BLVRA

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004074 biliverdin reductase [NAD(P)H] activity	IBA GO_REF:0000033	ACCEPT	Summary: Core molecular function of BLVRA, propagated by phylogenetic inference from the biliverdin reductase family tree (PANTHER PTN008681150). Fully consistent with the direct experimental characterization of the human enzyme. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt Reduces the gamma-methene bridge of the open tetrapyrrole, biliverdin IXalpha, to bilirubin with the concomitant oxidation of a NADH or NADPH cofactor
GO:0000166 nucleotide binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Generic InterPro-derived binding term reflecting the NAD(P)-binding Rossmann domain. True but uninformative on its own; it describes a substructure of the catalytic mechanism rather than a distinct function. Keep as non-core. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt KM=3.2 uM for NADPH
GO:0004074 biliverdin reductase [NAD(P)H] activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation of the core MF via InterPro/EC mapping (EC:1.3.1.24). Agrees with the experimental IDA annotations; retained as core. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt Reduces the gamma-methene bridge of the open tetrapyrrole, biliverdin IXalpha, to bilirubin with the concomitant oxidation of a NADH or NADPH cofactor
GO:0005737 cytoplasm	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Correct but less specific than the experimentally supported cytosol annotation. The enzyme is a soluble cytosolic protein; keep as non-core in favor of the more precise GO:0005829 (cytosol). Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt Cytoplasm, cytosol
GO:0005829 cytosol	IEA GO_REF:0000044	ACCEPT	Summary: Electronic subcellular-location annotation consistent with experimental IDA evidence that BVR-A is a cytosolic enzyme. Retained as the functional location. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt Cytoplasm, cytosol
GO:0008270 zinc ion binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: BVR-A purified from human liver contains ~1 Zn per subunit and exogenous Zn inhibits the NADPH-dependent (but not NADH-dependent) activity, so zinc binding is real. However UniProt records the cofactor/binding assignment as an inference (ECO:0000305/ECO:0000303) and the crystal structure (2H63) is NADP-bound without a modeled zinc; its physiological requirement is not fully established. Keep as a non-core cofactor-binding attribute rather than a core MF. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt Binds 1 zinc ion per subunit.
GO:0042167 heme catabolic process	IEA GO_REF:0000002	ACCEPT	Summary: Core biological process: BVR-A performs the terminal reduction step of the heme degradation pathway. Electronic annotation agrees with the experimental IDA annotation to the same term. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt Porphyrin-containing compound metabolism; protoheme
GO:0106276 biliberdin reductase (NADH) activity	IEA GO_REF:0000120	ACCEPT	Summary: NADH-specific child of the core biliverdin reductase activity. Electronic (Rhea/ARBA) annotation matching the experimentally demonstrated NADH-dependent activity at acidic pH; retained. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt Uses the reactants NADH or NADPH depending on the
GO:0106277 biliverdin reductase (NADPH) activity	IEA GO_REF:0000116	ACCEPT	Summary: NADPH-specific child of the core activity (NADPH is the probable physiological cofactor). Electronic Rhea annotation agreeing with experimental EXP/IDA evidence; retained. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt NADPH, however, is the probable reactant in biological
GO:0005515 protein binding	IPI PMID:18463290 Human biliverdin reductase is an ERK activator; hBVR is an E...	MARK AS OVER ANNOTATED	Summary: IPI capturing the BVR-A interaction with MAPK1/ERK2 (UniProtKB:P28482), which underlies the moonlighting ERK-scaffold function. Real and mechanistically meaningful, but the bare "protein binding" term is uninformative; the specific function is better represented by the protein serine/threonine kinase / ERK-scaffold core function. Not removed (experimental IPI); flagged as over-annotation of the generic term. Supporting Evidence: PMID:18463290 Human biliverdin reductase (hBVR) is a recently described Ser/Thr/Tyr kinase in the MAPK insulin/insulin-like growth factor 1 (IGF1)-signaling cascade
