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Newswise — DALLAS – March 04, 2025 – Using a powerful microscopy technique, a team led by researchers at UT Southwestern Medical Center has gained insights into how the body uses vitamin K, an essential nutrient that plays a pivotal role in blood clotting and other physiological functions. Their findings, published in , could eventually help scientists develop new anticoagulants to prevent or treat conditions including strokes, heart attacks, atrial fibrillation, and deep vein thrombosis, a type of clot that usually occurs in the legs.

“This research paves the way for innovative anticoagulation therapies by targeting the enzyme GGCX, a novel approach with the potential to overcome the limitations of current vitamin K antagonists such as warfarin,” said , Assistant Professor of  and member of the  at UT Southwestern. “This could result in safer, more effective options for patients with coagulation disorders.”

Vitamin K, which is fat-soluble and found in sources including leafy green vegetables, carrots, and organ meat, is necessary to activate a variety of proteins. These proteins are not only pivotal for clotting but also for bone and heart health, energy metabolism, brain development, and fertility, among other roles. Vitamin K activates these proteins through a chemical reaction called carboxylation, which is mediated by an enzyme called gamma-glutamyl carboxylase (GGCX). But how GGCX facilitates this reaction has been unclear.

To answer this question, Dr. Qi and his colleagues used cryo-electron microscopy (cryo-EM). By freezing molecules at temperatures around minus 196 C (about minus 320 F) and bombarding them with streams of electrons, cryo-EM produces images that can show the molecules’ three-dimensional structures at atomic resolution.

Dr. Qi’s team worked with UTSW’s  to perform cryo-EM on GGCX alone, when it was bound to a vitamin K-dependent protein called osteocalcin that plays a critical role in bone metabolism, and when it was bound to both osteocalcin and vitamin K. The findings showed that GGCX had a disordered structure when it wasn't bound to other molecules. But when bound to osteocalcin, GGCX formed a pocket of the right shape and size to attach to vitamin K. The structure of GGCX bound to both osteocalcin and vitamin K confirmed that vitamin K attached to the pocket, bringing osteocalcin and vitamin K in close contact to perform carboxylation.

Surprisingly, the researchers saw another molecule in all three structures. A closer look showed that it was cholesterol, which seems to play a role in stabilizing GGCX’s structure to facilitate binding to both osteocalcin and vitamin K. This role of cholesterol in vitamin K-dependent molecular pathways was previously unknown, Dr. Qi said. Now that scientists know the structure of GGCX and how it interacts with both vitamin K and its dependent proteins, Dr. Qi added, they could design drugs that interfere with binding.

“Structure is a powerful way to reveal a molecule’s function,” Dr. Qi said. “Here, we see the structure of vitamin K and its dependent protein binding to a critical enzyme, shedding light on how the chemical reaction that activates vitamin K-dependent proteins takes place.”

Dr. Qi said this study builds on his earlier postdoctoral work in the UTSW lab of , Associate Professor of  and . They collaborated to investigate cholesterol synthesis regulation with Nobel Laureates , Professor of Molecular Genetics and , and , Chair and Professor of Molecular Genetics, as well as , Professor of Molecular Genetics.

Other UTSW researchers who contributed to this study include first author Rong Wang, Ph.D., Senior Research Scientist; Baozhi Chen, M.D., Manager of the ; Alyssa Ayala, B.S., Research Assistant; and Ning Zhou, Ph.D., Postdoctoral Researcher.

Drs. Brown and Goldstein are Regental Professors at UTSW. Dr. Brown is Director of the Erik Jonsson Center for Research in Molecular Genetics and Human Disease. Dr. Brown holds the W.A. (Monty) Moncrief Distinguished Chair in Cholesterol and Arteriosclerosis Research and the Paul J. Thomas Chair in Medicine. Dr. Goldstein holds the Julie and Louis A. Beecherl, Jr. Distinguished Chair in Biomedical Research and the Paul J. Thomas Chair in Medicine. Dr. DeBose-Boyd holds the Beatrice and Miguel Elias Distinguished Chair in Biomedical Science. Dr. Li is a Rita C. and William P. Clements, Jr. Scholar in Biomedical Research. Dr. Qi is a Cancer Prevention and Research Institute of Texas Scholar (CPRIT) and a Michael L. Rosenberg Scholar in Medical Research. 

This study was funded by grants from the National Institutes of Health (P01HL160487), the Endowed Scholars Program in Medical Science of UT Southwestern Medical Center, and CPRIT (RR230054).

Related Video

Dr. Xiaofeng Qi discusses his vitamin K research during his presentation at UT Southwestern’s 2024 New Faculty Research Forum.

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.