Chemistry Newsblog

We welcome Dr. Christine Chow as our last seminar speaker of the fall semester. Dr. Chow will present her piece on Tools for Monitoring RNA Modifications and Drug Interactions at 3:00 p.m. Friday, via Zoom.

Abstract: Among different RNA modifications, the helix 69 (H69) region of the bacterial ribosomal RNA (rRNA) contains three pseudouridines (Ψs). H69 is functionally important due to its location in the heart of the ribosome. Several structural and functional studies have shown the importance of Ψ modifications in influencing the H69 conformation as well as maintaining key interactions in the ribosome during protein synthesis. Therefore, a need exists to understand the influence of modified nucleosides on conformational dynamics of the ribosome under solution conditions that mimic the cellular environment. We have used a variety of methods including fluorescence spectroscopy and chemical probing with dimethyl sulfate (DMS) to examine H69 conformational states and the influence of Ψ modifications under varying solution conditions in the context of model RNAs, ribosomal subunits, and full ribosomes. The use of DMS footprinting, electrospray ionization mass spectrometry, and fluorescence spectroscopy to study the binding of aminoglycosides to H69 as well as helix 44 of bacterial rRNA as antibiotic targets will also be discussed. As highlighted in our work, DMS probing and footprinting are versatile techniques that can be used to gain important insight into RNA local structure and RNA-drug interactions.

Bio: My group studies large RNAs in order to better understand the impacts of modifications, determine how drugs locate their preferred binding sites, and identify new drug target sites. We use a combination of synthetic, biochemical, bioinorganic, and biophysical techniques, including modified oligonucleotide synthesis, chemical modification of RNA and primer extension assays, phage display, mass spectrometry, and circular dichroism, fluorescence, and NMR spectroscopies. I have a broad background in nucleic acid chemistry, with specific expertise in modified ribosomal RNAs and small molecule-RNA interactions. To help prepare students for professional success after graduate school, I have been involved with the NIH-supported WSU Broadening Experiences in Scientific Training program (BEST, co-PI from 2013-2018 and PI2018-2019). My role was to develop seminar and workshop content for 7 different modules in business, communication, community engagement, government, law, research administration, and teaching), which involved two-hour seminars and all-day workshops with alumni, business partners, and experts in the various career tracks. I also initiated the “Mini-BEST” program at Wayne State, in which faculty in departments, centers, and cross-disciplinary programs across the campus were given guidance on how to establish their own career development events (funded by the Wayne State Graduate School).  The BEST program has served more than 1000 students at Wayne State University since 2013. In 2012, I helped develop and run a campus-wide “Fellowship Writing Bootcamp”, which guided graduate students and postdocs in preparing F31/F32 applications (2012–2017). The workshop included mock study panels and recruitment of faculty to serve as reviewers of the proposals prior to submission. I also initiated the use of mock study section panels for faculty across three colleges (Liberal Arts & Sciences, Engineering, and School of Medicine).

Chemistry welcomes Dr. Sangyoon Han from the Biomedical Engineering Department as our seminar speaker this Friday (November 13th). The virtual seminar will be held via Zoom at 3:00 PM. The passcode is 859189 if needed.

Toward Discovery of the Initial Stiffness-Sensing Mechanism by Adherent Cells

Abstract: The stiffness of the extracellular matrix (ECM) determines nearly every aspect of cellular/tissue development and contributes to metastasis of cancer. Adherent cells’ stiffness-sensing of the ECM triggers intracellular signaling that can affect proliferation, differentiation, and migration of the cells. However, biomechanical and molecular mechanisms behind this stiffness sensing have been largely unclear. One critical early event during the stiff-sensing is believed to be a force transmission through integrin-based adhesions, changing the molecular conformation of the molecules comprising the adhesions that link the ECM to the cytoskeleton. To understand this force transmission, my lab develops experimental and computational techniques, which include soft-gel-based substrates, live-cell imaging, computer-vision-based analysis, and inverse mechanics, etc. In this talk, I will talk about how we use soft-gel to quantify the spatial distribution of mechanical force transmitted by a cell, how we use light microscopy and computer vision to analyze the focal adhesions, and how these techniques are related to stiffness sensing. In particular, I will show you new data where cells can transmit different levels of traction forces in response to varying stiffness, even when the activity of the major motor protein, myosin, is inhibited. At the end of the talk, potential molecules responsible for the differential transmission will be discussed.

