UROD encodes uroporphyrinogen decarboxylase (URO-D; EC 4.1.1.37), the enzyme that catalyzes the fifth step of heme biosynthesis. It performs the sequential decarboxylation of the four acetate side chains of uroporphyrinogen III to methyl groups, releasing four molecules of CO2 and producing coproporphyrinogen III. The enzyme is cofactor-independent and acts as a homodimer with a single active-site aspartate (Asp86) that binds and activates the substrate and all partially decarboxylated intermediates at one catalytic center. Although either the I or III isomer of uroporphyrinogen can serve as substrate in vitro (the III isomer being processed more efficiently), only coproporphyrinogen III can ultimately be converted to heme. UROD is a soluble, cytosolic protein. Deficiency of UROD causes porphyria cutanea tarda (PCT), the commonest human porphyria, of which the familial form (FPCT) is autosomal dominant with low penetrance; complete/biallelic deficiency causes the severe childhood-onset hepatoerythropoietic porphyria (HEP), regarded as the homozygous form of PCT.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assertion that UROD is active in the cytosol. UROD is a soluble cytosolic enzyme of heme biosynthesis, consistent with the UniProt subcellular location and Reactome. Reason: Correct and well supported. UROD localizes to the cytosol where the fifth step of heme biosynthesis occurs; the IBA is concordant with experimental and UniProt evidence. Supporting Evidence: file:human/UROD/UROD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol Reactome:R-HSA-189425 Cytosolic uroporphyrinogen decarboxylase (UROD) catalyzes the sequntial removal of four carboxylic groups from the acetic acid side chains of uroporphyrinogen III (URO3) to form coproporphyrinogen III (COPRO3) |
| GO:0006783 heme biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assertion that UROD is involved in heme biosynthesis. UROD catalyzes the fifth step of the heme biosynthetic pathway. Reason: This is the core biological process for UROD. The decarboxylation of uroporphyrinogen III to coproporphyrinogen III is an obligate step of heme biosynthesis. Supporting Evidence: file:human/UROD/UROD-uniprot.txt participates in the fifth step in the heme biosynthetic pathway PMID:1634232 uroporphyrinogen decarboxylase (UROD), the fifth |
| GO:0004853 uroporphyrinogen decarboxylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assertion of uroporphyrinogen decarboxylase activity. This is the defining molecular function of UROD, supported experimentally and structurally. Reason: Core molecular function. The IBA is at the correct level of specificity and matches the EC 4.1.1.37 activity assayed for the human enzyme and its orthologs. Supporting Evidence: PMID:14633982 the heme biosynthetic pathway, catalyzes decarboxylation of all four acetate |
| GO:0004853 uroporphyrinogen decarboxylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (IEA) assertion of uroporphyrinogen decarboxylase activity from InterPro/ARBA family membership and the RHEA:19865 / EC 4.1.1.37 mapping. Consistent with the experimentally established function. Reason: The IEA family/EC mapping correctly recovers the core molecular function; UROD carries the URO-D fold and catalytic residues. Supporting Evidence: file:human/UROD/UROD-uniprot.txt side chains of uroporphyrinogen to form coproporphyrinogen and |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic (IEA) location in cytosol derived from the UniProt subcellular-location vocabulary mapping. Matches the established cytosolic localization. Reason: Correct; the UniProt SubCell mapping reproduces the experimentally supported cytosolic localization of this soluble enzyme. Supporting Evidence: file:human/UROD/UROD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0006779 porphyrin-containing compound biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (IEA) assertion that UROD is involved in porphyrin-containing compound biosynthesis. This is a correct parent-level biosynthetic term (coproporphyrinogen III is a porphyrin-containing compound produced en route to heme). Reason: Biologically correct, though more general than the specific heme biosynthetic process term. Acceptable as a broader IEA parent; the core, more informative term is GO:0006783 (heme biosynthetic process). Supporting Evidence: file:human/UROD/UROD-uniprot.txt coproporphyrinogen-III from 5-aminolevulinate: step 4/4. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Non-specific protein-binding (IPI) from a proteome-scale interactome screen (interaction with Q96KN1/LRATD2). Bare protein binding is uninformative and no functional partnership is established. Reason: Per curation guidelines, bare 'protein binding' derived from a high-throughput interactome map does not convey a molecular function. Not removed (experimental IPI is retained) but flagged as over-annotation; not a core function. Supporting Evidence: file:human/UROD/UROD-uniprot.txt P06132; Q96KN1: LRATD2 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: Non-specific protein-binding (IPI) from a proteome-scale interactome analysis. No informative molecular function is conveyed and no biologically meaningful partner is established for UROD. Reason: Bare 'protein binding' from a high-throughput dataset; retained as experimental IPI but flagged as an uninformative over-annotation, not a core function. