Affinage

CYB5R3

NADH-cytochrome b5 reductase 3 · UniProt P00387

Length
301 aa
Mass
34.2 kDa
Annotated
2026-06-09
69 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/9 claims corpus-supported (89%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CYB5R3 is an NADH-dependent flavoreductase that maintains cellular redox balance and serves as a hub coupling NADH oxidation to nitric oxide signaling, coenzyme Q metabolism, and mitochondrial function across multiple tissues (PMID:24450884, PMID:31487266). By regulating the NAD+/NADH ratio it supports mitochondrial electron transport, ATP production, and resistance to oxidative stress and senescence, and its transcription is driven by FOXO3a and Nrf2 binding antioxidant response elements in its promoter (PMID:24450884). In vascular smooth muscle it acts as a soluble guanylyl cyclase (sGC) heme reductase, reducing oxidized sGC heme (Fe3+→Fe2+) to sustain NO-dependent vasodilation; loss of smooth muscle CYB5R3 raises blood pressure and impairs vasodilation, defects rescued by the heme-independent sGC activator BAY 58-2667 and aggravated under hypoxia (PMID:31487266, PMID:34536439). In endothelium it localizes to the mitochondrial outer membrane and physically interacts with NOX4, where its activity and membrane association bias NOX4 output toward H2O2 over superoxide, limiting VCAM-1-driven inflammatory activation (PMID:34656824). It is essential for cardiomyocyte redox homeostasis and CoQ and ATP levels, with cardiomyocyte-specific loss causing hypertrophy, calcium mishandling, ventricular fibrillation, and sudden cardiac death (PMID:36106636). In pancreatic β-cells CYB5R3 links FoxO1 signaling to mitochondrial respiration and stabilizes glucokinase through a glucose-dependent interaction, coupling glucose utilization to insulin secretion; its loss phenocopies secondary sulfonylurea failure, which a CYB5R3 activator reverses in mice and human islets (PMID:32180563, PMID:36724243). In type II alveolar epithelial cells it suppresses TGF-β1 signaling via the sGC/cGMP/PKG–ERK1/2 axis to limit lung fibrosis (PMID:36749633). CYB5R3 protein is dynamically partitioned between mitochondria and ER membranes, with GGPP-dependent prenylation driving mitochondria-to-ER translocation (PMID:32913122), and on the ER it is ufmylated by UFL1/UFBP1 to an inactive form and degraded by CDK5RAP3-dependent ER-phagy, a process required for brain development (PMID:36543799). The common T117S (rs1800457) variant is a partial loss-of-function allele with reduced enzyme activity (PMID:36106636, PMID:32697331).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2014 High

    Established that CYB5R3 controls the cellular NAD+/NADH ratio and downstream mitochondrial bioenergetics, and that its expression is transcriptionally tuned by redox-responsive factors, framing it as a redox-homeostasis enzyme rather than a single-pathway reductase.

    Evidence CYB5R3-deficient cell lines with metabolic assays, senescence readout, FOXO3a/Nrf2 overexpression and ChIP of promoter elements

    PMID:24450884

    Open questions at the time
    • Does not resolve which intracellular acceptors (CoQ vs cytochrome b5) drive the NAD+/NADH effect
    • Promoter regulation studied in cell lines, not tissue-specific contexts
  2. 2018 Medium

    Tested whether elevating CYB5R3 levels has organismal benefit, showing overexpression mimics caloric-restriction phenotypes and engages the NAD+/sirtuin axis.

    Evidence Transgenic mouse overexpressing CYB5R3 plus NQO1 with lifespan, performance, inflammation and metabolic readouts

    PMID:29706024

    Open questions at the time
    • Effects confounded by co-overexpression of NQO1
    • Does not isolate CYB5R3-specific contribution to lifespan
  3. 2019 High

    Defined a tissue-level molecular function by showing smooth muscle CYB5R3 is the sGC heme reductase maintaining NO-dependent vasodilation and blood pressure.

