 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). 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 replacements: neutrophil extravasation Supporting Evidence: file:human/DPEP1/DPEP1-deep-research-falcon.md DPEP1 as an adhesion receptor for neutrophil recruitment to lung and liver endothelium remains a major recent conceptual advance |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | REMOVE | 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. 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. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | 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. 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. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | 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. 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. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Generic protein binding annotation from a proteome-scale interactome screen (interactor ACADS/P16219, mitochondrial). No specific molecular function is established for DPEP1. 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. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0030054 cell junction | IDA GO_REF:0000052 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:20824289 DPEP1 protein was observed on the apical side of the cancer cells |
| GO:0008800 beta-lactamase activity | IDA PMID:32325220 Structure of human DPEP3 in complex with the SC-003 antibody... | ACCEPT | Summary: In this comparative structural/biochemical study, DPEP1 (unlike the degenerate DPEP3) shows activity against imipenem, confirming its beta-lactamase activity. 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. Supporting Evidence: PMID:32325220 no in vitro activity against a variety of dipeptides and biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine) |
| GO:0016805 dipeptidase activity | IDA PMID:32325220 Structure of human DPEP3 in complex with the SC-003 antibody... | ACCEPT | 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. 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. Supporting Evidence: PMID:32325220 no in vitro activity against a variety of dipeptides and biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine) |
| GO:1901749 leukotriene D4 catabolic process | IDA PMID:32325220 Structure of human DPEP3 in complex with the SC-003 antibody... | ACCEPT | Summary: DPEP1 acts on leukotriene D4 (among its biological substrates), converting LTD4 to LTE4, in contrast to the inactive DPEP3. 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. Supporting Evidence: PMID:32325220 no in vitro activity against a variety of dipeptides and biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine) |
| GO:0006751 glutathione catabolic process | ISS GO_REF:0000024 | ACCEPT | 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. 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. Supporting Evidence: PMID:32325220 no in vitro activity against a variety of dipeptides and biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine) |
| GO:0016999 antibiotic metabolic process | IDA PMID:6334084 Beta-lactamase activity of purified and partially characteri... | ACCEPT | 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. 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. Supporting Evidence: PMID:6334084 beta-Lactamase activity of the purified human enzyme was demonstrated by measuring its activity against the two beta-lactam antibiotics, imipenem and SCH 29482. |
| GO:0008270 zinc ion binding | IDA PMID:12144777 Crystal structure of human renal dipeptidase involved in bet... | ACCEPT | Summary: The crystal structure shows DPEP1 binds two zinc ions per active site, forming the binuclear catalytic center bridged by Glu125. Reason: Zinc ion binding is directly and structurally demonstrated and is essential for catalysis. This is a core, well-supported molecular-function annotation. Supporting Evidence: PMID:12144777 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 |
| GO:0008800 beta-lactamase activity | IDA PMID:6334084 Beta-lactamase activity of purified and partially characteri... | ACCEPT | Summary: Purified human renal dipeptidase has beta-lactamase activity, hydrolyzing imipenem and SCH 29482 with cilastatin acting as a reversible competitive inhibitor. 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. Supporting Evidence: PMID:6334084 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. |
| GO:0070062 extracellular exosome | HDA PMID:11487543 Intestinal epithelial cells secrete exosome-like vesicles. | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:11487543 Intestinal epithelial cells secrete exosome-like vesicles. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | 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. Reason: This high-throughput exosome detection reflects vesicle shedding rather than the functional brush-border location of DPEP1; keep as non-core localization context. Supporting Evidence: PMID:23533145 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | 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. Reason: High-throughput urinary exosome proteomics localization is secondary to DPEP1's functional brush-border membrane site; keep as non-core context. Supporting Evidence: PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exosomes. |
| GO:0005886 plasma membrane | IDA PMID:12144777 Crystal structure of human renal dipeptidase involved in bet... | ACCEPT | 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. Reason: Plasma membrane localization is directly supported; more specific apical/microvillus membrane terms are also annotated. Correct cellular compartment for this GPI-anchored ectoenzyme. Supporting Evidence: PMID:12144777 it faces toward the microvillar membrane of a kidney tubule |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-266012 | ACCEPT | 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. Reason: Plasma membrane is the correct location and is consistent with the experimentally established GPI-anchored brush-border localization. Duplicates other plasma membrane annotations. Supporting Evidence: PMID:12144777 it faces toward the microvillar membrane of a kidney tubule |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5433067 | ACCEPT | 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. Reason: Plasma membrane is the correct cellular component and consistent with the GPI-anchored brush-border localization. Duplicates other plasma membrane annotations. Supporting Evidence: PMID:12144777 it faces toward the microvillar membrane of a kidney tubule |
| GO:0005615 extracellular space | ISS GO_REF:0000024 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:2303490 supporting the previous observation which suggested that mature MDP is anchored to the membrane by covalently attached phosphatidylinositol |
| GO:0016999 antibiotic metabolic process | IDA PMID:8737157 Comparative stability of carbapenem and penem antibiotics to... | ACCEPT | 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. Reason: This experimental study of DPEP1-mediated antibiotic hydrolysis directly supports the antibiotic metabolic process annotation; duplicates the other IDA antibiotic metabolism rows. Supporting Evidence: PMID:8737157 Comparative stability of carbapenem and penem antibiotics to human recombinant dehydropeptidase-I. |
