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Mathematical Modeling Makes a Breakthrough for a New CRSD Medication
PhD Candidate Dae Wook Kim (Left) and Professor Jae Kyoung Kim (Right)
- Systems approach reveals photosensitivity and PER2 level as determinants of clock-modulator efficacy -
Mathematicians’ new modeling has identified major sources of interspecies and inter-individual variations in the clinical efficacy of a clock-modulating drug: photosensitivity and PER2 level. This enabled precision medicine for circadian disruption.
A KAIST mathematics research team led by Professor Jae Kyoung Kim, in collaboration with Pfizer, applied a combination of mathematical modeling and simulation tools for circadian rhythms sleep disorders (CRSDs) to analyze the animal data generated by Pfizer. This study was reported in Molecular Systems Biology as the cover article on July 8.
Pharmaceutical companies have conducted extensive studies on animals to determine the candidacy of this new medication. However, the results of animal testing do not always translate to the same effects in human trials. Furthermore, even between humans, efficacy differs across individuals depending on an individual’s genetic and environmental factors, which require different treatment strategies.
To overcome these obstacles, KAIST mathematicians and their collaborators developed adaptive chronotherapeutics to identify precise dosing regimens that could restore normal circadian phase under different conditions.
A circadian rhythm is a 24-hour cycle in the physiological processes of living creatures, including humans. A biological clock in the hypothalamic suprachiasmatic nucleus in the human brain sets the time for various human behaviors such as sleep.
A disruption of the endogenous timekeeping system caused by changes in one’s life pattern leads to advanced or delayed sleep-wake cycle phase and a desynchronization between sleep-wake rhythms, resulting in CRSDs. To restore the normal timing of sleep, timing of the circadian clock could be adjusted pharmacologically.
Pfizer identified PF-670462, which can adjust the timing of circadian clock by inhibiting the core clock kinase of the circadian clock (CK1d/e). However, the efficacy of PF-670462 significantly differs between nocturnal mice and diurnal monkeys, whose sleeping times are opposite.
The research team discovered the source of such interspecies variations in drug response by performing thousands of virtual experiments using a mathematical model, which describes biochemical interactions among clock molecules and PF-670462. The result suggests that the effect of PF-670462 is reduced by light exposure in diurnal primates more than in nocturnal mice. This indicates that the strong counteracting effect of light must be considered in order to effectively regulate the circadian clock of diurnal humans using PF-670462.
Furthermore, the team also found the source of inter-patients variations in drug efficacy using virtual patients whose circadian clocks were disrupted due to various mutations. The degree of perturbation in the endogenous level of the core clock molecule PER2 affects the efficacy.
This explains why the clinical outcomes of clock-modulating drugs are highly variable and certain subtypes are unresponsive to treatment. Furthermore, this points out the limitations of current treatment strategies tailored to only the patient’s sleep and wake time but not to the molecular cause of sleep disorders.
PhD candidate Dae Wook Kim, who is the first author, said that this motivates the team to develop an adaptive chronotherapy, which identifies a personalized optimal dosing time of day by tracking the sleep-wake up time of patients via a wearable device and allows for a precision medicine approach for CRSDs.
Professor Jae Kyoung Kim said, "As a mathematician, I am excited to help enable the advancement of a new drug candidate, which can improve the lives of so many patients. I hope this result promotes more collaborations in this translational research.”
This research was supported by a Pfizer grant to KAIST (G01160179), the Human Frontiers Science Program Organization (RGY0063/2017), and a National Research Foundation (NRF) of Korea Grant (NRF-2016 RICIB 3008468 and NRF-2017-Fostering Core Leaders of the Future Basic Science Program/ Global Ph.D. Fellowship Program).
