(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.
In honor of UTSA's 50th Anniversary in 2019, the university is hosting Roadrunner Days Spring Edition - two weeks of semester-launching activities built around our deeply held values of student success, student involvement, community service and fun!Various locations, Main and Downtown Campuses
Opening Reception got exhibit featuring artists Miguel Aragon, Aaron Coleman, Sandra Fernandez, Annalise Gratovich, Marco Hernandez, Kristen Powers Nowlin, & Patricia Villalobos EcheverriaMain Art Gallery, Arts Building (ART 2.03.04), Main Campus
Tracy Cowden, Roland K. Blumberg Endowed Professor in Music and chair of the UTSA Department of Music launches the UTSA 50th Anniversary Scholars Speaker Series with Music as Medicine: The Power and Influence of Music on our Health.Radius Center, 106 Auditorium Cir. #120, San Antonio
UTSA African American Studies Program presents this series featuring Walter M. Kimbrough, president of Dillard University.Student Union Retama Auditorium (SU 2.02.02), Main Campus)
Join fellow Runners to walk for 10 minutes on the Main Campus. The event reminds us of the importance of exercise, diet and healthy habits in protecting our hearts.Outside the North Paseo Building, Main Campus
The annual event features authentic foods, music, dance, martial arts, shopping, games and entertainment from China, to the Indian Sub-continent, and the island nations of the Pacific. The Festival features two stages, a martial arts demonstration area, children’s hands on crafting area, anime activities, bonsai and ikebana displays, mahjong table and more.UTSA Institute of Texan Cultures, Hemisfair Campus
UTSA Libraries will host Bryan Gervais, UTSA assistant professor in the Dept. of Political Science & Geography, for his presentation "Political Incivility in the Digital Age." Pizza will be provided to UTSA students while supplies last.John Peace Library Assembly Room (JPL 4.04.22)
Level up your career with a graduate business degree from the UTSA College of Business. Join us for this Open House to learn which of our 13 degree programs is right for you.Business Building (BB 2.06.04), Main Campus
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