BLVRA is the soluble biliverdin IX-alpha reductase (EC 1.3.1.24) that converts biliverdin IX-alpha to bilirubin IX-alpha in the cytosolic terminal reduction step of heme catabolism. It uses NADPH or NADH with pH-dependent preferences; NADPH is generally favored as the physiological donor. Its preference for IX-alpha distinguishes it from the IX-beta reductase BLVRB, although BLVRA also reduces some other synthetic biliverdin configurations poorly. Purified human liver BLVRA contains approximately one zinc ion per protein molecule, and zinc binding is also demonstrated in recombinant human protein. Impaired BLVRA activity can contribute to biliverdin accumulation and hyperbiliverdinemia (green jaundice), particularly in the setting of cholestasis or liver failure. Human-cell experiments also report BLVRA binding to ERK and supporting MEK–ERK complex assembly and ERK nuclear trafficking.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004074 biliverdin reductase [NAD(P)H] activity | IBA GO_REF:0000033 | ACCEPT | Summary: The inherited biliverdin-reductase function agrees with direct human enzymology. Reason: The saved PTHR43377 PAINT row places GO:0004074 at IBD node PTN008681150 and includes experimentally characterized human P53004 among descendant seeds. Target self-inclusion is legitimate experimental grounding, not circular inference. Human enzymology independently supports the inherited activity; no contrary target-specific loss is evident. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt |
| GO:0000166 nucleotide binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Nucleotide binding describes the cofactor-binding component of the enzyme. Reason: The InterPro-derived annotation is consistent with the NAD(P)-binding domain and direct cofactor kinetics. Retain this biochemical attribute outside the core synthesis, which uses the complete reductase reaction; nucleotide binding alone does not specify a separate physiological function. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt |
| GO:0004074 biliverdin reductase [NAD(P)H] activity | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic mapping captures the established reductase reaction. Reason: GO_REF:0000120 combines automatic mappings. Direct human enzymology in PMID7929092, PMID8424666 and PMID8631357 establishes the reductase activity. The reversible reaction is conventionally written in the oxidative direction in GO; physiological biliverdin reduction uses its reverse direction and is fully consistent with this term. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt |
| GO:0005737 cytoplasm | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Cytoplasm is a correct broad location for a soluble cytosolic enzyme. Reason: The InterPro-derived location is compatible with human cytosolic purification. Retain the existing broad assertion outside the core location field, which uses experimentally supported cytosol; breadth alone does not make this location biologically false. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt location mapping agrees with cytosolic human enzymology. Reason: GO_REF:0000044 maps curated subcellular location vocabulary. Human liver cytosolic isolation independently supports the relevant functional compartment; this mapping does not establish that BLVRA is exclusively cytosolic in every signaling context. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt Cytoplasm, cytosol |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Zinc binding is experimentally supported as an enzyme-associated property. Reason: PMID8631357 reports approximately one zinc per purified human liver protein by atomic absorption. Isotope exchange additionally demonstrates zinc binding in both purified tissue protein and recombinant human protein. The abstract does not separately quantify one zinc per recombinant molecule. Retain this experimentally established enzyme-associated property outside the reaction-based core; an indispensable catalytic metal requirement under every assay condition was not established. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt PMID:8631357 protein purified from human liver contains Zn at an approximately 1:1 molar ratio. |
| GO:0042167 heme catabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: BLVRA performs the terminal reduction reaction in heme catabolism. Reason: The InterPro-based process assertion is consistent with direct conversion of the heme-breakdown intermediate biliverdin into bilirubin. BLVRA itself catalyzes this step, rather than being only a substrate or a perturbational requirement. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt |
| GO:0106276 biliberdin reductase (NADH) activity | IEA GO_REF:0000120 | ACCEPT | Summary: The NADH-specific electronic reaction is supported by human enzyme assays. Reason: The combined automatic annotation agrees with cofactor-use experiments in PMID7929092, PMID8424666 and PMID8631357. NADH-dependent catalysis is real even where NADPH is favored physiologically. The original GOA label, including its spelling, is preserved as source data. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt Uses the reactants NADH or NADPH |
