GO:0047058 vitamin-K-epoxide reductase (warfarin-insensitive) activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0047058 describes a vitamin-K-epoxide reductase activity that is insensitive to warfarin, distinguishing it from the warfarin-sensitive VKORC1-centered activity of the classical vitamin K cycle [1, 7].
• The reaction catalyzed is the reduction of vitamin K 2,3-epoxide to the hydroquinone form using a dithiol reductant, as defined by QuickGO and supported by biochemical studies of the vitamin K cycle [7, 8].
• VKORC1L1 is a principal enzyme associated with warfarin-insensitive vitamin K epoxide reductase activity and has been linked to p53-mediated tumor suppression through vitamin K metabolism.
• The activity is regulated by redox partners such as protein disulfide isomerase, which can enhance vitamin K epoxide reductase activity [3, 6].
• Vitamin K epoxide reductase regulation influences androgen receptor activity, connecting this activity to steroid hormone signaling and prostate cancer biology.
• Studying GO:0047058 requires integrating enzymology, redox biology, and CRISPR-based models to dissect warfarin-insensitive versus warfarin-sensitive contributions [1, 4, 8].
Description
GO:0047058, vitamin-K-epoxide reductase (warfarin-insensitive) activity, is a molecular function that catalyzes the reduction of vitamin K 2,3-epoxide to its hydroquinone form using a dithiol reductant such as dithiothreitol [7, 8]. This activity is embedded in the vitamin K cycle, a metabolic pathway essential for gamma-carboxylation of vitamin K-dependent proteins and for redox homeostasis. Unlike the warfarin-sensitive vitamin K epoxide reductase step classically associated with VKORC1, the warfarin-insensitive activity described by GO:0047058 represents a distinct catalytic context that remains active in the presence of 4-hydroxycoumarin anticoagulants [4, 7]. Understanding this distinction is important because it helps explain why some vitamin K-dependent processes persist under anticoagulant pressure and how vitamin K metabolism intersects with cancer, steroid signaling, and redox regulation [1, 2, 4]. The enzyme activity defined by GO:0047058 has been studied biochemically for decades, with early work establishing stereoselectivity of 4-hydroxycoumarin anticoagulants toward vitamin K 2,3-epoxide reductase. Structural and functional studies of vitamin K epoxide reductase have clarified the catalytic mechanism and the redox-active motifs required for turnover. More recent work has identified VKORC1L1 as a warfarin-insensitive paralog whose regulation is critical for p53-mediated tumor suppression through vitamin K metabolism. In parallel, protein disulfide isomerase has been shown to enhance vitamin K epoxide reductase activity, indicating that redox protein partners modulate this function [3, 6]. For researchers, GO:0047058 matters because it provides a precise ontology anchor for experiments that separate warfarin-insensitive vitamin K epoxide reduction from the canonical warfarin-sensitive step. This is relevant to anticoagulant pharmacology, cancer biology, androgen receptor signaling, and photosynthetic organisms that utilize vitamin K analogs [2, 4, 5]. The sections below define the term, outline its mechanism, list key genes, and describe CRISPR and biochemical methods for studying it.
vitamin-K-epoxide reductase (warfarin-insensitive) activity At A Glance
| GO ID | GO:0047058 |
|---|---|
| GO term | vitamin-K-epoxide reductase (warfarin-insensitive) activity |
| Ontology | molecular_function |
| Synonym | vitamin K 2,3-epoxide reductase activity |
| Definition | Catalysis of the reaction: 3-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone + oxidized dithiothreitol + H2O = 2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol |
| Major function | Reduction of vitamin K 2,3-epoxide to the hydroquinone form using a dithiol reductant, with insensitivity to warfarin |
| Associated enzyme | VKORC1L1 is a principal warfarin-insensitive vitamin K epoxide reductase linked to p53-mediated tumor suppression |
| Redox partner | Protein disulfide isomerase can enhance vitamin K epoxide reductase activity [3, 6] |
| Pathway context | Vitamin K cycle, supporting gamma-carboxylation and redox homeostasis [7, 8] |
What Is GO:0047058?