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: Non-specific protein-binding (IPI) from a systematic interaction-perturbation screen (interaction with Q96KN1). Uninformative bare protein binding. Reason: Bare 'protein binding' from a high-throughput interactome study; retained but flagged as over-annotation, not a core molecular function. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Non-specific protein-binding (IPI) from the HuRI binary reference interactome (several partners including C9JJ79/PILRA, P46019/PHKA2, Q96KN1/LRATD2, Q96PN8/TSSK3). Bare protein binding without functional context. Reason: Bare 'protein binding' from a large-scale Y2H map; retained as experimental IPI but flagged as uninformative over-annotation, not a core function. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Non-specific protein-binding (IPI) from the BioPlex dual cell-line AP-MS interactome (partners including A5A3E0/POTEF, Q08752/PPID). Bare protein binding, no functional partnership established. Reason: Bare 'protein binding' from a high-throughput dataset; retained but flagged as over-annotation, not a core molecular function. |
| GO:0006785 heme B biosynthetic process | IDA PMID:11069625 Co-inheritance of mutations in the uroporphyrinogen decarbox... | ACCEPT | Summary: IDA annotation that UROD is involved in heme B (protoheme/heme b) biosynthesis. UROD produces coproporphyrinogen III, an obligate intermediate on the route to heme b, so this is biologically correct and more specific than the parent heme biosynthetic process term. Reason: Correct and appropriately specific; heme b is the standard heme produced by the pathway and UROD deficiency causes accumulation of upstream porphyrins (porphyria cutanea tarda), confirming its role in the biosynthetic route. Experimental annotation whose full text was read by the curator; retained. Supporting Evidence: PMID:11069625 deficiency of hepatic uroporphyrin- |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | MARK AS OVER ANNOTATED | Summary: HPA immunofluorescence (IDA) placing UROD in the nucleoplasm. UROD is a soluble cytosolic heme-biosynthesis enzyme with no established nuclear function; a nucleoplasmic signal in an antibody-based screen most likely reflects diffuse/incidental staining rather than a functional nuclear localization. Reason: Not the established or functionally relevant localization. The enzyme acts in the cytosol (UniProt, Reactome, IBA/ISS/TAS all agree). The HPA IDA is retained but flagged as an over-annotation; it is not a core localization for UROD. Supporting Evidence: file:human/UROD/UROD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence (IDA) placing UROD in the cytosol. Concordant with the established cytosolic localization of this soluble enzyme. Reason: Correct localization, directly supported by experimental immunofluorescence and consistent with all other lines of evidence. Supporting Evidence: file:human/UROD/UROD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0005829 cytosol | ISS GO_REF:0000024 | ACCEPT | Summary: ISS assertion (transferred from mouse Urod, MGI:98916) that the enzyme is active in the cytosol. Consistent with the cytosolic localization of the mammalian enzyme. Reason: Correct; the sequence-similarity transfer recovers the established cytosolic site of activity of UROD. Supporting Evidence: file:human/UROD/UROD-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol |
| GO:0004853 uroporphyrinogen decarboxylase activity | IDA PMID:11069625 Co-inheritance of mutations in the uroporphyrinogen decarbox... | ACCEPT | Summary: IDA for uroporphyrinogen decarboxylase activity from a study of FPCT-causing UROD mutations, in which hepatic UROD activity deficiency underlies the disease. Reason: Directly supports the core molecular function; experimental annotation curated from the full text. Supporting Evidence: PMID:11069625 deficiency of hepatic uroporphyrin- |
| GO:0004853 uroporphyrinogen decarboxylase activity | IDA PMID:11719352 Functional consequences of naturally occurring mutations in ... | ACCEPT | Summary: IDA for uroporphyrinogen decarboxylase activity; recombinant wild-type and mutant URO-D proteins were expressed and their enzymatic activity measured (29-94% of normal for missense mutants). Reason: Directly supports the core molecular function via recombinant enzymatic assay of the human protein. Supporting Evidence: PMID:11719352 ranged from 29% to 94% of normal |