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: IPI from a large-scale human interactome map recording an interaction with LNX1 (UniProtKB:Q8TBB1). Bare "protein binding" is uninformative and the biological significance of this high-throughput interaction is unclear. Not removed (experimental IPI); marked as over-annotation.
GO:0005515 protein binding	IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m...	MARK AS OVER ANNOTATED	Summary: IPI from an interactome-perturbation study, again recording the LNX1 (Q8TBB1) interaction. Uninformative bare protein-binding term; not removed (experimental IPI) but marked as over-annotation.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: IPI from a large-scale variant-interaction study, LNX1 (Q8TBB1) partner. Bare protein binding; not removed (experimental IPI) but marked as over-annotation of an uninformative generic term.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Immunofluorescence-based (HPA) localization to the cytosol, consistent with the biochemically established cytosolic localization of BVR-A. Accepted as the functional location. 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: Experimental (EXP) support for the NADH-dependent biliverdin reductase activity, from kinetic characterization of the human enzyme. Core catalytic function; accepted. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt Uses the reactants NADH or NADPH depending on the
GO:0106277 biliverdin reductase (NADPH) activity	EXP PMID:10858451 Studies on the specificity of the tetrapyrrole substrate for...	ACCEPT	Summary: Experimental support for the NADPH-dependent biliverdin reductase activity. NADPH is the probable physiological cofactor. Core catalytic function; accepted. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt NADPH, however, is the probable reactant in biological
GO:0106277 biliverdin reductase (NADPH) activity	EXP PMID:7929092 Biliverdin-IX alpha reductase and biliverdin-IX beta reducta...	ACCEPT	Summary: Experimental support from purification of human liver biliverdin-IX alpha reductase; NADPH assumed to be the physiological electron donor. Core catalytic function; accepted. Supporting Evidence: PMID:7929092 It was assumed that NADPH rather than NADH was the
GO:0106277 biliverdin reductase (NADPH) activity	EXP PMID:8424666 Purification and characterization of human biliverdin reduct...	ACCEPT	Summary: Experimental support from purification/characterization of human biliverdin reductase, showing dual cofactor use with NADPH preferred at alkaline pH. Core catalytic function; accepted. Supporting Evidence: PMID:8424666 At pH 6.0-7.0 the NADH was the more effective cofactor, whereas at pH
GO:0106277 biliverdin reductase (NADPH) activity	EXP PMID:8631357 Human biliverdin IXalpha reductase is a zinc-metalloprotein....	ACCEPT	Summary: Experimental support from characterization of purified and recombinant human BVR-A, demonstrating dual pH/cofactor specificity including NADPH use. Core catalytic function; accepted. Supporting Evidence: PMID:8631357 BVR is unique among enzymes characterized to date in that it has dual pH/cofactor (NADH, NADPH) specificity
GO:0004074 biliverdin reductase [NAD(P)H] activity	IDA PMID:7929092 Biliverdin-IX alpha reductase and biliverdin-IX beta reducta...	ACCEPT	Summary: Direct assay of purified human liver biliverdin-IX alpha reductase. This is a primary line of experimental evidence for the core molecular function; accepted. Supporting Evidence: PMID:7929092 isozymes III and IV preferred biliverdin-IX
GO:0004074 biliverdin reductase [NAD(P)H] activity	IDA PMID:8424666 Purification and characterization of human biliverdin reduct...	ACCEPT	Summary: Direct experimental demonstration that the purified human liver enzyme converts biliverdin to bilirubin. Core molecular function; accepted. Supporting Evidence: PMID:8424666 Conversion of biliverdin to bilirubin is catalyzed by the cytosolic enzyme biliverdin reductase