    Evidence SMC-specific conditional KO mouse with radiotelemetry, wire myography, and BAY 58-2667 pharmacological rescue

    PMID:31487266

    Open questions at the time
    • Direct enzymatic reduction of sGC heme inferred pharmacologically rather than reconstituted
    • Does not address non-vascular sGC pools
  4. 2020 High

    Connected CYB5R3 to transcriptional and metabolic programs in β-cells and to subcellular trafficking, showing FoxO1-dependent expression supports β-cell mitochondrial function and that GGPP prenylation directs mitochondria-to-ER translocation for eicosanoid metabolism.

    Evidence β-cell-specific KO mouse with respirometry and EM; GGPPS KO cells with prenylation assays and eicosanoid profiling

    PMID:32180563 PMID:32913122

    Open questions at the time
    • Mechanism linking CYB5R3 reductase activity to insulin secretion not fully defined
    • Functional consequence of ER vs mitochondrial pools not quantitatively partitioned
  5. 2020 Medium

    Characterized natural and engineered loss-of-function alleles, establishing that reduced CYB5R3 activity elevates NADH/NAD+ and ROS while preserving dual ER/mitochondrial localization.

    Evidence Enzymatic activity assays of T117S in SCD erythrocytes; overexpression of a C-terminal extension mutant with localization, ROS and NAD+/NADH readouts

    PMID:32697331 PMID:39154701

    Open questions at the time
    • T117S enzymatic deficit is mild; clinical penetrance not established
    • Extension mutant studied by overexpression only
  6. 2021 Medium

    Revealed a redox-signaling role at the mitochondrial outer membrane where CYB5R3 partners with NOX4 to shape ROS species, linking the enzyme to endothelial inflammation, and extended the sGC reductase role to hypoxic cardiac protection.

    Evidence Endothelial KO/siRNA with APEX2 proximity EM, PLA, COQ6 epistasis; SMC KO under chronic hypoxia with myography and pressure-volume loops

    PMID:34536439 PMID:34656824

    Open questions at the time
    • Physical CYB5R3–NOX4 interface not mapped structurally
    • Hypoxia study from single lab
  7. 2022 High

    Identified CYB5R3 as a regulated ER substrate of the UFM1 system and showed cardiomyocyte requirement, establishing both a degradative control mechanism and a vital cardiac redox role.

    Evidence Ufmylation substrate ID, Co-IP and ufmylation-defective knock-in mice (microcephaly); cardiomyocyte-specific KO with ECG, calcium and CoQ readouts

    PMID:36106636 PMID:36543799

    Open questions at the time
    • How ufmylation inactivates the enzyme biochemically not resolved
    • Link between brain ER-phagy and CYB5R3 reductase activity per se unclear
  8. 2023 High

    Defined a substrate-stabilization mechanism by showing CYB5R3 binds and stabilizes glucokinase glucose-dependently, and extended the sGC axis to alveolar epithelial suppression of fibrotic TGF-β1 signaling.

    Evidence Glucose-dependent Co-IP, β-cell KO phenocopy of sulfonylurea failure with activator rescue in human islets; AECII-specific KO in bleomycin fibrosis with sGC agonist rescue

    PMID:36724243 PMID:36749633

    Open questions at the time
    • Whether GCK stabilization requires CYB5R3 enzymatic activity not separated from binding
    • AECII fibrosis pathway study from single lab
  9. 2024 Medium

    Expanded the functional reach of CYB5R3 to ER-stress-driven apoptosis in cancer cells and to hepatic lipid/cholesterol metabolism downstream of NRF2.

    Evidence Adenoviral overexpression in lung cancer cells with PARP16/PERK/IRE1α ADP-ribosylation assays and xenografts; APOO KO mice with AAV CYB5R3 restoration and lipid/cholesterol profiling

    PMID:38253797 PMID:38830896

    Open questions at the time
    • Apoptotic role observed under overexpression, physiological relevance uncertain
    • NRF2/CYB5R3 lipid axis tested in a specific APOO-deficient background
  10. 2025 Medium

    Proposed a novel endothelial calcium-signaling consequence of CYB5R3 loss, linking it through NO and PTPN1 oxidation to TRPV2/CRAC channel activation and enhanced vasorelaxation.

