A5087713399- Vitamin K Research Studies
- Pharmacogenetics and Drug Metabolism
- Hormonal Regulation and Hypertension
- Vitamin C and Antioxidants Research
- Breast Cancer Treatment Studies
- Eicosanoids and Hypertension Pharmacology
- Enzyme Structure and Function
- Biotin and Related Studies
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Enzyme function and inhibition
- Atrial Fibrillation Management and Outcomes
- Crystallization and Solubility Studies
- Blood Coagulation and Thrombosis Mechanisms
- Ion channel regulation and function
- Cancer Research and Treatments
- X-ray Diffraction in Crystallography
- Alcoholism and Thiamine Deficiency
- Advances in Oncology and Radiotherapy
- Hemophilia Treatment and Research
- Electrochemical sensors and biosensors
- Amino Acid Enzymes and Metabolism
- Muscle metabolism and nutrition
- Advanced Radiotherapy Techniques
- bioluminescence and chemiluminescence research
- Plant biochemistry and biosynthesis
University of North Carolina at Chapel Hill
2016-2025
Peking University Cancer Hospital
2020-2023
Peking University
1993-2023
National Institute of Environmental Health Sciences
2008
National Institutes of Health
2008
University of North Carolina Health Care
2006
Duke University Hospital
2000
Duke Medical Center
2000
Rosalind Franklin University of Medicine and Science
1994-1996
Beijing City University
1992-1993
Abstract Vitamin K is a vital micronutrient implicated in variety of human diseases. Warfarin, vitamin antagonist, the most commonly prescribed oral anticoagulant. Patients overdosed on warfarin can be rescued by administering high doses because existence warfarin-resistant reductase. Despite functional discovery reductase over eight decades ago, its identity remained elusive. Here, we report identification using genome-wide CRISPR-Cas9 knockout screen with K-dependent apoptotic reporter...
Vitamin K epoxide reductase (VKOR) catalyzes the conversion of vitamin 2,3-epoxide into in redox cycle. Recently, gene encoding catalytic subunit VKOR was identified as a 163-amino acid integral membrane protein. In this study we report experimentally derived topology VKOR. Our results show that four hydrophobic regions predicted potential transmembrane domains can individually insert across endoplasmic reticulum vitro. However, intact enzyme there are only three domains, residues 10–29,...
Vitamin K epoxide (or oxido) reductase (VKOR) is the target of warfarin and provides vitamin hydroquinone for carboxylation select glutamic acid residues K-dependent proteins which are important coagulation, signaling, bone metabolism. It has been known at least 20 years that cysteines required VKOR function. To investigate their importance, we mutated each seven in VKOR. In addition, made with both C43 C51 to alanine (C43A/C51A), as well a C43−C51 deleted. Each enzyme was purified...
Abstract Gamma-carboxylation, catalyzed by γ-glutamyl carboxylase (GGCX), is a critical post-translational modification essential for the biological activity of vitamin K-dependent proteins (VKDPs). Mutations in GGCX, depending on their specific location, result coagulation factor deficiency type 1 (VKCFD1), which encompasses broad spectrum clinical manifestations ranging from mild to severe, including bleeding disorders, osteoporosis, and vascular calcification. The limited knowledge GGCX’s...
Abstract Cubane was recently validated as a phenyl ring (bio)isostere, but highly strained caged carbocyclic systems lack π character, which is often critical for mediating key biological interactions. This electronic property restriction associated with cubane has been addressed herein cyclooctatetraene (COT), using known pharmaceutical and agrochemical compounds templates. COT either outperformed or matched in multiple cases suggesting that versatile complementarity exists between the two...
Vitamin K epoxide reductase complex subunit 1 (VKORC1) reduces vitamin in the cycle for post-translational modification of proteins that are involved a variety biological functions. However, physiological function VKORC1-like (VKORC1L1), paralogous enzyme sharing about 50% protein identity with VKORC1, is unknown. Here we determined structural and functional differences these two enzymes using fluorescence protease protection (FPP) assay an vivo cell-based activity assay. We show VKORC1L1 to...
Vitamin K-dependent carboxylation is a post-translational modification essential for the biological function of coagulation factors. Defects in are mainly associated with bleeding disorders. With discovery new vitamin proteins, importance now encompasses vascular calcification, bone metabolism, and other important physiological processes. Our current knowledge carboxylation, however, comes from vitro studies carried out under artificial conditions, which have limited usefulness understanding...
The vitamin K-dependent γ-glutamyl carboxylase binds an 18-amino acid sequence usually attached as a propeptide to its substrates. Price and Williamson (Protein Sci. (1993) 2, 1997–1998) noticed that residues 495–513 of the shares similarity with propeptide. They suggested this internal could bind intramolecularly binding site carboxylase, thereby preventing carboxylation substrates lacking recognition sequence. To test Price's hypothesis, we created nine mutant enzyme species have single or...
Vitamin K-dependent γ-glutamyl carboxylase is a 758 amino acid integral membrane glycoprotein that catalyzes the post-translational conversion of certain protein glutamate residues to γ-carboxyglutamate. Carboxylase has ten cysteine residues, but their form (sulfhydryl or disulfide) largely unknown. Pudota et al. in Pudota, B. N., Miyagi, M., Hallgren, K. W., West, A., Crabb, J. Misono, S., and Berkner, L. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 13033–13038 reported Cys-99 Cys-450 are...
Vitamin K epoxide reductase complex, subunit 1 (VKORC1) is a critical participant in the production of active forms reduced vitamin and required for modification K-dependent proteins. Homologues VKORC1 (VKORH) exist throughout evolution, but bacteria they appear to function oxidative protein folding as well quinone reduction. In current study we explore two questions: Do VKORHs mammalian cycle? Is pair loop cysteines-C43 C51 human VKORC1-conserved all VKORC1s, essential activity reduction?We...
Signal peptide (SP) is essential for protein secretion, and pathogenic variants in the SP of factor IX (FIX) have been identified hemophilia B (HB). However, underlying mechanism genotype-phenotype correlation these has not well studied. Here, we systematically examined effects 13 point FIX using different approaches. Our results showed that lead to HB by missense and/or aberrant premessenger RNA (pre-mRNA) splicing. The a hydrophobic core (h-region) mainly affected cotranslational...