| GO:0004853 uroporphyrinogen decarboxylase activity | IDA PMID:12071824 Description of a new mutation in hepatoerythropoietic porphy... | ACCEPT | Summary: IDA for uroporphyrinogen decarboxylase activity; HEP patient with F46L UROD showed low UROD activity and recombinant expression confirmed the deleterious effect. Reason: Supports the core molecular function; enzymatic activity measured directly and confirmed by recombinant expression. Supporting Evidence: PMID:12071824 We found low levels of UROD enzymatic activity |
| GO:0004853 uroporphyrinogen decarboxylase activity | IDA PMID:14633982 Structural basis for tetrapyrrole coordination by uroporphyr... | ACCEPT | Summary: IDA for uroporphyrinogen decarboxylase activity backed by crystal structures of URO-D in complex with its coproporphyrinogen I and III products, defining how one catalytic center decarboxylates all four acetate groups. Reason: Strong structural/biochemical support for the core molecular function. Supporting Evidence: PMID:14633982 the heme biosynthetic pathway, catalyzes decarboxylation of all four acetate |
| GO:0004853 uroporphyrinogen decarboxylase activity | IDA PMID:21668429 Hepatoerythropoietic porphyria due to a novel mutation in th... | ACCEPT | Summary: IDA for uroporphyrinogen decarboxylase activity; recombinant UROD (wild-type and G170D HEP variant) purified and assayed against uroporphyrinogen I and III substrates. Reason: Directly supports the core molecular function with a purified-protein enzymatic assay on both isomer substrates. Supporting Evidence: PMID:21668429 The recombinant UROD protein showed a relative activity of 17% and 60% |
| GO:0006778 porphyrin-containing compound metabolic process | IDA PMID:12071824 Description of a new mutation in hepatoerythropoietic porphy... | ACCEPT | Summary: IDA that UROD is involved in porphyrin-containing compound metabolism, from a HEP study showing UROD deficiency and abnormal (poly-carboxylated) porphyrin excretion. Reason: Biologically correct, though this is a high-level parent (metabolic) term. The more informative and core biological process is heme biosynthesis (GO:0006783); this parent is acceptable and retained. Supporting Evidence: PMID:12071824 profound deficiency (<10% of normal activity) of uroporphyrinogen decarboxylase |
| GO:0006787 porphyrin-containing compound catabolic process | IDA PMID:11069625 Co-inheritance of mutations in the uroporphyrinogen decarbox... | MODIFY | Summary: IDA annotating UROD to porphyrin-containing compound CATABOLIC process. This is directionally incorrect: UROD is an anabolic enzyme. Its decarboxylation of uroporphyrinogen III to coproporphyrinogen III is a heme-biosynthetic step, not degradation of a porphyrin-containing compound. Reason: The enzymatic reaction is genuine, but the process branch is wrong. UROD contributes to biosynthesis (production of coproporphyrinogen III on the route to heme), not catabolism. This appears to be a systematic mis-mapping applied to several UROD disease/structural papers. Replace with the biosynthetic terms that the reaction actually supports. Proposed replacements: heme biosynthetic process porphyrin-containing compound biosynthetic process Supporting Evidence: file:human/UROD/UROD-uniprot.txt participates in the fifth step in the heme biosynthetic pathway PMID:11069625 deficiency of hepatic uroporphyrin- |
| GO:0006787 porphyrin-containing compound catabolic process | IDA PMID:11719352 Functional consequences of naturally occurring mutations in ... | MODIFY | Summary: IDA annotating UROD to porphyrin-containing compound CATABOLIC process. As above, this is directionally wrong for an enzyme whose reaction is part of heme biosynthesis. Reason: The recombinant enzymatic-activity data in this paper support decarboxylase activity, but the correct process is biosynthetic, not catabolic. Replace with heme / porphyrin biosynthetic process. Proposed replacements: heme biosynthetic process porphyrin-containing compound biosynthetic process Supporting Evidence: PMID:11719352 ranged from 29% to 94% of normal |
| GO:0006787 porphyrin-containing compound catabolic process | IDA PMID:14633982 Structural basis for tetrapyrrole coordination by uroporphyr... | MODIFY | Summary: IDA annotating UROD to porphyrin-containing compound CATABOLIC process. The structural paper establishes decarboxylase activity, but the biological process direction is wrong. Reason: Decarboxylation of uroporphyrinogen to coproporphyrinogen is a biosynthetic step of heme synthesis, not porphyrin catabolism. Replace with the biosynthetic process terms. Proposed replacements: heme biosynthetic process porphyrin-containing compound biosynthetic process Supporting Evidence: PMID:14633982 the heme biosynthetic pathway, catalyzes decarboxylation of all four acetate |