Figure 1. Interspecies and Inter-patients Variations in PF-670462 Efficacy
Figure 2. Journal Cover Page
Publication:
Dae Wook Kim, Cheng Chang, Xian Chen, Angela C Doran, Francois Gaudreault, Travis Wager, George J DeMarco, and Jae Kyoung Kim. 2019. Systems approach reveals photosensitivity and PER2 level as determinants of clock-modulator efficacy. Molecular Systems Biology. EMBO Press, Heidelberg, Germany, Vol. 15, Issue No. 7, Article, 16 pages. https://doi.org/10.15252/msb.20198838
Profile: Prof. Jae Kyoung Kim, PhD
jaekkim@kaist.ac.kr
http://mathsci.kaist.ac.kr/~jaekkim
Associate Professor
Department of Mathematical Sciences
Korea Advanced Institute of Science and Technology (KAIST)
http://kaist.ac.kr Daejeon 34141, Korea
Profile: Dae Wook Kim, PhD Candidate
0308kdo@kaist.ac.kr
http://mathsci.kaist.ac.kr/~jaekkim
PhD Candidate
Department of Mathematical Sciences
Korea Advanced Institute of Science and Technology (KAIST)
http://kaist.ac.kr Daejeon 34141, Korea
Profile: Dr. Cheng Chang, PhD
cheng.chang@pfizer.com
Associate Director of Clinical Pharmacology
Clinical Pharmacology, Global Product Development
Pfizer
https://www.pfizer.com/ Groton 06340, USA
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2019.07.09 View 33593 -
Two Alumni Win the Korea Best Scientist and Technologist Awards
Vice Chairman Ki-Nam Kim (Left) and Distinguished Professor Sukbok Chang (Right)
<ⓒ Photo by MSIT and KOFST>
Distinguished KAIST Professor Sukbok Chang from the Department of Chemistry and Vice Chairman Ki-Nam Kim of Samsung Electronics were selected as the winners of the “2019 Korea Best Scientist and Technologist Awards” by the Ministry of Science and ICT (MSIT) and the Korean Federation of Science and Technology Societies (KOFST). The awards, which were first handed out in 2003, are the highest honor bestowed to the two most outstanding scientists in Korea every year, and this year’s awardees are of greater significance as they are both KAIST alumni.
Professor Chang was recognized for his pioneering achievements and lifetime contributions to the development of carbon-hydrogen activation strategies, especially for carbon-carbon, carbon-nitrogen, and carbon-oxygen formations. His research group has also been actively involved in the development of highly selective catalytic systems allowing the controlled defunctionalization of bio-derived platform substrates under mild conditions, and opening a new avenue for the utilization of biomass-derived platform chemicals. The results of his study have been introduced worldwide through many prestigious journals including Science, Nature Chemistry, and Nature Catalysis, making him one of the world's top 1% researchers by the number of references made to his papers by his peers over four consecutive years from 2015 to 2018.
Vice Chairman Kim, who received his M.E. degree from KAIST’s School of Electrical Engineering in 1983, has been credited with playing a leading role in the development of system semiconductors.
The awards were conferred on July 4 at the opening ceremony of the 2019 Korea Science and Technology Annual Meeting.
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2019.07.09 View 9783 -
Deep Learning-Powered 'DeepEC' Helps Accurately Understand Enzyme Functions
(Figure: Overall scheme of DeepEC)
A deep learning-powered computational framework, ‘DeepEC,’ will allow the high-quality and high-throughput prediction of enzyme commission numbers, which is essential for the accurate understanding of enzyme functions.
A team of Dr. Jae Yong Ryu, Professor Hyun Uk Kim, and Distinguished Professor Sang Yup Lee at KAIST reported the computational framework powered by deep learning that predicts enzyme commission (EC) numbers with high precision in a high-throughput manner.
DeepEC takes a protein sequence as an input and accurately predicts EC numbers as an output. Enzymes are proteins that catalyze biochemical reactions and EC numbers consisting of four level numbers (i.e., a.b.c.d) indicate biochemical reactions. Thus, the identification of EC numbers is critical for accurately understanding enzyme functions and metabolism.
EC numbers are usually given to a protein sequence encoding an enzyme during a genome annotation procedure. Because of the importance of EC numbers, several EC number prediction tools have been developed, but they have room for further improvement with respect to computation time, precision, coverage, and the total size of the files needed for the EC number prediction.