    Evidence siRNA and endothelial KO mice with Ca2+ imaging, SOCE blockers, PTPN1 oxidation assays and exercise testing (preprint)

    PMID:41279296

    Open questions at the time
    • Preprint, not peer-reviewed
    • Multistep signaling cascade requires independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CYB5R3's distinct enzymatic outputs (sGC heme reduction, CoQ reduction, NADH/NAD+ balancing) are partitioned across its mitochondrial and ER pools and selected in each tissue context remains unresolved.
  • No structural model of substrate selection across localization states
  • Relative contribution of each enzymatic activity to tissue phenotypes not dissected
  • Human disease genetics beyond T117S partial loss-of-function not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0140096 catalytic activity, acting on a protein 2 GO:0016740 transferase activity 1
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005739 mitochondrion 3 GO:0005886 plasma membrane 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 3 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9612973 Autophagy 1
Partners
CDK5RAP3GCKNOX4UFBP1UFL1

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2022 CYB5R3 is a UFM1 substrate on the ER membrane; ufmylation of CYB5R3 by the E3 components UFL1 and UFBP1 converts CYB5R3 to an inactive form, which is then recognized by UFBP1 via a UFM1-interacting motif and degraded in lysosomes in an Atg7- and CDK5RAP3-dependent manner, thereby inducing ER-phagy required for brain development. Substrate identification by mass spectrometry/biochemical screening; co-immunoprecipitation; ufmylation-defective Cyb5r3 knock-in mice showing microcephaly; lysosomal degradation assays; genetic epistasis with Atg7 and CDK5RAP3 Nature communications High 36543799
2019 Smooth muscle cell CYB5R3 acts as an sGC heme reductase in resistance arteries, reducing oxidized sGC heme (Fe3+→Fe2+) to maintain NO-dependent vasodilation; SMC-specific Cyb5r3 KO mice show elevated blood pressure and impaired acetylcholine-induced vasodilation, which is worsened by angiotensin II-induced oxidative stress and rescued by the heme-independent sGC activator BAY 58-2667. Conditional smooth muscle cell-specific Cyb5r3 knockout mouse; radiotelemetry blood pressure measurement; wire myography vasodilation assays; pharmacological rescue with BAY 58-2667 JCI insight High 31487266
2021 CYB5R3 cooperates with NOX4 via coenzyme Q (CoQ) to regulate endothelial inflammatory activation: CYB5R3 localizes to the mitochondrial outer membrane where it physically interacts with NOX4, and CYB5R3 activity and membrane association are required for optimal NOX4-dependent H2O2 generation; loss of CYB5R3 shifts NOX4 output from H2O2 toward O2•-, enhancing VCAM-1 expression and endothelial dysfunction. Endothelial-specific conditional Cyb5r3 KO mice; siRNA knockdown in human aortic endothelial cells; APEX2-based electron microscopy and proximity biotinylation; proximity ligation assay; super-resolution confocal microscopy; ROS measurements; functional rescue with inactive or non-membrane-bound CYB5R3; COQ6 knockdown epistasis Redox biology High 34656824
2022 CYB5R3 is essential for cardiomyocyte redox homeostasis; cardiomyocyte-specific CYB5R3 KO in male mice causes cardiac hypertrophy, bradycardia, ventricular fibrillation, and sudden cardiac death associated with calcium mishandling, decreased ATP and CoQ levels, increased oxidative stress, and hemoprotein dysregulation. The missense variant T117S (rs1800457) encodes a partial loss-of-function protein. Conditional cardiomyocyte-specific CYB5R3 knockout mouse (males); echocardiography; telemetric ECG; calcium handling assays; CoQ quantification; ATP measurements; oxidative stress markers; functional characterization of T117S variant The Journal of clinical investigation High 36106636
