LPO encodes lactoperoxidase, a secreted, heme-dependent mammalian peroxidase expressed in salivary and mammary glands and in airway submucosal glands. In saliva, milk, and airway secretions, LPO uses hydrogen peroxide to oxidize thiocyanate to hypothiocyanous acid/hypothiocyanite, an antimicrobial oxidant that inhibits bacteria at mucosal surfaces. Human airway secretions contain LPO activity and support LPO-dependent antibacterial activity against several airway pathogens. LPO can also oxidize iodide and other donors under suitable chemical conditions, but thiocyanate is the best-supported physiological substrate and product partitioning depends on pH, peroxide supply, and competing substrates. The canonical precursor comprises a signal peptide at residues 1-26, a propeptide at residues 27-80, and a mature chain at residues 81-712. Human secretions contain both processed and partially unprocessed LPO, and the function of propeptide retention is unresolved. The mature enzyme binds heme and calcium and is glycosylated and disulfide-bonded. Autocatalytic peroxide-dependent covalent heme attachment and the detailed distal heme-pocket architecture are supported mainly by recombinant or non-human LPO studies; their transfer to human LPO is strongly supported by conservation but is not a direct endogenous-human structural observation. UniProt isoform 2 lacks residues 26-108, spanning the signal/ propeptide boundary and the N terminus of the canonical mature chain. Although a propeptide-deleted recombinant variant was secreted and active, the endogenous abundance, processing, localization, and physiological function of isoform 2 are not established.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: Accepted as core LPO biology. Reason: LPO is a secreted enzyme that functions in extracellular airway, salivary, and mammary secretions. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1916925 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed extracellular region assignment for human LPO. PANTHER:PTN000895746 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed extracellular region assignment for human LPO. RGD:1592081 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed extracellular region assignment for human LPO. UniProtKB:A1KZ92 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed extracellular region assignment for human LPO. UniProtKB:P05164 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed extracellular region assignment for human LPO. UniProtKB:P22079 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed extracellular region assignment for human LPO. UniProtKB:P80025 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed extracellular region assignment for human LPO. UniProtKB:Q92626 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed extracellular region assignment for human LPO. WB:WBGene00004256 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed extracellular region assignment for human LPO. WB:WBGene00004257 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed extracellular region assignment for human LPO. |
| GO:0019731 antibacterial humoral response | IBA GO_REF:0000033 | ACCEPT | Summary: Accepted as core LPO biology. Reason: Antibacterial humoral response directly reflects secreted LPO generation of antimicrobial oxidants. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008518865 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed antibacterial humoral response assignment for human LPO. UniProtKB:P80025 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed antibacterial humoral response assignment for human LPO. |
| GO:0036393 thiocyanate peroxidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Accepted as core LPO biology. Reason: Thiocyanate peroxidase activity is the most specific core activity of LPO, producing antimicrobial hypothiocyanous acid. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008518865 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed thiocyanate peroxidase activity assignment for human LPO. UniProtKB:P22079 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed thiocyanate peroxidase activity assignment for human LPO. UniProtKB:P80025 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed thiocyanate peroxidase activity assignment for human LPO. |
| GO:0004601 peroxidase activity | IEA GO_REF:0000120 | MODIFY | Summary: The broad peroxidase assignment should be replaced by the substrate-specific core activity. Reason: Peroxidase activity is directionally correct but less informative than the established LPO reaction. Human LPO's core chemistry is hydrogen-peroxide- dependent thiocyanate oxidation, captured specifically by GO:0036393. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q5SW46 SUPPORTS TRANSFER The source supports peroxidase catalysis, but the transferred parent term is less informative than thiocyanate peroxidase activity for human LPO. ensembl:ENSMUSP00000099466 SUPPORTS TRANSFER The source supports peroxidase catalysis, but the transferred parent term is less informative than thiocyanate peroxidase activity for human LPO. InterPro:IPR010255 SUPPORTS TRANSFER The family mapping supports peroxidase catalysis, but the parent term underspecifies human LPO's thiocyanate reaction. Proposed replacements: thiocyanate peroxidase activity |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: Accepted as core LPO biology. Reason: LPO is a secreted enzyme that functions in extracellular airway, salivary, and mammary secretions. