(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.
Come celebrate the doctoral students graduating this commencement season.H-E-B Student Union Ballrooms, UTSA Main Campus
Celebrate the accomplishments of the graduates of the College for Health, Community and Policy, College of Liberal and Fine Arts and College of Sciences.Alamodome, 100 Montana St, San Antonio, TX 78203
Celebrate the accomplishments of the graduates of the Carlos Alvarez College of Business, College of Education and Human Development, Margie and Bill Klesse College of Engineering and Integrated Design and University College.Alamodome, 100 Montana St, San Antonio, TX 78203
First Friday Stargazing gives anyone free access to the night sky using university telescopes and teaching equipment. Weather permitting, experienced astronomers will provide a handful of telescopes of varying designs, give training on how each operates, and point to various astronomical objects that may appear in the sky for that given time of the year. If you have a telescope and do not know how to operate it, feel free to bring it and get instructions on its use.4th Floor of Flawn Science Building, 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.
UTSA is a proud Hispanic Serving Institution (HSI) as designated by the U.S. Department of Education.
The University of Texas at San Antonio, a Hispanic Serving Institution situated in a global city that has been a crossroads of peoples and cultures for centuries, values diversity and inclusion in all aspects of university life. As an institution expressly founded to advance the education of Mexican Americans and other underserved communities, our university is committed to ending generations of discrimination and inequity. UTSA, a premier public research university, fosters academic excellence through a community of dialogue, discovery and innovation that embraces the uniqueness of each voice.