| GO:0034235 GPI anchor binding | ISS GO_REF:0000024 | REMOVE | 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. 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. Supporting Evidence: PMID:2303490 supporting the previous observation which suggested that mature MDP is anchored to the membrane by covalently attached phosphatidylinositol |
| GO:0071277 cellular response to calcium ion | ISS GO_REF:0000024 | REMOVE | 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. 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. Supporting Evidence: file:human/DPEP1/DPEP1-deep-research-falcon.md DPEP1 is a disulfide-linked homodimer whose extracellular domain adopts an (alpha/beta)8-barrel fold typical of membrane-bound dipeptidases |
| GO:0071732 cellular response to nitric oxide | ISS GO_REF:0000024 | REMOVE | 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. 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. Supporting Evidence: file:human/DPEP1/DPEP1-deep-research-falcon.md DPEP1 is a disulfide-linked homodimer whose extracellular domain adopts an (alpha/beta)8-barrel fold typical of membrane-bound dipeptidases |
| GO:0070573 metallodipeptidase activity | IDA PMID:12144777 Crystal structure of human renal dipeptidase involved in bet... | ACCEPT | 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). 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. Supporting Evidence: PMID:12144777 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. |
| GO:0072340 lactam catabolic process | TAS PMID:12144777 Crystal structure of human renal dipeptidase involved in bet... | ACCEPT | Summary: DPEP1 is involved in hydrolytic metabolism of penem and carbapenem beta-lactam (lactam) antibiotics, supporting a lactam catabolic process annotation. Reason: Lactam catabolic process accurately captures DPEP1's beta-lactam ring hydrolysis activity and is well supported by the structural and enzymatic literature. Supporting Evidence: PMID:12144777 Human renal dipeptidase is a membrane-bound glycoprotein hydrolyzing dipeptides and is involved in hydrolytic metabolism of penem and carbapenem beta-lactam antibiotics. |
| GO:0005886 plasma membrane | TAS PMID:20031578 Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma... | ACCEPT | 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. 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. Supporting Evidence: PMID:12144777 it faces toward the microvillar membrane of a kidney tubule |
| GO:0006749 glutathione metabolic process | TAS PMID:20031578 Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma... | ACCEPT | 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. 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. Supporting Evidence: PMID:32325220 no in vitro activity against a variety of dipeptides and biological substrates (imipenem, leukotriene D4 and cystinyl-bis-glycine) |
| GO:0008270 zinc ion binding | IDA PMID:19879002 Dipeptide hydrolysis by the dinuclear zinc enzyme human rena... | ACCEPT | 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. 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.) Supporting Evidence: PMID:19879002 The reaction mechanism of the dinuclear zinc enzyme human renal dipeptidase is investigated using hybrid density functional theory. |
| GO:0030336 negative regulation of cell migration | IMP PMID:20824289 DPEP1, expressed in the early stages of colon carcinogenesis... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:20824289 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. |
| GO:0045177 apical part of cell | IDA PMID:20824289 DPEP1, expressed in the early stages of colon carcinogenesis... | ACCEPT | Summary: Immunohistochemistry showed DPEP1 protein on the apical side of colon cancer cells, consistent with its apical-membrane localization in epithelia. Reason: Apical localization is directly observed and consistent with the GPI-anchored brush-border/apical-membrane nature of DPEP1. Correct cellular-component annotation. Supporting Evidence: PMID:20824289 DPEP1 protein was observed on the apical side of the cancer cells |
| GO:0050667 homocysteine metabolic process | IDA PMID:20031578 Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma... | REMOVE | 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. 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. Supporting Evidence: PMID:20031578 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)). |
| GO:0070573 metallodipeptidase activity | IDA PMID:19879002 Dipeptide hydrolysis by the dinuclear zinc enzyme human rena... | ACCEPT | Summary: This study models dipeptide hydrolysis by DPEP1 as a dinuclear zinc enzyme, supporting its metallodipeptidase activity. 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. Supporting Evidence: PMID:19879002 This enzyme catalyzes the hydrolysis of dipeptides and beta-lactam antibiotics. |
| GO:0072341 modified amino acid binding | IDA PMID:20031578 Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma... | REMOVE | 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. 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. Supporting Evidence: PMID:20031578 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)). |
| GO:0050839 cell adhesion molecule binding | IDA file:human/DPEP1/DPEP1-deep-research-falcon.md | NEW | 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. 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. Supporting Evidence: file:human/DPEP1/DPEP1-deep-research-falcon.md A catalytically inert E141D DPEP1 mutant maintained neutrophil adhesion comparable to wild-type in cellular assays, while LSALT peptide binding to DPEP1 inhibited adhesion |
| GO:0008235 metalloexopeptidase activity | TAS PMID:2303490 Primary structure of human microsomal dipeptidase deduced fr... | ACCEPT | Summary: DPEP1 is a metallo-dependent exopeptidase (dipeptidase) cleaving the terminal peptide bond of dipeptides. Metalloexopeptidase activity is an accurate broader functional classification. 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. Supporting Evidence: PMID:2303490 Two cDNA clones corresponding to human microsomal dipeptidase (MDP, formerly referred to as dehydropeptidase-I or renal dipeptidase |
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Download this section (compressed HTML)Q: 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)?
Suggested experts: Choudhury SR, Senger DL, Kubes P
Q: 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)?
Suggested experts: Paré G, Chasman DI
Experiment: 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.
Hypothesis: DPEP1 contributes to renal/intestinal glutathione catabolism by hydrolyzing luminal cysteinylglycine, and loss of DPEP1 alters extracellular cysteine/glutathione flux.
Type: targeted metabolomics with genetic and pharmacological perturbation
Experiment: 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.
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.
Type: structure-function and cell adhesion assay
Experiment: 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.
Hypothesis: The DPEP1 locus association with plasma homocysteine reflects an indirect metabolic link rather than direct homocysteine hydrolysis by DPEP1.
Type: enzymatic assay and metabolic perturbation
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