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0243 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed extracellular region assignment for human LPO. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: The cytoplasm assignment is an over-propagated localization for a secretory-pathway protein. Reason: LPO is synthesized with an N-terminal signal peptide and enters the secretory pathway before acting extracellularly. Synthesis of a precursor by cytosolic ribosomes does not establish cytoplasm as a location of the LPO protein or its activity. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: UniProtKB:Q5SW46 SUPPORTS SOURCE BUT NOT TARGET The mouse donor does not establish cytoplasmic localization of human LPO. ensembl:ENSMUSP00000099466 SUPPORTS SOURCE BUT NOT TARGET The mouse donor does not establish cytoplasmic localization of human LPO. UniProtKB-SubCell:SL-0086 SUPPORTS SOURCE BUT NOT TARGET The generic cytoplasm mapping conflicts with LPO's signal-peptide-directed secretory localization. |
| GO:0006979 response to oxidative stress | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: The annotation overstates the demonstrated role of LPO. Reason: LPO uses hydrogen peroxide to generate reactive antimicrobial products, but this does not by itself establish LPO as a general cellular oxidative-stress response component. Propagation Review Root cause: PROPAGATION BAD Failure modes: ROLE CONFLATION Sources checked: InterPro:IPR010255 SUPPORTS SOURCE BUT NOT TARGET Exact WITH/FROM source; it does not establish the overextended response to oxidative stress role for human LPO. |
| GO:0018969 thiocyanate metabolic process | IEA GO_REF:0000108 | ACCEPT | Summary: Accepted as core LPO biology. Reason: Thiocyanate metabolism directly includes LPO-catalyzed oxidation of thiocyanate to hypothiocyanous acid. Propagation Review Root cause: NO FAILURE CORE Sources checked: GO:0036393 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed thiocyanate metabolic process assignment for human LPO. |
| GO:0020037 heme binding | IEA GO_REF:0000002 | ACCEPT | Summary: Accepted as core LPO biology. Reason: Heme binding is essential to the mammalian peroxidase catalytic mechanism and is conserved in LPO. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR010255 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed heme binding assignment for human LPO. |
| GO:0036393 thiocyanate peroxidase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Accepted as core LPO biology. Reason: Thiocyanate peroxidase activity is the most specific core activity of LPO, producing antimicrobial hypothiocyanous acid. Propagation Review Root cause: NO FAILURE CORE Sources checked: RHEA:69416 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed thiocyanate peroxidase activity assignment for human LPO. |
| GO:0098869 cellular oxidant detoxification | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: The annotation overstates the demonstrated role of LPO. Reason: Consumption of hydrogen peroxide during peroxidase catalysis does not establish a general cellular oxidant-detoxification role; LPO primarily generates antimicrobial oxidants extracellularly. Propagation Review Root cause: PROPAGATION BAD Failure modes: ROLE CONFLATION Sources checked: GO:0004601 SUPPORTS SOURCE BUT NOT TARGET Exact WITH/FROM source; it does not establish the overextended cellular oxidant detoxification role for human LPO. GO:0140825 SUPPORTS SOURCE BUT NOT TARGET Exact WITH/FROM source; it does not establish the overextended cellular oxidant detoxification role for human LPO. |
| GO:0140825 lactoperoxidase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Retained as experimentally plausible alternate-donor peroxidase chemistry, but not as the core LPO reaction. Reason: GO:0140825 denotes the phenolic-donor lactoperoxidase reaction represented by RHEA:56136/EC:1.11.1.7. LPO can oxidize alternate electron donors under suitable assay conditions, but the best-supported physiological core is extracellular thiocyanate oxidation to HOSCN/OSCN rather than this exact phenolic-donor reaction. Propagation Review Root cause: NO FAILURE CORE Sources checked: RHEA:56136 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed lactoperoxidase activity assignment for human LPO. EC:1.11.1.7 SUPPORTS TRANSFER Exact WITH/FROM source consistent with the reviewed lactoperoxidase activity assignment for human LPO. |
| GO:0004601 peroxidase activity | IDA PMID:6295491 The peroxidation of thiocyanate catalysed by myeloperoxidase... | MODIFY | Summary: The demonstrated reaction is better represented by thiocyanate peroxidase activity. Reason: PMID:6295491 directly studies LPO-catalyzed conversion of thiocyanate to hypothiocyanite, and this source row carries matching hydrogen peroxide, thiocyanate, water, and hypothiocyanous-acid extensions. GO:0036393 captures that chemistry more informatively than the parent peroxidase term. Proposed replacements: thiocyanate peroxidase activity Supporting Evidence: PMID:6295491 Peroxidation of SCN- to OSCN-, catalysed by myeloperoxidase and lactoperoxidase, was studied. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8855490 | ACCEPT | Summary: Accepted as core LPO biology. Reason: LPO is a secreted enzyme that functions in extracellular airway, salivary, and mammary secretions. |