| GO:0106277 biliverdin reductase (NADPH) activity | IEA GO_REF:0000116 | ACCEPT | Summary: The Rhea-derived NADPH reaction is supported experimentally. Reason: The GO_REF:0000116 reaction mapping agrees with human NADPH-dependent biliverdin reduction. A preferred physiological donor does not imply that the enzyme cannot use NADH. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt |
| GO:0005515 protein binding | IPI PMID:18463290 Human biliverdin reductase is an ERK activator; hBVR is an E... | MODIFY | Summary: Refine the demonstrated MAPK1 interaction to MAP-kinase binding. Reason: GOA identifies MAPK1/P28482. The cached Discussion and selected primary Results/Figure 1 describe human-cell co-immunoprecipitation and interaction-dependent ERK activation, including a kinase-deficient BLVRA control. GO:0051019 captures this partner class. It does not assign ERK phosphorylation to BLVRA or equate binding with intrinsic kinase activity. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:18463290 in the complex, hBVR functions as a scaffold. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | UNDECIDED | Summary: Retain the positive LNX1 association as evidence while deferring its molecular-function refinement. Reason: IntAct GOA identifies LNX1/Q8TBB1, and the published BLVRA and LNX1 UniProt records reciprocally list this pair. This positive association is not rejected. The canonical LNX1 record identifies an E3 ligase, but isoform 2 replaces residues 1–127, including the RING region at 41–79. PMID25416956 has no pair-level assay table in its available extraction. Consequently, the gene-level partner identity does not establish that the screened construct was the E3-containing form needed to justify GO:0031625. The same pair in three related screens is not three independent physiological validations. Use UNDECIDED pending the exact partner construct or isoform and its relevant binding context; neither a false interaction nor ubiquitination regulation is inferred. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt P53004; Q8TBB1: LNX1; NbExp=5; file:human/LNX1/LNX1-uniprot.txt Full=E3 ubiquitin-protein ligase LNX; |
| GO:0005515 protein binding | IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m... | UNDECIDED | Summary: Retain the positive LNX1 association as evidence while deferring its molecular-function refinement. Reason: IntAct GOA identifies LNX1/Q8TBB1, and the published BLVRA and LNX1 UniProt records reciprocally list this pair. This positive association is not rejected. The canonical LNX1 record identifies an E3 ligase, but isoform 2 replaces residues 1–127, including the RING region at 41–79. PMID29892012 does not expose the pair-specific mutant construct in the available extraction. Consequently, the gene-level partner identity does not establish that the screened construct was the E3-containing form needed to justify GO:0031625. The same pair in three related screens is not three independent physiological validations. Use UNDECIDED pending the exact partner construct or isoform and its relevant binding context; neither a false interaction nor ubiquitination regulation is inferred. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt P53004; Q8TBB1: LNX1; NbExp=5; file:human/LNX1/LNX1-uniprot.txt Full=E3 ubiquitin-protein ligase LNX; |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | UNDECIDED | Summary: Retain the positive LNX1 association as evidence while deferring its molecular-function refinement. Reason: IntAct GOA identifies LNX1/Q8TBB1, and the published BLVRA and LNX1 UniProt records reciprocally list this pair. This positive association is not rejected. The canonical LNX1 record identifies an E3 ligase, but isoform 2 replaces residues 1–127, including the RING region at 41–79. PMID31515488 pair-level supplementary clone data were not inspected. Consequently, the gene-level partner identity does not establish that the screened construct was the E3-containing form needed to justify GO:0031625. The same pair in three related screens is not three independent physiological validations. Use UNDECIDED pending the exact partner construct or isoform and its relevant binding context; neither a false interaction nor ubiquitination regulation is inferred. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt P53004; Q8TBB1: LNX1; NbExp=5; file:human/LNX1/LNX1-uniprot.txt Full=E3 ubiquitin-protein ligase LNX; |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Cytosolic localization agrees with direct biochemical evidence. Reason: Retain the HPA immunofluorescence-based curator assertion. The underlying image was not independently inspected; orthogonal human cytosolic purification in PMID7929092 and PMID8424666 supports the location. No exclusive localization is inferred. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt Cytoplasm, cytosol |