DeepEC uses three convolutional neural networks (CNNs) as a major engine for the prediction of EC numbers, and also implements homology analysis for EC numbers if the three CNNs do not produce reliable EC numbers for a given protein sequence. DeepEC was developed by using a gold standard dataset covering 1,388,606 protein sequences and 4,669 EC numbers.
In particular, benchmarking studies of DeepEC and five other representative EC number prediction tools showed that DeepEC made the most precise and fastest predictions for EC numbers. DeepEC also required the smallest disk space for implementation, which makes it an ideal third-party software component.
Furthermore, DeepEC was the most sensitive in detecting enzymatic function loss as a result of mutations in domains/binding site residue of protein sequences; in this comparative analysis, all the domains or binding site residue were substituted with L-alanine residue in order to remove the protein function, which is known as the L-alanine scanning method.
This study was published online in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) on June 20, 2019, entitled “Deep learning enables high-quality and high-throughput prediction of enzyme commission numbers.”
“DeepEC can be used as an independent tool and also as a third-party software component in combination with other computational platforms that examine metabolic reactions. DeepEC is freely available online,” said Professor Kim.
Distinguished Professor Lee said, “With DeepEC, it has become possible to process ever-increasing volumes of protein sequence data more efficiently and more accurately.”
This work was supported by the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries from the Ministry of Science and ICT through the National Research Foundation of Korea. This work was also funded by the Bio & Medical Technology Development Program of the National Research Foundation of Korea funded by the Korean government, the Ministry of Science and ICT.
Profile:
-Professor Hyun Uk Kim (ehukim@kaist.ac.kr)
https://sites.google.com/view/ehukim
Department of Chemical and Biomolecular Engineering
-Distinguished Professor Sang Yup Lee (leesy@kaist.ac.kr)
Department of Chemical and Biomolecular Engineering
http://mbel.kaist.ac.kr
2019.07.09 View 34544 -
Three Professors Receive Han Sung Science Awards
Three KAIST professors swept the 2nd Han Sung Science Awards. Professor Bum-Ki Min from the Departments of Mechanical Engineering and Physics, Professor Sun-Kyu Han from the Department of Chemistry, and Professor Seung-Jae Lee from the Department of Biological Sciences won all three awards presented by the Han Sung Scholarship Foundation, which recognizes promising mid-career scientists in the fields of physics, chemistry, and biological sciences. The awards ceremony will take place on August 16 in Hwaseong.
Professor Min was declared as the winner of the physics field in recognition of his outstanding research activities including searching for new application areas for metamaterials and investigating their unexplored functionalities. The metamaterials with a high index of refraction developed by Professor Min’s research team have caught the attention of scientists worldwide, as they can help develop high-resolution imaging systems and ultra-small, hyper-sensitive optical devices.
The chemistry field winner, Professor Han, is the youngest awardee so far at 36 years of age. He is often described as one of the most promising next-generation Korean scientists in the field of the total synthesis of complex natural products. Given the fact that this field takes very long-term research, he is making unprecedented research achievements. He is focusing on convergent and flexible synthetic approaches that enable access to not only a single target but various natural products with structural and biosynthetic relevance as well as unnatural products with higher biological potency.
Professor Lee was recognized for his contributions to the advancement of biological sciences, especially in aging research. Professor Lee’s team is taking a novel approach by further investigating complex interactions between genetic and environmental factors that affect aging, and identifying genes that mediate the effects. The team has been conducting large-scale gene discovery efforts by employing RNA sequencing analysis, RNAi screening, and chemical mutagenesis screening. They are striving to determine the functional significance of candidate genes obtained from these experiments and mechanistically characterize these genes.
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2019.07.03 View 7899 -
5 Biomarkers for Overcoming Colorectal Cancer Drug Resistance Identified
< Professor Kwang-Hyun Cho's Team >
KAIST researchers have identified five biomarkers that will help them address resistance to cancer-targeting therapeutics. This new treatment strategy will bring us one step closer to precision medicine for patients who showed resistance.
Colorectal cancer is one of the most common types of cancer worldwide. The number of patients has surpassed 1 million, and its five-year survival rate significantly drops to about 20 percent when metastasized. In Korea, the surge of colorectal cancer has been the highest in the last 10 years due to increasing Westernized dietary patterns and obesity. It is expected that the number and mortality rates of colorectal cancer patients will increase sharply as the nation is rapidly facing an increase in its aging population.