GO:0047058 is defined by QuickGO as the catalysis of the reaction: 3-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone + oxidized dithiothreitol + H2O = 2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol. In simpler terms, it is a vitamin K epoxide reductase activity that reduces vitamin K 2,3-epoxide to the corresponding hydroquinone using a dithiol reductant, and it is characterized as warfarin-insensitive. The synonym vitamin K 2,3-epoxide reductase activity reflects this catalytic role within the vitamin K cycle [7, 8].
Why Is vitamin-K-epoxide reductase (warfarin-insensitive) activity Important in Cell Biology?
GO:0047058 is important because it defines a warfarin-insensitive vitamin K epoxide reductase activity that operates alongside the canonical warfarin-sensitive step of the vitamin K cycle. This distinction has direct implications for understanding anticoagulant pharmacology, since 4-hydroxycoumarin drugs such as warfarin target the sensitive activity while the insensitive activity can sustain vitamin K recycling under certain conditions [4, 7]. The activity is also relevant to cancer biology, as regulation of VKORC1L1 is critical for p53-mediated tumor suppression through vitamin K metabolism. In addition, vitamin K epoxide reductase regulation influences androgen receptor activity, linking this redox function to steroid hormone signaling. Protein disulfide isomerase enhances vitamin K epoxide reductase activity, showing that the redox environment and partner proteins modulate this function [3, 6]. Finally, vitamin K-dependent redox chemistry is conserved in photosynthetic organisms, broadening the biological scope of this activity.
• Provides a mechanistic explanation for warfarin-insensitive vitamin K epoxide reduction, complementing the warfarin-sensitive VKORC1 step [4, 7].
• Links vitamin K metabolism to p53-mediated tumor suppression through regulation of VKORC1L1.
• Connects vitamin K epoxide reductase activity to androgen receptor signaling and prostate cancer biology.
• Highlights the role of redox partners such as protein disulfide isomerase in enhancing enzyme activity [3, 6].
• Supports understanding of the vitamin K cycle, which is essential for gamma-carboxylation of vitamin K-dependent proteins [7, 8].
• Relevant to anticoagulant pharmacology because warfarin sensitivity versus insensitivity determines drug response.
• Provides an ontology anchor for separating paralog-specific functions of VKORC1 and VKORC1L1 [1, 8].
• Extends to photosynthetic organisms, where vitamin K chemistry participates in redox processes.
• Guides CRISPR-based experiments to test causality of candidate genes in vitamin K metabolism [1, 8].
• Offers a framework for studying redox regulation in cancer, coagulation, and steroid signaling [1, 2, 3].
What Happens During vitamin-K-epoxide reductase (warfarin-insensitive) activity?
Substrate binding and epoxide recognition
In simple terms: The enzyme first grabs the vitamin K epoxide substrate.
The reaction defined by GO:0047058 begins with binding of the substrate 2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone, the vitamin K 2,3-epoxide, at the active site of the enzyme. Structural and functional studies of vitamin K epoxide reductase have characterized the enzyme architecture and substrate handling that support this step. The warfarin-insensitive nature of this activity distinguishes it from the warfarin-sensitive vitamin K epoxide reductase step, as established in biochemical studies of 4-hydroxycoumarin stereoselectivity. In the vitamin K cycle, this epoxide reduction is a central reaction that regenerates the hydroquinone form of vitamin K.
Dithiol-dependent reduction
In simple terms: A dithiol molecule supplies electrons to convert the epoxide back to the reduced form.
The catalytic reaction uses oxidized dithiothreitol as the reductant, which is converted to 1,4-dithiothreitol as the vitamin K epoxide is reduced to 3-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone. This dithiol-dependent mechanism is consistent with the redox chemistry of the vitamin K cycle, in which reducing equivalents are transferred to regenerate the hydroquinone [7, 8]. Protein disulfide isomerase has been shown to enhance vitamin K epoxide reductase activity, indicating that protein thiol-disulfide exchange can support this reduction [3, 6]. The involvement of redox protein partners places GO:0047058 within a broader redox network rather than an isolated catalytic event [3, 6].