Bio: Sangyoon Han received his Ph.D. in Mechanical Engineering at the University of Washington (UW) in 2012 and did postdoctoral training with Dr. Gaudenz Danuser in the Department of Cell Biology at Harvard Medical School and the University of Texas Southwestern Medical Center for five years until 2017. Before the Ph.D., he received B.S and M.S. degree from Mechanical Engineering at Seoul National University, Seoul, Korea in 2002 and 2004. He joined Michigan Tech, Biomedical Engineering from this fall, 2017, and started Mechanobiology Laboratory. His lab’s interests are in understanding the dynamic nature of force modulation occurring across cell adhesions and cytoskeleton that regulate cells’ environmental sensing. His lab develops a minimally-perturbing experimental approach and computational techniques, including soft-gel fabrication, nano-mechanical tools, live-cell microscopy, and image data modeling, to capture the coupling between force modulation and cellular molecular dynamics.

Dr. Karana Shah, Vice President of Technology at Dixie Chemical Company will be speaking this Friday, November 6th, 2020 at 3:00 p.m., via Zoom.

How to Get Hired and Progress in an Industrial Career from the Perspective of a PhD Graduate

Abstract: From R&D scientist to technical marketing to company leadership, Karana Shah has had an interesting career in industry since receiving her PhD from MSU in 2006. Taking a leap from academia to industry can be a decision fraught with worry. Graduate students and postdocs can have a tough time framing their extensive technical training into tangible skills that employers are looking for. Job seekers at all levels want to figure out if a position will be a good fit, with a company that will support future growth and professional development. Karana will describe some of the steps she took to find her first role out of graduate school and offer suggestions to those just starting out. She has successfully moved between positions and companies several times and will describe learnings from that process. At her current company, she has taken on increased responsibility with a promotion to a senior leadership role. A solid foundation with BS (2000) and MS (2002) degrees from MTU Chemistry helped lay the groundwork for the path she is on today.

BIO: Dr. Karana Shah joined Dixie Chemical in 2013 as Technical Services Manager and was promoted to VP of Technology in 2016. Prior to joining Dixie, she worked for Zoltek (now part of Toray Group), a global manufacturer of carbon fiber. At Zoltek, she supported the Composite Intermediates product line including pultruded profiles and prepreg. Karana also previously worked for Evonik Jayhawk Fine Chemicals as Technical Service Marketing Manager for Specialty Anhydrides and for TAMKO Building Products as a Research and Development Engineer for thermoplastic composite products. Dr. Shah earned her BS and MS degrees in Chemistry from Michigan Technological University in Houghton, MI. Her MS degree was completed under the guidance of Dr. Patricia Heiden in 2002. She also earned her Ph.D. in polymer composites with advisor Dr. Laurent Matuana from the Department of Forestry at Michigan State University, East Lansing, MI in 2006.

Chemistry’s own Dr. Christo Z. Christov will be our seminar speaker this Friday (October 30th). The virtual seminar will be held via Zoom at 3:00 PM. The passcode is 859189 if needed.

Computational Insight into Catalytic Mechanisms of Non-Heme Fe(II)- and 2-Oxoglutarate-Dependent Oxygenases

Abstract: “Mononuclear non-heme Fe(II) and 2-oxoglutarate (2OG)-dependent enzymes catalyze an incredibly diverse arsenal of chemical reactions with vital biological roles, making them attractive targets for therapeutics and biotechnology developments. Some of the chemical transformations performed by this family of enzymes include hydroxylation, demethylation, desaturation, and cyclization. One of the essential reactions performed by non-heme iron enzymes is histone demethylation. The class of enzymes responsible for histone lysine demethylation is called Histone Lysine Demethylases (KDMs). These enzymes couple decarboxylation of 2OG with substrate oxidation. Important demethylation reactions are catalyzed also by DNA demethylases such as the bacterial AlkB and its human homolog AlkBH2 in single-stranded (ss)- and double-stranded (ds) DNA. Also, an unusual enzymatic transformation performed by the Ethylene-Forming Enzyme (EFE) on its co-substrate (2OG) produces ethylene.”