| GO:0106276 biliberdin reductase (NADH) activity | EXP PMID:10858451 Studies on the specificity of the tetrapyrrole substrate for... | ACCEPT | Summary: NADH-dependent reduction is established for human BLVRA. Reason: The cited abstract directly examines human reductase substrate specificity but does not detail the cofactor-specific assay. Retain the curator EXP assignment with independent NADH evidence from PMID7929092 and PMID8424666; the source-specific experimental protocol remains uninspected. Supporting Evidence: |
| GO:0106277 biliverdin reductase (NADPH) activity | EXP PMID:10858451 Studies on the specificity of the tetrapyrrole substrate for... | ACCEPT | Summary: NADPH-dependent reduction is established for human BLVRA. Reason: PMID10858451 addresses human enzyme substrate specificity; its cached abstract does not expose the NADPH-specific protocol. The curator EXP assertion is consistent with independent human NADPH kinetics in PMID7929092 and PMID8424666, without pretending the original assay was re-read. Supporting Evidence: |
| GO:0106277 biliverdin reductase (NADPH) activity | EXP PMID:7929092 Biliverdin-IX alpha reductase and biliverdin-IX beta reducta... | ACCEPT | Summary: Purified human liver reductase uses NADPH. Reason: The complete abstract distinguishes IX-alpha-preferring isozymes III/IV from IX-beta-preferring I/II and reports NADPH and NADH use. NADPH is proposed as the physiological donor on kinetic grounds. These biochemical forms are not equated to current curated protein isoforms. The shared dual-donor excerpt is recorded with the NADH annotation from the same paper. Supporting Evidence: |
| GO:0106277 biliverdin reductase (NADPH) activity | EXP PMID:8424666 Purification and characterization of human biliverdin reduct... | ACCEPT | Summary: Human liver biliverdin reductase has NADPH-dependent activity. Reason: The purified human enzyme uses NADPH preferentially in the reported alkaline-pH assays. This is direct support for the cofactor-specific reaction, not a universal claim that intracellular pH has that value. Supporting Evidence: PMID:8424666 NADPH was the preferred cofactor |
| GO:0106277 biliverdin reductase (NADPH) activity | EXP PMID:8631357 Human biliverdin IXalpha reductase is a zinc-metalloprotein.... | ACCEPT | Summary: Human tissue and recombinant BLVRA show NADPH-dependent reduction. Reason: The complete abstract links human cDNA to purified human protein and reports dual pH/cofactor behavior in the expressed protein. E. coli is the expression host, not the species of the assayed gene product. Supporting Evidence: PMID:8631357 demonstrated dual pH and cofactor dependence. |
| GO:0004074 biliverdin reductase [NAD(P)H] activity | IDA PMID:7929092 Biliverdin-IX alpha reductase and biliverdin-IX beta reducta... | ACCEPT | Summary: Human liver IX-alpha reductase catalyzes biliverdin reduction. Reason: The purified III/IV enzyme forms preferentially use IX-alpha among the tested biliverdin isomers. The abstract supports preference rather than an absolute inability to reduce every other synthetic substrate. Supporting Evidence: PMID:7929092 isozymes III and IV preferred biliverdin-IX alpha |
| GO:0004074 biliverdin reductase [NAD(P)H] activity | IDA PMID:8424666 Purification and characterization of human biliverdin reduct... | ACCEPT | Summary: The purified human enzyme reduces biliverdin to bilirubin. Reason: Human liver purification and characterization directly establish the reaction. Differences from rat protein reported in the paper are not evidence that the human annotation is misattributed. The complete reaction-and-compartment sentence from this paper is quoted in the reductase core. Supporting Evidence: |
| GO:0004074 biliverdin reductase [NAD(P)H] activity | IDA PMID:8631357 Human biliverdin IXalpha reductase is a zinc-metalloprotein.... | ACCEPT | Summary: Purified and recombinant human BLVRA perform the reductase reaction. Reason: The human 296-residue cDNA was matched to peptides of purified protein and expressed for functional characterization. The abstract identifies the biliverdin-to-bilirubin reaction and the recombinant enzyme retains dual cofactor dependence, quoted with the NADPH annotation from this paper. Supporting Evidence: |
| GO:0005829 cytosol | IDA PMID:7929092 Biliverdin-IX alpha reductase and biliverdin-IX beta reducta... | ACCEPT | Summary: The catalytic enzyme was purified from human liver cytosol. Reason: The complete abstract explicitly places the starting activity in human liver cytosolic fractions. Retain the original is_active_in qualifier; it is more informative here than a generic protein-location statement. Supporting Evidence: PMID:7929092 human liver cytosolic fractions |
| GO:0005829 cytosol | IDA PMID:8424666 Purification and characterization of human biliverdin reduct... | ACCEPT | Summary: Cytosol is supported as a compartment of reductase activity. Reason: The abstract describes biliverdin reduction by the cytosolic enzyme and human liver purification. Retain is_active_in as supplied by GOA; the assay does not rule out additional context-dependent compartments. The complete reaction-and-compartment sentence from this paper is quoted in the reductase core. Supporting Evidence: |