Warfarin insensitivity and paralog specificity
In simple terms: This version of the enzyme keeps working even when warfarin blocks the other version.
A defining feature of GO:0047058 is its insensitivity to warfarin, which contrasts with the warfarin-sensitive vitamin K epoxide reductase activity targeted by 4-hydroxycoumarin anticoagulants [4, 7]. VKORC1L1 is a principal enzyme associated with warfarin-insensitive vitamin K epoxide reductase activity, and its regulation is critical for p53-mediated tumor suppression through vitamin K metabolism. This paralog specificity helps explain how vitamin K-dependent processes can persist under anticoagulant pressure and why VKORC1L1 has emerged as a distinct research target [1, 8]. The stereoselectivity of 4-hydroxycoumarin anticoagulants further supports the existence of mechanistically distinct epoxide reductase activities.
Integration with the vitamin K cycle
In simple terms: The reaction feeds back into the cycle that recycles vitamin K for other proteins.
The reduction catalyzed by GO:0047058 is part of the vitamin K cycle, which maintains the reduced hydroquinone form of vitamin K required for gamma-carboxylation of vitamin K-dependent proteins. Structure-function studies of vitamin K epoxide reductase have clarified how the enzyme contributes to this cycle. In photosynthetic organisms, vitamin K chemistry participates in redox processes, indicating that related epoxide reductase activities have broader biological roles. The cycle context is essential because it links GO:0047058 to coagulation, bone biology, and other vitamin K-dependent functions [7, 8].
Regulation by redox environment and signaling
In simple terms: The surrounding redox proteins and signaling pathways tune how active the enzyme is.
The activity described by GO:0047058 is modulated by the redox environment, as shown by the enhancement of vitamin K epoxide reductase activity by protein disulfide isomerase [3, 6]. Regulation of VKORC1L1 is critical for p53-mediated tumor suppression, demonstrating that this activity is integrated into tumor suppressor signaling through vitamin K metabolism. Vitamin K epoxide reductase regulation also influences androgen receptor activity, connecting the activity to steroid hormone signaling. Together, these findings indicate that GO:0047058 is not a constitutive housekeeping function but is subject to redox and signaling control [1, 2, 3].
Key Genes Involved in GO:0047058 vitamin-K-epoxide reductase (warfarin-insensitive) activity
The following genes and proteins are directly implicated in vitamin-K-epoxide reductase (warfarin-insensitive) activity or its regulation, based on the verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| VKORC1L1 | Warfarin-insensitive vitamin K epoxide reductase paralog; regulation critical for p53-mediated tumor suppression through vitamin K metabolism | Central candidate for studying GO:0047058 and cancer-related vitamin K metabolism |
| VKORC1 | Canonical vitamin K epoxide reductase of the vitamin K cycle, classically warfarin-sensitive [7, 8] | Reference enzyme for comparing warfarin-sensitive versus warfarin-insensitive activities [4, 8] |
| PDI (P4HB) | Protein disulfide isomerase that enhances vitamin K epoxide reductase activity [3, 6] | Redox partner for mechanistic and enhancement studies [3, 6] |
| AR | Androgen receptor whose activity is regulated by vitamin K epoxide reductase | Links GO:0047058 to steroid hormone signaling and prostate cancer |
| TP53 | Tumor suppressor whose pathway depends on VKORC1L1 regulation and vitamin K metabolism | Connects GO:0047058 to p53-mediated tumor suppression |
| GGCX | Gamma-glutamyl carboxylase that consumes reduced vitamin K generated in the cycle | Downstream effector of vitamin K cycle flux |
| F9 | Vitamin K-dependent coagulation factor requiring reduced vitamin K | Physiological readout of vitamin K cycle activity |
| F2 | Prothrombin, a vitamin K-dependent clotting factor | Coagulation-related readout of vitamin K status |