| GO:0005576 extracellular region | EXP PMID:12626341 Lactoperoxidase and human airway host defense. | ACCEPT | Summary: Accepted as core LPO biology. Reason: Human airway secretions directly contained measurable LPO enzyme activity and LPO-sized immunoreactive bands, supporting extracellular localization. Supporting Evidence: PMID:12626341 The data showed that normal human airway secretions contained LPO enzyme activity (0.65 +/- 0.09 microg/mg secreted protein; n = 17), and Western blots of secretions demonstrated bands of the expected sizes for LPO. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: The cytoplasm assignment is an over-propagated localization for a secretory-pathway protein. Reason: LPO is synthesized with an N-terminal signal peptide and enters the secretory pathway before acting extracellularly. Synthesis of a precursor by cytosolic ribosomes does not establish cytoplasm as a location of the LPO protein or its activity. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: UniProtKB:Q5SW46 SUPPORTS SOURCE BUT NOT TARGET The mouse donor does not establish cytoplasmic localization of human LPO. |
| GO:0001580 detection of chemical stimulus involved in sensory perception of bitter taste | IDA PMID:24248522 Salivary protein profiles are linked to bitter taste accepta... | MARK AS OVER ANNOTATED | Summary: The annotation overstates the demonstrated role of LPO. Reason: The study reports an association between salivary LPO abundance and infant bitter-solution acceptance, not direct chemical-stimulus detection by LPO; the causal sensory-process annotation overstates the evidence. Supporting Evidence: PMID:24248522 while higher abundance of bands containing lactoperoxidase, prolactin-inducible protein and S-type cystatins was associated to a higher bitterness acceptance. |
| GO:0005576 extracellular region | IDA PMID:24248522 Salivary protein profiles are linked to bitter taste accepta... | ACCEPT | Summary: Accepted as core LPO biology. Reason: Lactoperoxidase-containing protein bands were identified from donated infant saliva, directly supporting LPO occurrence in this extracellular fluid. Supporting Evidence: PMID:24248522 Salivary proteins were separated by one-dimensional electrophoresis and bands were semi-quantified by image analysis. Partial least square (PLS) regression analyses were performed for each taste at both ages to explain intake ratios by band intensities. Bitterness acceptance in the younger infants was unique in the sense that salivary protein profiles could partly predict bitter taste acceptance. At that age, infants were on average indifferent to the 0.18-M urea solution, but great variability in acceptance was observed. The six bands considered as the best predictors for bitterness acceptance were identified by MALDI-TOF mass spectrometry. Higher abundance of bands containing secretory component, zinc-Ξ±-2-glycoprotein and carbonic anhydrase 6 was associated to a lower bitterness acceptance, while higher abundance of bands containing lactoperoxidase, prolactin-inducible protein and S-type cystatins was associated to a higher bitterness acceptance. |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | KEEP AS NON CORE | Summary: Retained as a secondary localization context. Reason: Detection in parotid exosome preparations is a high-throughput secretion-context observation and does not establish exosome-dependent LPO function. The experimental or curator-attributed assertion is retained with curator deference. |
| GO:0036393 thiocyanate peroxidase activity | IDA PMID:12626341 Lactoperoxidase and human airway host defense. | ACCEPT | Summary: Accepted as core LPO biology. Reason: Human airway secretions contained LPO activity together with thiocyanate at concentrations sufficient for LPO catalysis, directly supporting the substrate-specific activity. Supporting Evidence: PMID:12626341 SCN-, LPO's substrate, was present in undiluted airway secretions at concentrations sufficient for LPO catalysis (0.46 +/- 0.19 mM; n = 8), and diluted secretions contained antibacterial activity with LPO-like properties. |
| GO:0016323 basolateral plasma membrane | IDA PMID:19059195 Molecular heterogeneity and alternative splicing of human la... | KEEP AS NON CORE | Summary: Retained as a secondary localization context. Reason: Immunolocalization directly placed most total-LPO signal at the basolateral aspect of airway gland cells, a context-specific localization distinct from LPO's defining extracellular catalytic activity. Supporting Evidence: PMID:19059195 The vast majority of the anti-rhLPO antibody signal (Fig. 6B) was in the basolateral aspect of the cells whereas anti-Ex4p1 showed that proLPO was homogeneously distributed throughout the cells (Fig. 6F). |
| GO:0042742 defense response to bacterium | IDA PMID:12626341 Lactoperoxidase and human airway host defense. | ACCEPT | Summary: Accepted as core LPO biology. Reason: Human airway experiments demonstrate LPO-dependent antibacterial activity against multiple bacterial pathogens. The experimental or curator-attributed assertion is retained with curator deference. Supporting Evidence: PMID:12626341 Thus, a functional LPO system exists in human airways and may contribute to airway host defense against infection. |
| GO:0006979 response to oxidative stress | NAS PMID:8964511 Cloning and sequence analysis of the human salivary peroxida... | MARK AS OVER ANNOTATED | Summary: The annotation overstates the demonstrated role of LPO. Reason: LPO uses hydrogen peroxide to generate reactive antimicrobial products, but this does not by itself establish LPO as a general cellular oxidative-stress response component. |
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Download this section (compressed HTML)Q: Which molecular forms and processing states of LPO predominate in human saliva, milk, and airway surface liquid?