| GO:0106276 biliberdin reductase (NADH) activity | IDA PMID:7929092 Biliverdin-IX alpha reductase and biliverdin-IX beta reducta... | ACCEPT | Summary: Purified human reductase can use NADH as electron donor. Reason: The abstract directly reports NADH use by the purified enzyme forms. Lower apparent affinity than for NADPH does not invalidate the NADH reaction annotation. Supporting Evidence: PMID:7929092 NADPH and NADH as electron donors for the reduction of biliverdin. |
| GO:0106276 biliberdin reductase (NADH) activity | IDA PMID:8424666 Purification and characterization of human biliverdin reduct... | ACCEPT | Summary: Human reductase uses NADH efficiently under the reported acidic-pH conditions. Reason: The complete human liver-enzyme abstract states that NADH is more effective at pH 6.0–7.0. Retain the experimentally demonstrated cofactor reaction without extrapolating its relative flux in vivo. Supporting Evidence: PMID:8424666 NADH was the more effective cofactor |
| GO:0106276 biliberdin reductase (NADH) activity | IDA PMID:8631357 Human biliverdin IXalpha reductase is a zinc-metalloprotein.... | ACCEPT | Summary: Recombinant human BLVRA retains NADH-dependent reduction. Reason: The human protein expressed in E. coli retains dual cofactor and pH dependence. The abstract also discusses possible physiological NADH use in human BLVRA. The shared recombinant-enzyme excerpt is recorded with the NADPH annotation from this paper. Supporting Evidence: |
| GO:0042167 heme catabolic process | IDA PMID:10858451 Studies on the specificity of the tetrapyrrole substrate for... | ACCEPT | Summary: The reductase reaction is a catalytic step of heme breakdown. Reason: The cited abstract characterizes human biliverdin-reductase substrate specificity. Combined with the chemically established conversion of a heme-breakdown intermediate, this supports participation in heme catabolism. No unobserved heme-cleavage activity is assigned to BLVRA. Supporting Evidence: |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Retain the curator-reported urinary exosome detection outside the core. Reason: The complete abstract describes human urinary-exosome proteomics, but the BLVRA-specific peptide/table entry is not in the normal abstract-only cache and was not independently verified. Retain the HDA detection as a curator-supported non-core association; do not assert that BLVRA is common vesicle cargo, a secretion factor, or incapable of extracellular function. Supporting Evidence: PMID:19056867 we used LC-MS/MS to profile the proteome of human urinary exosomes. |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: Retain the curator-reported B-cell exosome detection outside the core. Reason: The abstract reports exosome proteomics but does not expose the BLVRA-specific table entry. Keep the curated HDA association with that limitation; detection does not itself establish an extracellular catalytic role or a role in exosome biogenesis. Supporting Evidence: PMID:20458337 we first analyzed the total proteome of highly purified B cell-derived exosomes |
| GO:0005829 cytosol | TAS Reactome:R-HSA-189384 | ACCEPT | Summary: The curated cytosolic reaction location agrees with human purification studies. Reason: The saved Reactome summary names the biliverdin-reduction reaction but does not itself display its compartment. Retain the Reactome TAS location with independent human cytosolic enzyme evidence from PMID7929092 and PMID8424666, rather than presenting the summary as a location experiment. Supporting Evidence: Reactome:R-HSA-189384 BIL is formed from the reduction of biliverdin (BV) by bilverdin reductases BLVRA and BLVRB |
| GO:0004074 biliverdin reductase [NAD(P)H] activity | IDA PMID:10858451 Studies on the specificity of the tetrapyrrole substrate for... | ACCEPT | Summary: Human biliverdin-IX-alpha reductase has experimentally characterized substrate preference. Reason: The complete abstract compares human IX-alpha and IX-beta enzymes with synthetic biliverdins. Bridging propionates favor IX-alpha-reductase activity, while other tested configurations can be poor substrates. This supports the core reaction without the older review’s categorical claim of exclusive IX-alpha specificity. Supporting Evidence: PMID:10858451 All other configurations studied were substrates for human biliverdin-IXalpha reductase, albeit poor ones. |
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Download this section (compressed HTML)Q: Which endogenous human contexts require the BLVRA–LNX1 association, and which LNX1 isoform and interaction interface were represented in the curated high-throughput pairs?
Q: How do the documented interaction-dependent MAPK effects relate to BLVRA catalytic activities under physiological expression levels?
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