| PROC | Protein C, a vitamin K-dependent anticoagulant protein | Links vitamin K cycle to anticoagulation balance |
| PROS1 | Protein S, a vitamin K-dependent protein | Coagulation-related readout |
| MGP | Matrix Gla protein, vitamin K-dependent | Vascular calcification-related readout |
| BGLAP | Osteocalcin, vitamin K-dependent | Bone biology readout of vitamin K cycle |
| GAS6 | Vitamin K-dependent protein | Cell signaling readout |
| NQO1 | Quinone oxidoreductase involved in redox cycling of quinones | Redox context for vitamin K-related chemistry |
| TXNRD1 | Thioredoxin reductase contributing to cellular redox state | Redox environment affecting dithiol-dependent reduction |
| NXN | Nucleoredoxin, a redox protein | Potential redox modulator of vitamin K epoxide reductase |
| VKORC1L1 (paralog context) | Distinct from VKORC1 in warfarin sensitivity [1, 4] | Key for paralog-specific CRISPR studies [1, 4] |
| p53 pathway genes | Downstream effectors of VKORC1L1-regulated vitamin K metabolism | Cancer biology models |
How Is vitamin-K-epoxide reductase (warfarin-insensitive) activity Regulated?
The activity described by GO:0047058 is regulated at multiple levels. Redox protein partners such as protein disulfide isomerase enhance vitamin K epoxide reductase activity, indicating that the thiol-disulfide environment modulates catalysis [3, 6]. Regulation of VKORC1L1 is critical for p53-mediated tumor suppression through vitamin K metabolism, showing that this activity is integrated into tumor suppressor signaling. Vitamin K epoxide reductase regulation also influences androgen receptor activity, linking the activity to steroid hormone signaling pathways. In addition, the warfarin sensitivity of the canonical vitamin K epoxide reductase step provides a pharmacological layer of regulation, since 4-hydroxycoumarin anticoagulants selectively inhibit the warfarin-sensitive activity while the warfarin-insensitive activity described by GO:0047058 remains functional [4, 7]. The vitamin K cycle as a whole is regulated by the availability of reduced vitamin K and the demand for gamma-carboxylation of vitamin K-dependent proteins [7, 8].
vitamin-K-epoxide reductase (warfarin-insensitive) activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| VKORC1L1 | p53-mediated tumor suppression through vitamin K metabolism | VKORC1L1 knockout and overexpression cell models with p53 pathway readouts |
| AR | Androgen receptor signaling and prostate cancer | AR reporter assays in vitamin K epoxide reductase-modulated cells |
| VKORC1 | Warfarin sensitivity and anticoagulant response [4, 7] | Point-mutation knock-in models of VKORC1 variants [4, 8] |
| GGCX | Vitamin K-dependent coagulation and bone biology | Knockout models with gamma-carboxylation readouts |
| PDI (P4HB) | Redox modulation of vitamin K epoxide reductase [3, 6] | Overexpression and knockdown models for activity enhancement [3, 6] |
Cancer and p53-mediated tumor suppression
Regulation of VKORC1L1 is critical for p53-mediated tumor suppression through vitamin K metabolism, directly linking the warfarin-insensitive vitamin K epoxide reductase activity described by GO:0047058 to cancer biology. This connection suggests that vitamin K metabolism supports tumor suppressor functions and that dysregulation of VKORC1L1 may contribute to tumorigenesis. The redox chemistry of vitamin K epoxide reduction is therefore relevant to understanding how metabolic pathways influence p53 activity.
Prostate cancer and androgen receptor signaling
Vitamin K epoxide reductase regulation influences androgen receptor activity, connecting GO:0047058 to steroid hormone signaling and prostate cancer biology. This finding indicates that vitamin K cycle enzymes can modulate nuclear receptor function, providing a rationale for studying vitamin K epoxide reductase in hormone-dependent cancers. The interplay between redox metabolism and androgen receptor activity highlights a potential therapeutic angle.