2020 Cyb5r3 links FoxO1 signaling to β-cell mitochondrial function: FoxO1-deficient β cells have reduced Cyb5r3 expression; β-cell-specific Cyb5r3 KO mice have impaired glucose-stimulated insulin secretion, glucose intolerance, and blunted mitochondrial respiratory response to glucose, with mitochondrial and secretory granule ultrastructural abnormalities; FoxO1 requires Cyb5r3 to maintain β-cell differentiation markers. β-cell-specific Cyb5r3 knockout mouse; glucose tolerance tests; insulin secretion assays; Seahorse respirometry; electron microscopy; FoxO1 genetic interaction studies; gene expression analysis Molecular metabolism High 32180563
2023 Cyb5r3 stabilizes glucokinase (Gck) through a glucose-dependent interaction, maintaining islet glucose utilization; chronic sulfonylurea exposure reduces Cyb5r3 abundance and impairs Gck stabilization; Cyb5r3 β-cell KO phenocopies secondary sulfonylurea failure; a Cyb5r3 activator rescues secondary sulfonylurea failure in mice and restores insulin secretion in human islets ex vivo. Co-immunoprecipitation (glucose-dependent Cyb5r3-Gck interaction); β-cell-specific Cyb5r3 KO mouse; ex vivo islet glucose utilization assays; pharmacological Cyb5r3 activator in vivo and in human islets Science translational medicine High 36724243
2014 CYB5R3 deficiency decreases the NAD+/NADH ratio, mitochondrial respiration, ATP production, and mitochondrial electron transport chain activities, and increases oxidative stress and cellular senescence; CYB5R3 transcription is upregulated by FOXO3a and Nrf2 binding to antioxidant response elements in the CYB5R3 promoter, demonstrated by chromatin immunoprecipitation. CYB5R3-deficient cell lines; mitochondrial respiration and ATP assays; NAD+/NADH ratio measurements; β-galactosidase senescence assay; overexpression of FOXO3a and Nrf2; Nrf2 genetic ablation; chromatin immunoprecipitation of promoter elements Antioxidants & redox signaling High 24450884
2021 SMC CYB5R3 is required for NO-dependent vasodilation under chronic hypoxia; SMC-specific CYB5R3 KO mice under 3-week hypoxia develop greater biventricular hypertrophy and blunted NO-dependent vasodilation in coronary and pulmonary arteries compared to controls, implicating CYB5R3 as a sGC heme reductase protective against hypoxic cardiac remodeling. SMC-specific CYB5R3 KO mice; chronic hypoxia model; echocardiography; pressure-volume loops; wire myography of coronary and pulmonary arteries Journal of molecular and cellular cardiology Medium 34536439
2023 CYB5R3 in type II alveolar epithelial cells suppresses TGF-β1 signaling by regulating ERK1/2 phosphorylation and the sGC/cGMP/PKG axis; AECII-specific CYB5R3 deficiency leads to sustained TGF-β1 activation and increased lung fibrosis susceptibility; sGC agonists reduce fibrotic outcomes of AECII CYB5R3 deficiency in vivo. Conditional AECII-specific Cyb5r3 KO mice; bleomycin lung fibrosis model; ERK1/2 phosphorylation assays; cGMP measurements; sGC agonist pharmacological rescue in vivo JCI insight Medium 36749633
2024 CYB5R3 overexpression in lung cancer cells induces ER stress-mediated apoptosis via PERK-ATF4 and IRE1α-JNK pathways; increased NAD+ production from CYB5R3 activates PARP16, which ADP-ribosylates PERK and IRE1α; CYB5R3 is predominantly localized to the ER and also induces ROS generation and caspase-9-dependent intrinsic apoptosis. Adenoviral CYB5R3 overexpression in lung cancer cells; transcriptome and metabolomic analysis; subcellular fractionation/immunofluorescence localization; PARP16 activity assays; PERK/IRE1α ADP-ribosylation assays; caspase activity assays; mouse xenograft tumor models Experimental & molecular medicine Medium 38253797