Recently, anticancer agents targeting only specific molecules of colon cancer cells have been developed. Unlike conventional anticancer medications, these selectively treat only specific target factors, so they can significantly reduce some of the side-effects of anticancer therapy while enhancing drug efficacy.
Cetuximab is the most well-known FDA approved anticancer medication. It is a biomarker that predicts drug reactivity and utilizes the presence of the ‘KRAS’ gene mutation. Cetuximab is prescribed to patients who don’t carry the KRAS gene mutation.
However, even in patients without the KRAS gene mutation, the response rate of Cetuximab is only about fifty percent, and there is also resistance to drugs after targeted chemotherapy. Compared with conventional chemotherapy alone, the life expectancy only lasts five months on average.
In research featured in the FEBS Journal as the cover paper for the April 7 edition, the KAIST research team led by Professor Kwang-Hyun Cho at the Department of Bio and Brain Engineering presented five additional biomarkers that could increase Cetuximab responsiveness using systems biology approach that combines genomic data analysis, mathematical modeling, and cell experiments. The experimental inhibition of newly discovered biomarkers DUSP4, ETV5, GNB5, NT5E, and PHLDA1 in colorectal cancer cells has been shown to overcome Cetuximab resistance in KRAS-normal genes. The research team confirmed that when suppressing GNB5, one of the new biomarkers, it was shown to overcome resistance to Cetuximab regardless of having a mutation in the KRAS gene.
Professor Cho said, “There has not been an example of colorectal cancer treatment involving regulation of the GNB5 gene.” He continued, “Identifying the principle of drug resistance in cancer cells through systems biology and discovering new biomarkers that could be a new molecular target to overcome drug resistance suggest real potential to actualize precision medicine.”
This study was supported by the National Research Foundation of Korea (NRF) and funded by the Ministry of Science and ICT (2017R1A2A1A17069642 and 2015M3A9A7067220).
Image 1. The cover of FEBS Journal for April 2019
2019.05.27 View 57459 -
Engineered Microbial Production of Grape Flavoring
(Image 1: Engineered bacteria that produce grape flavoring.)
Researchers report a microbial method for producing an artificial grape flavor. Methyl anthranilate (MANT) is a common grape flavoring and odorant compound currently produced through a petroleum-based process that uses large volumes of toxic acid catalysts.
Professor Sang-Yup Lee’s team at the Department of Chemical and Biomolecular Engineering demonstrated production of MANT, a naturally occurring compound, via engineered bacteria. The authors engineered strains of Escherichia coli and Corynebacetrium glutamicum to produce MANT through a plant-based engineered metabolic pathway.
The authors tuned the bacterial metabolic pathway by optimizing the levels of AAMT1, the key enzyme in the process. To maximize production of MANT, the authors tested six strategies, including increasing the supply of a precursor compound and enhancing the availability of a co-substrate. The most productive strategy proved to be a two-phase extractive culture, in which MANT was extracted into a solvent. This strategy produced MANT on the scale of 4.47 to 5.74 grams per liter, a significant amount, considering that engineered microbes produce most natural products at a scale of milligrams or micrograms per liter.
According to the authors, the results suggest that MANT and other related molecules produced through industrial processes can be produced at scale by engineered microbes in a manner that would allow them to be marketed as natural one, instead of artificial one.
This study, featured at the Proceeding of the National Academy of Sciences of the USA on May 13, was supported by the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries from the Ministry of Science and ICT.
(Image 2. Overview of the strategies applied for the microbial production of grape flavoring.)
2019.05.15 View 52778 -
First Korean Member of OceanObs' Organizing Committee
Professor Sung Yong Kim from the Department of Mechanical Engineering became the first Korean to be elected as an organizing committee member of the international conference OceanObs’19’, specializing in the ocean observing field.
Professor Kim has been actively engaged in advisory panels, technical committees, and working groups for the North Pacific Marine Science Organization (PICES). Through numerous activities, he was recognized for his professionalism and academic achievements, which led him to be appointed as a member of the organizing committee.