Anticoagulation and warfarin pharmacology
The warfarin-insensitive nature of GO:0047058 is directly relevant to anticoagulant pharmacology, because 4-hydroxycoumarin drugs such as warfarin target the warfarin-sensitive vitamin K epoxide reductase step [4, 7]. The stereoselectivity of 4-hydroxycoumarin anticoagulant activity toward vitamin K 2,3-epoxide reductase has been established biochemically, providing a foundation for understanding variable drug responses. The persistence of warfarin-insensitive activity may contribute to residual vitamin K cycle function during anticoagulant therapy [4, 7].
Vitamin K deficiency and coagulation disorders
The vitamin K cycle, in which GO:0047058 participates, is essential for gamma-carboxylation of vitamin K-dependent coagulation factors such as prothrombin and factor IX. Disruption of vitamin K cycle enzymes can impair coagulation and bone metabolism, as reviewed in the context of the vitamin K cycle. Structure-function studies of vitamin K epoxide reductase provide a mechanistic basis for understanding how mutations or inhibitors affect this pathway.
From vitamin-K-epoxide reductase (warfarin-insensitive) activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does VKORC1L1 mediate warfarin-insensitive vitamin K epoxide reductase activity? | VKORC1L1 knockout cell model with enzymatic activity assay |
| How does VKORC1L1 regulate p53-mediated tumor suppression? | VKORC1L1 knockout and overexpression models with p53 readouts |
| Does protein disulfide isomerase enhance vitamin K epoxide reductase activity? | PDI overexpression cell model with activity measurement [3, 6] |
| How does vitamin K epoxide reductase regulate androgen receptor activity? | AR reporter cell model with vitamin K epoxide reductase modulation |
| What is the effect of warfarin-sensitive versus warfarin-insensitive enzyme variants? | Point-mutation knock-in models of VKORC1 and VKORC1L1 [4, 8] |
| Can tagged vitamin K epoxide reductase be used for localization studies? | Tagged knock-in model for imaging and proteomics |
How to Study the vitamin-K-epoxide reductase (warfarin-insensitive) activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Enzymatic activity assay | Vitamin K epoxide reduction using dithiothreitol [7, 8] | Quantifying warfarin-insensitive activity |
| CRISPR knockout | Loss-of-function effects on vitamin K metabolism | Testing VKORC1L1 causality |
| Overexpression | Gain-of-function effects on enzyme activity [3, 6] | Testing PDI enhancement of activity [3, 6] |
| Reporter assay | Androgen receptor transcriptional activity | Linking vitamin K epoxide reductase to AR signaling |
| RNA-seq | Transcriptional changes after enzyme modulation | Identifying p53 pathway effects |
| Metabolic profiling | Vitamin K metabolite levels | Assessing flux through the vitamin K cycle |
| Protein interaction assay | Redox partner binding [3, 6] | Mapping PDI and other redox interactions [3, 6] |
| Point-mutation knock-in | Effect of specific variants on warfarin sensitivity [4, 8] | Modeling anticoagulant response |
Enzymatic activity assays
Direct measurement of vitamin K epoxide reductase activity is the primary method for studying GO:0047058. Biochemical assays using dithiothreitol as a reductant and vitamin K 2,3-epoxide as substrate can quantify the reaction defined by QuickGO [7, 8]. Such assays have been used to characterize the stereoselectivity of 4-hydroxycoumarin anticoagulants toward vitamin K 2,3-epoxide reductase. Activity assays are also used to test enhancement by protein disulfide isomerase [3, 6].