2020 GGPP prenylates CYB5R3 and the prenylated form translocates from the mitochondrial to the ER pool; CYB5R3 is identified as an NADH-dependent reductase necessary for eicosanoid metabolism in the ER; GGPP depletion (via GGPPS deletion) inhibits CYB5R3 translocation and disrupts eicosanoid metabolism, causing metaflammation. GGPPS knockout cell line; CYB5R3 subcellular fractionation; prenylation assays; eicosanoid metabolite profiling; simvastatin pharmacological inhibition The Journal of biological chemistry Medium 32913122
2025 CYB5R3 loss in endothelial cells activates a Ca2+ influx pathway: CYB5R3 deficiency upregulates ORAI2, ORAI3, and TRPV2; loss of CYB5R3 increases Ca2+ entry through CRAC channels and TRPV2 upon ER Ca2+ store depletion; mechanistically, CYB5R3 loss increases NO production via CRAC channels, which oxidatively inhibits PTPN1, preventing TRPV2 dephosphorylation and sustaining JAK1-dependent TRPV2 activation; endothelial Cyb5r3 KO in vivo enhances acetylcholine-induced vasorelaxation and exercise capacity. siRNA knockdown and endothelial-specific Cyb5r3 KO mice; Ca2+ imaging; pharmacological SOCE blockers; TRPV2 genetic knockdown and inhibition; PTPN1 oxidation assays; NO measurements; exercise capacity testing; vasodilation assays bioRxivpreprint Medium 41279296
2020 The CYB5R3 T117S variant (rs1800457/c.350C>G) shows mildly lower enzyme activity and higher NADH/NAD+ ratios compared to wild-type CYB5R3 in sickle cell disease erythrocytes, representing a partial loss-of-function. Functional enzymatic activity assay in SCD erythrocytes; NADH/NAD+ ratio measurement; comparison of T117S vs wild-type CYB5R3 activity American journal of hematology Medium 32697331
2020 The CYB5R3 mutation c.906A>G (p.*302Trpext*42) results in a larger ~55 kDa protein with undetectable NADH cytochrome b5 reductase activity; the mutant protein retains ER and mitochondrial localization but increases intracellular ROS and decreases the NAD+/NADH ratio, consistent with loss of CYB5R3 function. Overexpression of mutant construct in cells; Western blotting; immunofluorescence localization; ROS measurement; NAD+/NADH ratio assay; enzymatic activity assay Clinica chimica acta Medium 39154701
2018 Overexpression of CYB5R3 (together with NQO1) in transgenic mice mimics aspects of caloric restriction, including modest lifespan extension, improved physical performance, reduced chronic inflammation, protection against carcinogenesis, enhanced metabolic flexibility, and significant upregulation of the NAD+/sirtuin pathway. Transgenic mouse overexpressing CYB5R3 and NQO1; lifespan analysis; physical performance tests; inflammation markers; carcinogenesis models; NAD+/NADH ratio and sirtuin pathway measurements; metabolic flexibility assays Aging cell Medium 29706024
2024 APOO deficiency reduces CYB5R3 expression in liver via the NRF2/CYB5R3 axis; AAV-mediated restoration of CYB5R3 expression in Apoo−/− mice reversed reduced phospholipid unsaturation and decreased blood cholesterol levels, demonstrating that CYB5R3 regulates phospholipid unsaturation and cholesterol metabolism downstream of NRF2. APOO global knockout mouse; Apoo−/−Apoe−/− and Apoo−/−Ldlr−/− models; AAV-mediated CYB5R3 restoration in vivo; phospholipid unsaturation analysis; plasma cholesterol measurements; NRF2 and CYB5R3 expression analysis Cell death & disease Medium 38830896
2024 Cyb5r3 activation reverses secondary sulfonylurea failure and restores insulin secretion in mice and ex vivo human islets but does not reverse β-cell dedifferentiation; chronic SU treatment combined with Cyb5r3 KO shows more pronounced β-cell dedifferentiation and glucose intolerance. Cyb5r3 KO mice with chronic SU treatment; β-cell dedifferentiation markers; glucose tolerance tests; insulin secretion assays; Cyb5r3 activator pharmacological treatment in mice and human islets PloS one Medium 38335173