The organizing committee is comprised of leading scholars and researchers from 20 countries, and Professor Kim will be the first Korean scientist to participate on the committee.
Since 1999, the conference has been held every decade. Global experts specializing in oceanic observation gather to discuss research directions for the next ten years by monitoring physical, biological, and chemical variables in regional, national, and global oceans and applying marine engineering.
This year, approximately 20 institutes including NASA’s Jet Propulsion Laboratory (JPL), the National Science Foundation, the National Oceanic and Atmospheric Administration, and the European Space Agency will support funds as well as high-tech equipment to the conference.
This year’s conference theme is the governance of global ocean observing systems such as underwater gliders, unmanned vehicles, remote sensing, and observatories. The conference will hold discussions on monitoring technology and information systems to ensure human safety as well as to develop and preserve food resources. Additionally, participants will explore ways to expand observational infrastructures and carry out multidisciplinary approaches.
There will also be collaborations with the Global Ocean Observing System (GOOS) and the Partnership for Observation of the Global Oceans (POGO) to organize ocean observing programs and discuss priorities.
Finally, they will set a long-term plan for solving major scientific issues, such as climate change, ocean acidification, energy, and marine pollution.
Professor Kim said, “Based on the outcomes drawn from the conference, I will carry out research on natural disasters and climate change monitoring by using unmanned observing systems. I will also encourage more multidisciplinary research in this field.”
2019.01.25 View 9055 -
A Novel Material for Transparent and Flexible Displays
(Research team led by Professor Sang Youl Kim from the Department of Chemistry)
The next generation of flexible and transparent displays will require a high-performing and flexible polymeric material that has the optical and thermal properties of glass. The material must be transparent to visible light and have a low coefficient of thermal expansion (CTE). Unfortunately, such a polymeric material has not been available. A KAIST research team has succeeded in making a new polymeric material with an exceptionally low CTE value while retaining high transparency and excellent thermal and mechanical properties. The method developed for amorphous polymers with a controlled CTE can be applied to control the thermal expansion of organic materials as well.
Most of objects expands upon heating and shrinks by cooling, and organic polymers have a relatively large CTE compared to that of ceramics or metals. Thin, light-weight planar substrates for semiconductor devices should have a similar CTE of ceramics. Otherwise, the device can be cracked due to the stress caused by thermal expansion and contraction. Therefore, matching the CTE of the semiconductor device and the substrate is crucial for successful manufacturing of display devices. Forming a network structure by connecting polymer chains is a well-known method of reducing the CTE of amorphous polymers. However, polymers with a network structure eventually lose their flexibility and becomes brittle.
As an alternative method, Professor Sang Youl Kim from the Department of Chemistry and his team chose to adjust the distance and interaction between polymer chains. Thermal expansion and contraction of polymer films can be minimized by introducing interaction forces between the polymer chains and by arranging the direction of the force perpendicularly. The team successfully implemented this approach by appropriately designing the chemical structure of a transparent polymeric material. It is called poly (amide-imide) film, which is a transparent, flexible, and high-performing polymeric material. It is thermally stable enough to be used in the AMOLED (active-matrix organic light-emitting diode) fabrication process (stable at >400℃) with a low CTE (4ppm/℃).
The team made IGZO TFT (Indium Gallium Zinc Oxide Thin Film Transistor) devices on the newly synthesized transparent poly(amide-imide) film, and confirmed that the device could indeed operate normally even when it is folded down to a radius of 1mm.
Professor Kim said, “Our results suggest a way of controlling the thermal expansion of amorphous polymers similar to a level of glass without chemical cross-linking, which has long been regarded as a challenging problem. At the same time, we succeeded in making the polymer transparent and flexible. We expect that it can be applied to controlling the thermal expansion of various organic materials.”
This research, led by researchers Sun Dal Kim and Byungyoung Lee, was published in Science Advances on October 26. (DOI: 10.1126/sciadv.aau1956v)
2019.01.24 View 5550 -
New Members of KAST and Y-KAST 2019
(Professor Eui-Cheol Shin from the Graduate School of Medical Science and Engineering)
Professor Eui-Cheol Shin from the Graduate School of Medical Science and Engineering became a new fellow of the Korean Academy of Science and Technology (KAST) along with 25 other scientists in Korea. He is one of the top virus immunologists in Korea and has published a review article in Nature Reviews Immunology.