CRISPR knockout and overexpression models
CRISPR-based knockout and overexpression models allow causal testing of candidate genes such as VKORC1L1 in vitamin K epoxide reductase activity. Knockout of VKORC1L1 can reveal its contribution to p53-mediated tumor suppression through vitamin K metabolism. Overexpression of protein disulfide isomerase has been used to demonstrate enhancement of vitamin K epoxide reductase activity [3, 6]. These models are essential for separating warfarin-sensitive and warfarin-insensitive activities [1, 4].
Redox and protein interaction studies
Because GO:0047058 is a dithiol-dependent redox reaction, methods that measure cellular redox state and protein thiol-disulfide exchange are important [3, 6]. Protein disulfide isomerase has been shown to enhance vitamin K epoxide reductase activity, making interaction studies valuable [3, 6]. Redox protein partners such as thioredoxin-related proteins may modulate the activity, and their study requires biochemical and cellular redox assays.
Transcriptomic and metabolic profiling
RNA-seq and metabolic profiling can reveal downstream effects of modulating vitamin K epoxide reductase activity, including changes in p53 target genes and androgen receptor signaling [1, 2]. Vitamin K metabolism profiling can connect enzyme activity to cellular metabolic states. Such approaches help place GO:0047058 within broader metabolic and signaling networks [1, 2].
How CRISPR Can Be Used to Study GO:0047058 vitamin-K-epoxide reductase (warfarin-insensitive) activity
Knockout
CRISPR knockout of VKORC1L1 is used to test whether this paralog is required for warfarin-insensitive vitamin K epoxide reductase activity and for p53-mediated tumor suppression through vitamin K metabolism. Knockout models can also be used to assess the contribution of redox partners such as protein disulfide isomerase to enzyme activity [3, 6]. By comparing knockout phenotypes with wild-type cells, researchers can determine the specific contribution of GO:0047058 to cellular vitamin K metabolism [1, 8].
Point Mutation
Point-mutation knock-in models are valuable for studying the structural determinants of warfarin sensitivity and insensitivity in vitamin K epoxide reductase [4, 8]. Structure-function studies of vitamin K epoxide reductase provide a basis for selecting residues that affect catalysis and inhibitor binding. Such models can help explain the stereoselectivity of 4-hydroxycoumarin anticoagulants toward vitamin K 2,3-epoxide reductase. They also allow testing of whether specific residues distinguish VKORC1 from VKORC1L1 [1, 8].
Knock-in
Tagged knock-in of vitamin K epoxide reductase genes enables localization, interaction, and proteomic studies while preserving endogenous regulation. Knock-in of disease-associated or pharmacologically relevant variants can model anticoagulant response and vitamin K cycle dysfunction [4, 7]. These models are particularly useful for studying the vitamin K cycle in a physiological context [7, 8].
Overexpression
Overexpression of VKORC1L1 or its redox partners can enhance vitamin K epoxide reductase activity and reveal downstream effects on p53 and androgen receptor signaling [1, 2, 3]. Overexpression of protein disulfide isomerase has been shown to enhance vitamin K epoxide reductase activity, demonstrating the utility of gain-of-function models [3, 6]. Such models complement knockout studies by providing bidirectional control over enzyme activity [1, 3].
How EDITGENE Supports vitamin-K-epoxide reductase (warfarin-insensitive) activity Research
Researchers studying vitamin-K-epoxide reductase (warfarin-insensitive) activity-related genes often need to determine whether a candidate gene is causally involved in the redox reaction, how specific variants affect warfarin sensitivity, and which downstream pathways such as p53 or androgen receptor signaling are engaged [1, 2, 4]. Answering these questions requires precise, reproducible cell models that can isolate the warfarin-insensitive activity from the canonical vitamin K cycle [1, 4, 8].
Contact EDITGENE today to design your custom CRISPR model for vitamin-K-epoxide reductase (warfarin-insensitive) activity research.
Frequently Asked Questions About vitamin-K-epoxide reductase (warfarin-insensitive) activity
What is GO:0047058?