Source papers

Stage 0 corpus · 69 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Deletion of the vaccinia virus B5R gene encoding a 42-kilodalton membrane glycoprotein inhibits extracellular virus envelope formation and dissemination. Journal of virology 181 8331727
2001 Visualization of intracellular movement of vaccinia virus virions containing a green fluorescent protein-B5R membrane protein chimera. Journal of virology 134 11312352
2004 Antibodies against the extracellular enveloped virus B5R protein are mainly responsible for the EEV neutralizing capacity of vaccinia immune globulin. Virology 114 15246280
2006 LC16m8, a highly attenuated vaccinia virus vaccine lacking expression of the membrane protein B5R, protects monkeys from monkeypox. Journal of virology 106 16698998
1998 Functional analysis of vaccinia virus B5R protein: essential role in virus envelopment is independent of a large portion of the extracellular domain. Journal of virology 80 9420227
2022 The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3. Nature communications 79 36543799
2008 Vaccination of BALB/c mice with Escherichia coli-expressed vaccinia virus proteins A27L, B5R, and D8L protects mice from lethal vaccinia virus challenge. Journal of virology 79 18199639
2005 Epitope-mapping studies define two major neutralization sites on the vaccinia virus extracellular enveloped virus glycoprotein B5R. Journal of virology 78 15858010
1998 The extracellular domain of vaccinia virus protein B5R affects plaque phenotype, extracellular enveloped virus release, and intracellular actin tail formation. Journal of virology 63 9499104
2000 Golgi network targeting and plasma membrane internalization signals in vaccinia virus B5R envelope protein. Journal of virology 58 10729152
2014 Membrane-bound CYB5R3 is a common effector of nutritional and oxidative stress response through FOXO3a and Nrf2. Antioxidants & redox signaling 46 24450884
2001 Vaccinia virus F13L protein with a conserved phospholipase catalytic motif induces colocalization of the B5R envelope glycoprotein in post-Golgi vesicles. Journal of virology 46 11462025
1997 The cytoplasmic and transmembrane domains of the vaccinia virus B5R protein target a chimeric human immunodeficiency virus type 1 glycoprotein to the outer envelope of nascent vaccinia virions. Journal of virology 46 9060681
2011 MicroRNA regulation of glycoprotein B5R in oncolytic vaccinia virus reduces viral pathogenicity without impairing its antitumor efficacy. Molecular therapy : the journal of the American Society of Gene Therapy 41 21386827
2003 Mutations in the vaccinia virus A33R and B5R envelope proteins that enhance release of extracellular virions and eliminate formation of actin-containing microvilli without preventing tyrosine phosphorylation of the A36R protein. Journal of virology 38 14581563
2019 Loss of smooth muscle CYB5R3 amplifies angiotensin II-induced hypertension by increasing sGC heme oxidation. JCI insight 37 31487266
1993 The ps/hr gene (B5R open reading frame homolog) of rabbitpox virus controls pock color, is a component of extracellular enveloped virus, and is secreted into the medium. Journal of virology 35 8394457
2018 Overexpression of CYB5R3 and NQO1, two NAD+ -producing enzymes, mimics aspects of caloric restriction. Aging cell 34 29706024
2020 Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure. Molecular metabolism 31 32180563
2009 CYB5R3: a key player in aerobic metabolism and aging? Aging 28 20228936
2001 A mutational analysis of the vaccinia virus B5R protein. The Journal of general virology 28 11297695
2002 Replacing the SCR domains of vaccinia virus protein B5R with EGFP causes a reduction in plaque size and actin tail formation but enveloped virions are still transported to the cell surface. The Journal of general virology 26 11807225