GO:0004074 biliverdin reductase [NAD(P)H] activity	IDA PMID:8631357 Human biliverdin IXalpha reductase is a zinc-metalloprotein....	ACCEPT	Summary: Direct assay of purified and E. coli-expressed human BVR-A converting biliverdin to bilirubin. Core molecular function; accepted. Supporting Evidence: PMID:8631357 Biliverdin IXalpha reductase (BVR) catalyzes the conversion of the heme b degradation product, biliverdin, to bilirubin
GO:0005829 cytosol	IDA PMID:7929092 Biliverdin-IX alpha reductase and biliverdin-IX beta reducta...	ACCEPT	Summary: BVR-A activity was isolated from human liver cytosolic fractions, establishing the cytosol as the site of the catalytic activity (is_active_in). Accepted as the functional location. Supporting Evidence: PMID:7929092 in human liver cytosolic
GO:0005829 cytosol	IDA PMID:8424666 Purification and characterization of human biliverdin reduct...	ACCEPT	Summary: Experimental evidence that biliverdin-to-bilirubin conversion is catalyzed by the cytosolic enzyme, supporting cytosol as the active-in location. Accepted. Supporting Evidence: PMID:8424666 catalyzed by the cytosolic enzyme
GO:0106276 biliberdin reductase (NADH) activity	IDA PMID:7929092 Biliverdin-IX alpha reductase and biliverdin-IX beta reducta...	ACCEPT	Summary: Direct evidence that the purified human enzyme uses NADH as an electron donor for biliverdin reduction. NADH-specific child of the core activity; accepted. Supporting Evidence: PMID:7929092 The purified enzymes used 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: Direct evidence for NADH-dependent activity (more effective cofactor at acidic pH). NADH-specific child of the core biliverdin reductase activity; accepted. Supporting Evidence: PMID:8424666 At pH 6.0-7.0 the 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: Direct evidence for NADH-dependent activity as part of the demonstrated dual pH/cofactor specificity of human BVR-A. NADH-specific child of core activity; accepted. Supporting Evidence: PMID:8631357 the human enzyme may also use NADH as cofactor
GO:0042167 heme catabolic process	IDA PMID:10858451 Studies on the specificity of the tetrapyrrole substrate for...	ACCEPT	Summary: BVR-A performs the terminal reduction step of heme catabolism, converting biliverdin IX-alpha to bilirubin. Core biological process; accepted. Supporting Evidence: file:human/BLVRA/BLVRA-uniprot.txt Reduces the gamma-methene bridge of the open tetrapyrrole, biliverdin IXalpha, to bilirubin
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: High-throughput MS detection of BVR-A in urinary exosomes. BVR-A is a soluble cytosolic enzyme that is a common cargo of secreted vesicles; this does not reflect a functional extracellular location. Keep as non-core. Supporting Evidence: PMID:19056867 the analysis identified 1132 proteins unambiguously
GO:0070062 extracellular exosome	HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote...	KEEP AS NON CORE	Summary: High-throughput MS detection of BVR-A in B-cell-derived exosomes. As with the urinary-exosome dataset, this reflects vesicular cargo rather than a functional extracellular location. Keep as non-core. Supporting Evidence: PMID:20458337 highly purified B cell-derived exosomes
GO:0005829 cytosol	TAS Reactome:R-HSA-189384	ACCEPT	Summary: Reactome traceable-author-statement placing the BLVRA-catalyzed biliverdin-to-bilirubin reaction in the cytosol. Consistent with experimental localization; accepted. 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: Direct kinetic characterization of the human biliverdin-IX alpha reductase substrate specificity, supporting the core molecular function. Accepted. Supporting Evidence: PMID:10858451 at least one "bridging propionate" is necessary for

Gene Description

Existing Annotations Review

Core Functions

Cytosolic NAD(P)H-dependent biliverdin reductase catalyzing the terminal step of heme catabolism: reduction of biliverdin IX-alpha to bilirubin IX-alpha, using NADH at acidic pH and NADPH (the probable physiological cofactor) at alkaline pH. Specific for the IX-alpha isomer.

References

📚 Additional Documentation

Notes

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