Meanwhile KAST selected and announced 26 young scientists under the age 43 who have shown great potential and the creativity to carry out next-generation research. The list of Y-KAST (Young Korean Academy of Science and Technology) includes six KAIST professors: Professor Ji Oon Lee from the Department of Mathematical Sciences, Professor Mi Hee Lim from the Department of Chemistry, Professor Shin-Hyun Kim from the Department of Chemical and Biomolecular Engineering, Professor Jung-Ryul Lee from the Department of Aerospace Engineering, Professor Hyunjoo Jenny Lee from the School of Electrical Engineering, and Professor Yeon Sik Jung from the Department of Materials Science and Engineering.
KAST conferred their fellowships and Y-KAST membership during the New Year Reception.
2019.01.22 View 7590 -
Dr. Sejeong Kim Recognized as Excellent Young Scientist
(Dr. Sejeong Kim)
Dr. Sejeong Kim, a postdoctoral research associate in the School of Mathematical and Physical Sciences at the University of Technology Sydney was honored to receive the Excellence Award for a Young Scientist by the Korea Federation of Women’s Science & Technology Association (KOFWST). The award ceremony will be held on October 31 in Seoul.
KOFWST recognizes ten promising young female scientists and engineers every year who show significant potential, passion, and remarkable achievement in their work. The awardees are selected among those who finished their degree within the previous five years. Dr. Kim earned her Ph.D. in physics at KAIST in 2014 and was selected as the winner in the field of physics in recognition of her outstanding research activities in photonics.
Dr. Kim conducted various research activities in the field of photonics and was published in high impact journals including Nano Letters and Advanced materials. In July, she developed the first photonic cavity from van der Waals materials and published the study in Nature Communications titled “Photonic Crystal Cavities from Hexagonal Boron Nitride.” At UTS, she carries out research activities supervised by Professor Igor Aharonovich and has engaged in many science outreach activities.
2018.10.18 View 4905 -
A Novel Biosensor to Advance Diverse High-Level Production of Microbial Cell Factories
A research group at KAIST presented a novel biosensor which can produce diverse, high-level microbial cell factories. The biosensor monitors the concentration of products and even intermediates when new strains are being developed. This strategy provides a new platform for manufacturing diverse natural products from renewable resources. The team succeeded in creating four natural products of high-level pharmaceutical importance with this strategy.
Malonyl-CoA is a major building block for many value-added chemicals including diverse natural products with pharmaceutical importance. However, due to the low availability of malonyl-CoA in bacteria, many malonyl-CoA-derived natural products have been produced by chemical synthesis or extraction from natural resources that are harmful to the environment and are unsustainable. For the sustainable biological production of malonyl-CoA-derived natural products, increasing the intracellular malonyl-CoA pool is necessary. To this end, the development of a robust and efficient malonyl-CoA biosensor was required to monitor the concentration of intracellular malonyl-CoA abundance as new strains are developed.
Metabolic engineering researchers at KAIST addressed this issue. This research reports the development of a simple and robust malonyl-CoA biosensor by repurposing a type III polyketide synthase (also known as RppA), which produces flaviolin, a colorimetric indicator of malonyl-CoA. Subsequently, the RppA biosensor was used for the rapid and efficient colorimetric screening of gene manipulation targets enabling enhanced malonyl-CoA abundance. The screened beneficial gene targets were employed for the high-level production of four representative natural products derived from malonyl-CoA. Compared with the previous strategies, which were expensive and time-consuming, the new biosensor could be easily applied to industrially relevant bacteria including Escherichia coli, Pseudomonas putida, and Corynebacterium glutamicum to enable a one-step process.