1998 Functional analysis of vaccinia virus B5R protein: role of the cytoplasmic tail. Virology 24 9878625
2013 L1R, A27L, A33R and B5R vaccinia virus genes expressed by fowlpox recombinants as putative novel orthopoxvirus vaccines. Journal of translational medicine 23 23578094
2021 Cooperation between CYB5R3 and NOX4 via coenzyme Q mitigates endothelial inflammation. Redox biology 21 34656824
2019 Partial Deletion of Glycoprotein B5R Enhances Vaccinia Virus Neutralization Escape while Preserving Oncolytic Function. Molecular therapy oncolytics 21 31236440
2022 Loss of cardiomyocyte CYB5R3 impairs redox equilibrium and causes sudden cardiac death. The Journal of clinical investigation 18 36106636
2021 Smooth muscle cell CYB5R3 preserves cardiac and vascular function under chronic hypoxic stress. Journal of molecular and cellular cardiology 18 34536439
1997 Attenuation of B5R mutants of rabbitpox virus in vivo is related to impaired growth and not an enhanced host inflammatory response. Virology 18 9201221
2020 Mutation update: Variants of the CYB5R3 gene in recessive congenital methemoglobinemia. Human mutation 17 31898843
2018 Novel mutation (R192C) in CYB5R3 gene causing NADH-cytochrome b5 reductase deficiency in eight Indian patients associated with autosomal recessive congenital methemoglobinemia type-I. Hematology (Amsterdam, Netherlands) 17 29482478
2024 CYB5R3 functions as a tumor suppressor by inducing ER stress-mediated apoptosis in lung cancer cells via the PERK-ATF4 and IRE1α-JNK pathways. Experimental & molecular medicine 16 38253797
2015 Vaccinia virus strain LC16m8 defective in the B5R gene keeps strong protection comparable to its parental strain Lister in immunodeficient mice. Vaccine 15 26241947
2012 Evaluation of polymorphisms in the sulfonamide detoxification genes NAT2, CYB5A, and CYB5R3 in patients with sulfonamide hypersensitivity. Pharmacogenetics and genomics 15 22850190
2014 Polymorphisms in the carcinogen detoxification genes CYB5A and CYB5R3 and breast cancer risk in African American women. Cancer causes & control : CCC 13 25225034
2012 Sequence and phylogenetic analysis of host-range (E3L, K3L, and C7L) and structural protein (B5R) genes of buffalopox virus isolates from buffalo, cattle, and human in India. Virus genes 12 22872567
1999 The effects of targeting the vaccinia virus B5R protein to the endoplasmic reticulum on virus morphogenesis and dissemination. Virology 12 10603324
2023 Cyb5r3-based mechanism and reversal of secondary failure to sulfonylurea in diabetes. Science translational medicine 11 36724243
2020 Mitochondrial adaptations in liver and skeletal muscle to pro-longevity nutritional and genetic interventions: the crosstalk between calorie restriction and CYB5R3 overexpression in transgenic mice. GeroScience 11 32323139
2009 In vitro human CD4+ T cell response to the vaccinia protective antigens B5R and A33R. Molecular immunology 11 19193441
2023 CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling. JCI insight 10 36749633
2020 The CYB5R3c .350C>G and G6PD A alleles modify severity of anemia in malaria and sickle cell disease. American journal of hematology 10 32697331
2023 Molecular Dynamic Simulation Analysis of a Novel Missense Variant in CYB5R3 Gene in Patients with Methemoglobinemia. Medicina (Kaunas, Lithuania) 9 36837579
2020 GGPP depletion initiates metaflammation through disequilibrating CYB5R3-dependent eicosanoid metabolism. The Journal of biological chemistry 9 32913122
2007 Microarray assay for evaluation of the genetic stability of modified vaccinia virus Ankara B5R gene. Journal of medical virology 9 17457926
2013 [Population frequency and age of c.806C > T mutation in CYB5R3 gene as cause of recessive congenital methemoglobinemia in Yakutia]. Genetika 8 23866629
2012 Evaluation of polymorphisms in the sulfonamide detoxification genes CYB5A and CYB5R3 in dogs with sulfonamide hypersensitivity. Journal of veterinary internal medicine 7 22816446
