(Sept. 5, 2018) -- A groundbreaking discovery by chemists at UTSA will have a significant impact on how pharmaceutical companies develop new drug treatments. The breakthrough involves fluorine, which forms the second strongest carbon bond (C-F) known to science, after the carbon-silicon (C-Si) bond.
Fluorine is one of the most fundamental elements of life. In its fluoride form, it’s a mineral with anti-acid properties used in toothpaste and drinking water to prevent dental cavities. It is also widely used by medicinal chemists in cancer treatment, antibiotics, anti-depressants, steroids and other drugs. Fluorine is prevalent in modern drugs because it stabilizes drugs and improves their biological activity.
For many years, researchers in the UTSA Metalloprotein Research Laboratory, led by Aimin Liu, a Lutcher Brown Distinguished Professor, have been studying the regulation of thiols, compounds that affect a variety of biological functions in mammals such as redox stress levels, energy balance, cellular signaling, heart health, and autoimmune and neurological conditions. When thiol levels are stable, individuals are generally healthy. When they increase too much and for too long, conditions such as rheumatoid arthritis, breast cancer, Alzheimer's and Parkinson's diseases can develop.
Cysteine dioxygenase (CDO) and cysteamine dioxygenase (ADO) regulate the body’s thiol levels. When the thiol levels are elevated, CDO and ADO develop catalytic amplifiers to quickly remove thiol from the body. Scientists don’t yet know precisely how the enzymes make the amplifiers. The UTSA researchers were studying this when they made their significant discovery.
The scientists performed a technique on CDO called genetic code expansion. The cutting-edge technique was brought to UTSA by post-doctoral fellow Jiasong Li, and was initially invented by The Peter G. Schultz laboratory at The Scripps Research Institute.
The researchers created a new form of CDO with two very strong carbon-fluorine bonds. This should have made it more difficult for the enzyme to break those carbon-fluorine bonds and produce its catalytic amplifier. What they observed, however, surprised them. They discovered that the modified CDO was still able to break its carbon-fluorine bonds to generate its full catalytic assembly.
This is the first time that scientists have demonstrated the cleavage (breakage) of a carbon-fluorine bond through oxidation in proteins. This means that it may be possible that human bodies are capable of breaking these bonds in the drugs that are consumed.
The UTSA researchers also uncovered clues as to how thiols generate their catalytic amplifiers after the proteins are built. Their discovery is described in Nature Chemical Biology.
“This is an important discovery. More than 20 percent of pharmaceutical drugs contain fluorine,” said Michael Doyle, the Rita and John Feik Distinguished University Chair in Medicinal Chemistry at UTSA. “Because of their strength, fluorine-carbon bonds resist normal drug metabolism and can extend the beneficial lifetime of the drug in the body. Fluorine in drug molecules can also increase their ability to cross membrane barriers and enter cells. That the carbon-fluorine is strongly resistant to cleavage is a long-held belief in medicinal chemistry. Professor Liu's discovery changes that.”
To expand on their discovery, the Liu lab, including a third-year UTSA undergraduate student, graduate students, post-doctoral fellows and two staff chemists—Wendell Griffith and Daniel Wherritt—utilized a similar approach to determine the catalytic assembly of ADO, a sibling enzyme to CDO. In addition to successfully identifying the catalytic amplifier in ADO, they discovered a unique structural motif that hindered its detection by routine lab techniques. These findings are reported in another paper recently published in Angewandte Chemie, an internationally renowned chemical journal.
“Dr. Liu’s laboratory provides excellent opportunities for students to get involved in very interesting and impactful research projects,” said Waldemar Gorski, professor and chair of the UTSA Department of Chemistry.
While fluoride is widely used by medicinal chemists in drug treatments, Liu says his team’s discovery should remind pharmaceutical companies that fluorine chemistry is very complex. Although valuable, he recommends that they proceed with caution, because there is still much to learn.
“We see a rush by pharmaceutical companies to get drugs through development, into clinical trials and on the market,” said Liu. “This research reminds us that we need to be thorough and careful. Fluorine chemistry is very complex.”
“This research is vitally important,” said Howard Grimes, Interim Dean of the College of Sciences at UTSA. “Understanding the C-F bond is critical to our understanding of drug design and improving the lives of patients.”
This research was supported by multiple grants from National Institute of General Medical Sciences, National Institute of Mental Health, National Science Foundation and Lutcher Brown Endowment Funds from The University of Texas at San Antonio.
Learn more about the UTSA Metalloprotein Research Laboratory.
Learn more about UTSA Professor Aimin Liu, who specializes in cofactor biosynthesis, mechanistic enzymology, metabolism and other areas.
Learn more about UTSA degree programs in chemistry.
The NSA Codebreaker Challenge provides students with a hands-on opportunity to develop their reverse-engineering, low-level code analysis skills while working on a realistic problem set centered around the NSA’s mission. Developer Eric Bryant will present a Tech Talk and answer questions about the challenge. Doors open at 2:30 p.m. Free pizza. Open to all.John Peace Library (JPL 4.04.22), Main Campus
UTSA's Office of Sustainability hosts a full day of activities to celebrate the opening of the Tito Bradshaw Bicycle Repair Shop. A ribbon-cutting at 6 p.m.will include President Eighmy, Mayor Nirenberg, Councilman Pelaez and Councilwoman Gonzales.Ximenes Ave. between Ximenes Ave. Lot and Brackenridge Ave. Lot 1, Main Campus
Annual symposium to highlight the importance of effective translation and interpreting in our global community.H-E-B Student Union Travis Room (HSU 2.202), Main Campus
The UTSA Institute for Law and Public Affairs and the Southwest Association of Prelaw Advisors will host the annual Law School Fair for students interested in attending law school. Attendees will have the opportunity to meet with representatives from approximately 90 ABA approved law schools (including all law schools in Texas), and learn about admissions, financing, course offerings, student life, program reputation, with the opportunity to gain application fee waivers.H-E-B Student Union, Ballroom (HSU 1.104), Main Campus
This event will showcase the new Large-Scale Testing Laboratory, built to serve students and researchers in UTSA's Department of Civil and Environmental Engineering. The Grand Opening will feature speakers, a live demonstration, and tours.Large Scale Testing Laboratory, Main Campus
To prepare, graduation candidates should attend to obtain important information about the ceremony and life after UTSA. At the event, they can order their ceremonial cap and gown and other Commencement-related items as well as win prizes and capture lasting memories with fellow Roadrunners at a selfie station. UTSA ID Card required; no reservation needed.Buena Vista Street Building, Meeting Assembly Room (BVB 1.338), Downtown Campus
To prepare, graduation candidates should attend to obtain important information about the ceremony and life after UTSA. At the event, they can order their ceremonial cap and gown and other Commencement-related items as well as win prizes and capture lasting memories with fellow Roadrunners at a selfie station. UTSA ID Card required; no reservation needed.H-E-B Student Union, Ballrooms (HSU 1.104 and 1.106), Main Campus
The University of Texas at San Antonio is dedicated to the advancement of knowledge through research and discovery, teaching and learning, community engagement and public service. As an institution of access and excellence, UTSA embraces multicultural traditions and serves as a center for intellectual and creative resources as well as a catalyst for socioeconomic development and the commercialization of intellectual property - for Texas, the nation and the world.
To be a premier public research university, providing access to educational excellence and preparing citizen leaders for the global environment.
We encourage an environment of dialogue and discovery, where integrity, excellence, inclusiveness, respect, collaboration and innovation are fostered.