Many top-selling drugs used to treat cancer and lower cholesterol are made from organic compounds called polyketides, which are found in nature but historically difficult for chemists to alter and reproduce in large quantities.
For the first time, scientists at UC Irvine have discovered how polyketides form their ringlike shape, making it easier for chemists to manipulate them into new drugs.
The key, they found, is an enzyme called aromatase/cyclase, which forms a C-shape mold in which polyketides can form one molecule at a time. By changing this mold, chemists can control the size and shape of the polyketide, resulting in the formation of new drugs.
“Almost every polyketide has rings in its chemical structure, and if we can control ring formation, we can produce more polyketide drugs,” said Sheryl Tsai, lead author of this study and an assistant professor of molecular biology and biochemistry and chemistry at UCI. “Until now, polyketide ring formation was a mystery that hampered our efforts to produce new drugs.”
The research appears online this week in the Proceedings of the National Academy of Sciences.
Polyketide-based drugs and products account for more than $35 billion in sales annually. They include antibiotics that can cure a bacteria infection (tetracycline and erythromycin); anti-cancer drugs used in chemotherapy (doxorubicin and mithramycin); anti-oxidants that help prevent cancer and promote heart strength (EGCG and resverastrol); and drugs that lower cholesterol levels (Zocor). Green tea and red wine also contain beneficial polyketides.
Polyketides are made naturally by bacteria, fungi, plants and marine animals. Those organisms produce polyketides to kill their predators, be it another bacteria or fungi. They can produce different types of polyketides that kill different types of enemies.
“Because bacteria do not have arthritis or diabetes, they would not evolutionally select polyketides that could be used for arthritis or diabetes treatment,” Tsai said. “But we can coax the bacteria to do precisely that, if we can control the ring formation in the polyketides.”
Prior to this study, it was not known how nature controls the polyketide ring shape, which is essential for antibiotic and anti-cancer properties.
By using molecular cloning and chemical biology techniques, Tsai and her scientific team discovered that the aromatase/cyclase enzyme has a pocket that shapes the polyketide, promoting a unique ring pattern.
Said Tsai: “We hope this will lead to the development of new drugs in such areas as cancer therapeutics, obesity treatment and stem cell research.”
UCI scientists Brian Ames, Tyler Korman, Peter Smith, Thanh Vu, along with UCLA researchers Yi Tang and Wenjun Zhang, also worked on this study, which was funded by the Pew Foundation and the National Institutes of Health.
About the University of California, Irvine: The University of California, Irvine is a top-ranked university dedicated to research, scholarship and community service. Founded in 1965, UCI is among the fastest-growing University of California campuses, with more than 27,000 undergraduate and graduate students and nearly 2,000 faculty members. The third-largest employer in dynamic Orange County, UCI contributes an annual economic impact of $3.6 billion. For more UCI news, visit www.today.uci.edu.
News Radio: UCI maintains on campus an ISDN line for conducting interviews with its faculty and experts. The use of this line is available free-of-charge to radio news programs/stations who wish to interview UCI faculty and experts. Use of the ISDN line is subject to availability and approval by the university.
Jennifer Fitzenberger | EurekAlert!
Newly designed molecule binds nitrogen
23.02.2018 | Julius-Maximilians-Universität Würzburg
Atomic Design by Water
23.02.2018 | Max-Planck-Institut für Eisenforschung GmbH
A newly developed laser technology has enabled physicists in the Laboratory for Attosecond Physics (jointly run by LMU Munich and the Max Planck Institute of Quantum Optics) to generate attosecond bursts of high-energy photons of unprecedented intensity. This has made it possible to observe the interaction of multiple photons in a single such pulse with electrons in the inner orbital shell of an atom.
In order to observe the ultrafast electron motion in the inner shells of atoms with short light pulses, the pulses must not only be ultrashort, but very...
A group of researchers led by Andrea Cavalleri at the Max Planck Institute for Structure and Dynamics of Matter (MPSD) in Hamburg has demonstrated a new method enabling precise measurements of the interatomic forces that hold crystalline solids together. The paper Probing the Interatomic Potential of Solids by Strong-Field Nonlinear Phononics, published online in Nature, explains how a terahertz-frequency laser pulse can drive very large deformations of the crystal.
By measuring the highly unusual atomic trajectories under extreme electromagnetic transients, the MPSD group could reconstruct how rigid the atomic bonds are...
Quantum computers may one day solve algorithmic problems which even the biggest supercomputers today can’t manage. But how do you test a quantum computer to...
For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.
In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...
Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale
Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
23.02.2018 | Physics and Astronomy
23.02.2018 | Health and Medicine
23.02.2018 | Physics and Astronomy