2014 Genetic variation in CYB5R3 is associated with methemoglobin levels in preterm infants receiving nitric oxide therapy. Pediatric research 6 25521918
2007 B5r gene based sequence analysis of Indian buffalopox virus isolates in relation to other orthopoxviruses. Acta virologica 6 17432943
2024 Cyb5r3 activation rescues secondary failure to sulfonylurea but not β-cell dedifferentiation. PloS one 5 38335173
2023 Methemoglobinemia, Increased Deformability and Reduced Membrane Stability of Red Blood Cells in a Cat with a CYB5R3 Splice Defect. Cells 5 37048064
2019 Crystal structures of the naturally fused CS and cytochrome b5 reductase (b5R) domains of Ncb5or reveal an expanded CS fold, extensive CS-b5R interactions and productive binding of the NAD(P)+ nicotinamide ring. Acta crystallographica. Section D, Structural biology 5 31282472
2018 A single-nucleotide polymorphism in the canine cytochrome b5 reductase (CYB5R3) gene is associated with sulfonamide hypersensitivity and is overrepresented in Doberman Pinschers. Journal of veterinary pharmacology and therapeutics 4 29336038
2024 Novel Compound Heterogeneous Mutations in CYB5R3 Gene Leading to Methemoglobinemia (Type I) in a Chinese Boy: Case Report and Relevant Comprehensive Analysis. Acta haematologica 3 38781945
2024 Apolipoprotein O modulates cholesterol metabolism via NRF2/CYB5R3 independent of LDL receptor. Cell death & disease 3 38830896
2024 CYB5R3 overexpression exhibits sexual dimorphism: Mitochondrial and metabolic adaptations in transgenic female mice during calorie restriction. Free radical biology & medicine 3 39069267
2022 Three novel mutations in CYB5R3 gene causing NADH-cytochrome b5 reductase enzyme deficiency leads to recessive congenital methaemoglobinemia. Molecular biology reports 3 35064402
2022 CYB5R3 homozygous pathogenic variant as a rare cause of cyanosis in the newborn. Clinical biochemistry 3 35104462
2015 Isolation of buffalo poxvirus from clinical case and variations in the genetics of the B5R gene over fifty passages. Virus genes 3 26070368
2010 Comparative sequence analysis of B5R gene of zoonotic buffalo pox virus isolates with other orthopoxviruses. Tropical animal health and production 2 20936505
2026 Untargeted Serum Proteomics in the Fontan Circulation Reveals Three Distinct Molecular Signatures of Fontan Physiology with CYB5R3 Among Key Proteins. International journal of molecular sciences 1 41683646
2025 Exploration of the multiomics-based mechanisms of Gancao Nourishing-Yin decoction in regulating mitochondrial metabolic genes CYB5R3 and PICK1 to influence glioma progression. Discover oncology 1 40198489
2024 A novel stoploss mutation CYB5R3 c.906A>G(p.*302Trpext*42) involved in the pathogenesis of hereditary methemoglobinemia. Clinica chimica acta; international journal of clinical chemistry 1 39154701
2012 [Novel large deletion c.22-1320_633+1224del in the CYB5R3 gene from patients with hereditary methemoglobinemia]. Genetika 1 23297489
2026 Potent protective ability of vaccinia virus LC16 strains lacking the B5R gene. Virology 0 41875596
2025 Rare Case of Homozygosity for CYB5R3 Variant c.235C > T p.(Arg79Trp) Causing Type II Methemoglobinemia. Hemoglobin 0 40366646
2025 Adaptations of mitochondrial, autophagy and nutrient sensing pathways in the liver from long-lived mice overexpressing CYB5R3 are sex-dependent and involve inter-organ responses. GeroScience 0 40580248
2025 Endothelial CYB5R3 couples store-operated calcium entry to TRPV2 activation and vascular fitness. bioRxiv : the preprint server for biology 0 41279296
2023 Identification of High-Risk Single Nucleotide Polymorphisms in the Human CYB5R3 Gene Responsible for Recessive Congenital Methemoglobinemia: A Computational Approach. Molecular syndromology 0 37901856

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