The study employs synthetic small regulatory RNA (sRNA) technology to rapidly and efficiently reduce endogenous target gene expression for improved malonyl-CoA production. The researchers constructed an E. coli genome-scale synthetic sRNA library targeting 1,858 genes covering all major metabolic genes in E. coli. This library was employed with the RppA biosensor to screen for gene targets which are believed to be beneficial for enhancing malonyl-CoA accumulation upon their expression knockdown.
From this colorimetric screening, 14 gene targets were selected, all of which were successful at significantly increasing the production of four natural products (6-methylsalicylic acid, aloesone, resveratrol, and naringenin). Although specific examples are demonstrated in E. coli as a host, the researchers showed that the biosensor is also functional in P. putida and C. glutamicum, industrially important representative gram-negative and gram-positive bacteria, respectively. The malonyl-CoA biosensor developed in this research will serve as an efficient platform for the rapid development of strains capable of producing natural products crucial for the pharmaceutical, chemical, cosmetics, and food industries.
An important aspect of this work is that the high-performance strains constructed in this research were developed rapidly and easily by utilizing the simple approach of colorimetric screening, without involving extensive metabolic engineering approaches. 6-Methylsalicylic acid (an antibiotic) could be produced to the highest titer reported for E. coli, and the microbial production of aloesone (a precursor of aloesin, an anti-inflammatory agent/whitening agent) was achieved for the first time.
“A sustainable process for producing diverse natural products using renewable resources is of great interest. This study represents the development of a robust and efficient malonyl-CoA biosensor generally applicable to a wide range of industrially important bacteria. The capability of this biosensor for screening a large library was demonstrated to show that the rapid and efficient construction of high-performance strains is feasible. This research will be useful for further accelerating the development process of strains capable of producing valuable chemicals to industrially relevant levels,” said Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering, who led the research.
This study entitled “Repurposing type III polyketide synthase as a malonyl-CoA biosensor for metabolic engineering in bacteria,” was published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) on October 02.
PhD students Dongsoo Yang and Won Jun Kim, MS student Shin Hee Ha, research staff Mun Hee Lee, Research Professor Seung Min Yoo, and Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering and Dr. Jong Hyun Choi of the Applied Microbiology Research Center at the Korea Research Institute of Bioscience and Biotechnology (KRIBB) participated in this research.
Figure: Type III polyketide synthase (RppA) as a malonyl-CoA biosensor. RppA converts five molecules of malonyl-CoA into one molecule of red-colored flaviolin. This schematic diagram shows the overall conceptualization of the malonyl-CoA biosensor by indicating that higher malonyl-CoA abundance leads to higher production and secretion of flaviolin, resulting in a deeper red color of the culture. This system was employed for the enhanced production of four representative natural products (6-methylsalicylic acid, aloesone, resveratrol, and naringenin) from engineered E. coli strains.
2018.10.11 View 8523 -
Scientist of October, Professor Haeshin Lee
(Professor Haeshin Lee from the Department of Chemistry)
Professor Haeshin Lee from the Department of Chemistry received the ‘Science and Technology Award of October’ from the Ministry of Science and ICT and the National Research Foundation of Korea for his contribution to developing an antibleeding injection needle. This novel outcome will fundamentally prevent the problem of secondary infections of AIDS, Ebola and Hepatitis viruses transmitting from patients to medical teams.
This needle’s surface is coated with hemostatic materials. Its concept is simple and the key to this technology is to make materials that are firmly coated on the needle so that they can endure frictional force when being injected into skin and blood vessels. Moreover, the materials should be adhesive to skin and the interior of blood vessels, but harmless to humans.
Professor Lee found a solution from natural polymer ingredients. Catecholamine can be found in mussels. Professor Lee conjugated catechol groups on the chitosan backbone. He applied this mussel-inspired adhesive polymer Chitosan-catechol, which immediately forms an adhesive layer with blood, as a bioadhesion for the antibleeding injection needle.
Professor Lee said, “Chitosan-catechol, which copies the adhesive mechanism of mussels, shows high solubility in physiological saline as well as great mucoadhesion. Hence, it is perfectly suitable for coating the injection needle. Combining it with proteins allows for efficient drug delivery to the heart, which is a challenging injection location, so it will be also useful for treating incurable heart disease.”
2018.10.05 View 8469