| GO:0006787 porphyrin-containing compound catabolic process | IDA PMID:21668429 Hepatoerythropoietic porphyria due to a novel mutation in th... | MODIFY | Summary: IDA annotating UROD to porphyrin-containing compound CATABOLIC process. The HEP study supports decarboxylase activity, but this catabolic BP is directionally incorrect. Reason: UROD acts in heme biosynthesis; the reaction produces coproporphyrinogen III on the route to heme rather than degrading a porphyrin. Replace with heme / porphyrin biosynthetic process. Proposed replacements: heme biosynthetic process porphyrin-containing compound biosynthetic process Supporting Evidence: PMID:21668429 results from a deficiency of uroporphyrinogen decarboxylase (UROD) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-189425 | ACCEPT | Summary: TAS (Reactome) location in cytosol for the UROD reaction converting uroporphyrinogen III to coproporphyrinogen III. Consistent with the established cytosolic localization. Reason: Correct; Reactome explicitly describes cytosolic UROD. Supporting Evidence: Reactome:R-HSA-189425 Cytosolic uroporphyrinogen decarboxylase (UROD) catalyzes the sequntial removal of four carboxylic groups from the acetic acid side chains of uroporphyrinogen III (URO3) to form coproporphyrinogen III (COPRO3) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-190182 | ACCEPT | Summary: TAS (Reactome) location in cytosol for the UROD reaction converting uroporphyrinogen I to coproporphyrinogen I (the less-efficient isomer I reaction). Consistent with the established cytosolic localization. Reason: Correct; Reactome describes cytosolic UROD activity on the isomer I substrate. Supporting Evidence: Reactome:R-HSA-190182 Cytosolic uroporphyrinogen decarboxylase (UROD) catalyzes the sequential removal of four carboxylic groups from the acetic acid side chains of uroporphyrinogen I (URO1) to form coproporphyrinogen I (COPRO1) |
| GO:0006783 heme biosynthetic process | IC PMID:18004775 Human uroporphyrinogen III synthase: NMR-based mapping of th... | ACCEPT | Summary: IC (inferred by curator) that UROD is involved in heme biosynthesis, based on its uroporphyrinogen decarboxylase activity (with:GO:0004853). UROD is one of the cytosolic heme-biosynthesis enzymes. Reason: Core biological process, correctly inferred from the enzymatic activity. Although this paper's primary subject is uroporphyrinogen III synthase, it treats UROD as one of the cytosolic heme-biosynthesis enzymes; the curator inference to heme biosynthesis is sound. Supporting Evidence: PMID:18004775 cytosolic enzymes of heme biosynthesis file:human/UROD/UROD-uniprot.txt participates in the fifth step in the heme biosynthetic pathway |
| GO:0004853 uroporphyrinogen decarboxylase activity | IDA PMID:18004775 Human uroporphyrinogen III synthase: NMR-based mapping of th... | ACCEPT | Summary: IDA for uroporphyrinogen decarboxylase activity anchored to a study that expressed and purified the cytosolic heme-biosynthesis enzymes (including URO-decarboxylase) and probed a possible URO-synthase/URO-decarboxylase complex. Reason: Supports the core molecular function. The paper foregrounds uroporphyrinogen III synthase in its title, but per policy an experimental annotation whose full text the curator read is not overruled from the abstract alone; the abstract confirms preparation of purified URO-decarboxylase. Retained as supporting the enzymatic activity. Supporting Evidence: PMID:18004775 cytosolic enzymes of heme biosynthesis |
| GO:0004853 uroporphyrinogen decarboxylase activity | TAS PMID:1634232 Characterization of a new mutation (R292G) and a deletion at... | ACCEPT | Summary: TAS for uroporphyrinogen decarboxylase activity; the paper describes UROD as the fifth enzyme of the heme biosynthetic pathway and studies HEP-causing mutations. Reason: Supports the core molecular function; author statement (TAS) that UROD is the fifth heme biosynthetic enzyme. Supporting Evidence: PMID:1634232 uroporphyrinogen decarboxylase (UROD), the fifth |
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Download this section (compressed HTML)Q: Does UROD have any biologically meaningful non-cytosolic (e.g. nuclear) pool or moonlighting function, or is the HPA nucleoplasmic immunofluorescence signal purely incidental?
Q: Are any of the high-throughput interactome partners (e.g. PPID, PHKA2, LRATD2) reproducible and functionally relevant to UROD folding, stability, or heme-pathway channeling?
Experiment: Metabolic-channeling / complex-formation assays (co-IP, proximity labeling, size-exclusion with purified proteins) to test whether UROD physically associates with adjacent cytosolic heme-biosynthesis enzymes (UROS, HMBS) under physiological conditions, given that NMR did not detect a stable URO-synthase/URO-decarboxylase complex.
Experiment: Quantitative subcellular fractionation and validated-antibody immunofluorescence to confirm that endogenous UROD is essentially confined to the cytosol and to assess the reported nucleoplasmic signal.
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