GO:0047058 is the Gene Ontology molecular function term for vitamin-K-epoxide reductase (warfarin-insensitive) activity, defined as catalysis of the reduction of vitamin K 2,3-epoxide to the hydroquinone form using a dithiol reductant, and it is characterized as warfarin-insensitive [7, 8].
What does vitamin-K-epoxide reductase (warfarin-insensitive) activity do?
It catalyzes the reduction of vitamin K 2,3-epoxide to 3-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone using oxidized dithiothreitol, which is converted to 1,4-dithiothreitol, as defined by QuickGO and supported by vitamin K cycle studies [7, 8].
What genes are involved in vitamin-K-epoxide reductase (warfarin-insensitive) activity?
VKORC1L1 is a principal gene associated with warfarin-insensitive vitamin K epoxide reductase activity, and redox partners such as protein disulfide isomerase enhance the activity [1, 3, 6].
How is GO:0047058 different from warfarin-sensitive vitamin K epoxide reductase activity?
The warfarin-insensitive activity described by GO:0047058 remains functional in the presence of 4-hydroxycoumarin anticoagulants, whereas the canonical VKORC1-centered activity is warfarin-sensitive, as shown by biochemical stereoselectivity studies [4, 7].
Why is vitamin K epoxide reductase important in cancer?
Regulation of VKORC1L1 is critical for p53-mediated tumor suppression through vitamin K metabolism, linking this activity to cancer biology.
Does vitamin K epoxide reductase affect androgen receptor signaling?
Yes, vitamin K epoxide reductase regulation influences androgen receptor activity, connecting the activity to steroid hormone signaling and prostate cancer biology.
What redox partners regulate vitamin K epoxide reductase activity?
Protein disulfide isomerase has been shown to enhance vitamin K epoxide reductase activity, indicating that redox protein partners modulate this function [3, 6].
What is the vitamin K cycle?
The vitamin K cycle is the metabolic pathway that recycles vitamin K to its reduced hydroquinone form, supporting gamma-carboxylation of vitamin K-dependent proteins, and GO:0047058 participates in this cycle [7, 8].
How can researchers study GO:0047058 in the lab?
Researchers can use enzymatic activity assays with dithiothreitol, CRISPR knockout and overexpression models, and redox interaction studies to investigate GO:0047058 [1, 3, 4, 7].
Is vitamin K epoxide reductase found in photosynthetic organisms?
Vitamin K chemistry participates in redox processes in photosynthetic organisms, indicating that related epoxide reductase activities have broader biological roles.
Conclusion
GO:0047058, vitamin-K-epoxide reductase (warfarin-insensitive) activity, defines a redox reaction that reduces vitamin K 2,3-epoxide using a dithiol reductant and is distinguished by its insensitivity to warfarin [4, 7, 8]. Its association with VKORC1L1 links it to p53-mediated tumor suppression and vitamin K metabolism, while its regulation by protein disulfide isomerase and its influence on androgen receptor activity connect it to redox biology and steroid signaling [1, 2, 3, 6]. Understanding this activity requires integrating enzymology, redox biology, and CRISPR-based models [1, 4, 8]. For researchers, GO:0047058 provides a precise ontology anchor for experiments that separate warfarin-insensitive vitamin K epoxide reduction from the canonical warfarin-sensitive step. CRISPR knockout, point-mutation, knock-in, and overexpression models, combined with enzymatic and metabolic assays, offer a robust path to dissect its mechanism and disease relevance [1, 2, 4, 8].
References
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- 3. Chetot T et al.. 2022. Overexpression of protein disulfide isomerase enhances vitamin K epoxide reductase activity.. Biochem Cell Biol 100(2):152-161 PMID: 35007172
- 4. Thijssen HH et al.. 1988. Vitamin K 2,3-epoxide reductase: the basis for stereoselectivity of 4-hydroxycoumarin anticoagulant activity.. Br J Pharmacol 95(3):675-82 PMID: 3207986
- 5. Kruk J et al.. 2026. Vitamin K in photosynthetic organisms.. Planta 264(3) PMID: 42570116
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