Q: Is UniProt isoform 2 translated and secreted endogenously, and does its residues 26-108 deletion alter heme loading, stability, or catalysis?
Q: How is covalent heme attachment established in human LPO, and what fraction of endogenous enzyme carries fully matured heme?
Q: How do physiological pH, peroxide delivery, and competing donors determine HOSCN/OSCN, HOI, and other oxidant production in each secretion?
Q: Which epithelial peroxide-generating system supplies LPO in each tissue, and is coupling based on proximity or on diffusible peroxide alone?
Q: Does reversible aggregation modulate LPO persistence or antimicrobial activity in native human secretions?
Experiment: Apply isoform-resolved targeted proteomics and N-terminomics to fresh human saliva, milk, and airway surface liquid to quantify canonical, propeptide- retaining, and residues-26-108-deleted LPO forms.
Hypothesis: LPO processing and isoform abundance differ by secretory tissue, with canonical mature LPO predominant but measurable incompletely processed forms.
Experiment: Use CRISPR-edited human salivary- and airway-gland organoids to express each endogenous LPO splice form separately and measure secretion, heme loading, thiocyanate turnover, and bacterial killing.
Hypothesis: The residues-26-108 deletion changes LPO maturation or stability even if the secreted protein retains measurable peroxidase activity.
Experiment: Analyze affinity-purified endogenous human LPO by intact-mass spectrometry, heme-peptide mapping, and structural spectroscopy.
Hypothesis: Endogenous human LPO carries the conserved covalent heme architecture inferred from recombinant and non-human lactoperoxidases.
Experiment: Reconstitute human LPO at secretion-matched concentrations while varying pH, hydrogen-peroxide flux, thiocyanate, iodide, bromide, and urate, and quantify products by orthogonal chemical assays.
Hypothesis: Thiocyanate dominates at basal physiological concentrations, whereas donor competition and pH shift oxidant partitioning in a tissue-specific manner.
Experiment: Perturb DUOX enzymes and LPO independently in differentiated human airway and salivary organoids, then measure extracellular peroxide, HOSCN/OSCN, and pathogen survival with genetic rescue controls.
Hypothesis: Epithelial DUOX activity supplies peroxide required for LPO-dependent antimicrobial chemistry at mucosal surfaces.
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The occupancy, covalent attachment, and maturation pathway of heme in endogenous human LPO have not been established directly; key mechanistic and structural assignments derive from recombinant or non-human LPO.
Gap: The abundance and processing of canonical LPO, incompletely processed LPO, and UniProt isoform 2 across saliva, milk, and airway secretions are unknown. Isoform 2 deletes residues 26-108, extending beyond the annotated propeptide into the canonical mature chain, so activity of a recombinant propeptide-deleted construct does not establish its endogenous function.
Gap: Physiological partitioning among thiocyanate, iodide, bromide, urate, and other donors remains incompletely quantified under the pH, peroxide flux, and substrate concentrations found in different human secretions.
Gap: The tissue-specific peroxide sources and physical or functional coupling of LPO to DUOX-family oxidases in salivary, mammary, and airway epithelia remain incompletely resolved.
Gap: The biological effects of propeptide removal or retention on LPO folding, secretion, stability, and antimicrobial activity are not known.
Gap: Human salivary preparations contain monomeric and reversibly aggregated LPO, but the native oligomeric state and physiological significance of this behavior in intact secretions are unresolved.
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