“In this talk, I will present how applying state-of-the-art computational chemistry methods such as molecular dynamics (MD) and Combined Quantum Mechanical/Molecular Mechanical (QM/MM) we provide a mechanistic insight that cannot be received experimentally. The discussion will focus on: i) the histone demethylases PHF8 (KDM7B) and KDM4A (JMJD2A), which differ in their substrate specificity and domain organization; ii) DNA demethylases AlkB and AlkBH2 that differ in their preference to ss- or ds DNA; and iii) the Ethylene-Forming Enzyme (EFE) that performs a unique transformation of 2OG leading to the production of ethylene. The atomic and molecular orbital interactions along the reaction process within the enzyme environment will be discussed. The studies emphasize the critical importance of the protein environment and dynamics, especially focusing on the second sphere’s interactions and beyond for the catalytic process. The outcomes contribute to a fundamental understanding of enzyme mechanisms and have a long-term impact on enzyme engineering and drug design.”

Bio: Dr. Christo Z. Christov grew up in the town of Sevlievo, Bulgaria. He received MSc in Biochemistry at the University of Sofia, Sofia, and a Ph.D. in Theoretical Chemistry at the Bulgarian Academy of Sciences, Sofia, Bulgaria. Following postdoctoral studies in Spain and the UK, Christo gained a tenured faculty position at the Department of Applied Sciences at Northumbria University, UK in 2010. He was awarded a Fulbright Senior Grant and a Marie Curie International Outgoing Career Development Fellowship for the Department of Chemistry (The Solomon Lab) at Stanford University (2010-2013). Since 2017 Christo is an Associate Professor of Chemistry at the Department of Chemistry at Michigan Technological University, Houghton MI. Christo’s Research interests are in Computational Bioinorganic Chemistry with a focus on non- heme Fe(II) and 2OG-Dependent Oxygenase such as Histone Demethylases and TET enzymes involved in the epigenetic regulation and the Ethylene Forming Enzyme. Currently, Christo’s research is supported by the National Science Foundation of USA.

We welcome Dr. Christopher N. Bowman as our second seminar speaker of the year! You can join us in learning at 3:00 p.m., via Zoom.

Dr. Bowman will be presenting his piece on “Smart, Responsive Polymers Based on Covalent Adaptable Networks: Photoactivatable Dynamic Covalent Chemistry and Its Applications in Polymer Networks.”

Abstract: Polymer networks possessing dynamic covalent crosslinks constitute a class of materials with unique capabilities including the capacity for adapting to an externally applied stimulus. These covalent adaptable networks (CANs) represent a paradigm in polymer network fabrication aimed at the rational design of structural materials possessing dynamic characteristics for specialty applications and functions. Here, we explore several distinct approaches to CANs based on photochemically triggered responses. First, those in which the reversible bond formation, based on addition-fragmentation, occurs only during exposure to light will be discussed, enabling polymer network relaxation, photoinduced actuation and shape memory effects, and stress relaxation. Using liquid crystalline elastomer networks of this type, we will demonstrate the solution to fitting a square peg into a round hole, reversibly. Secondly, using thiol-thioester exchange chemistry, we will discuss the formation of a material that is capable of undergoing a bistable transition from a viscoelastic solid to a viscoelastic fluid, induced by light. Using this approach, we demonstrate recyclability, healing, and enhanced toughness of materials based on these types of networks. Ultimately, the potential for CANs-based materials to impact numerous materials applications will be presented in light of their distinctive array of material properties.

Bio: Professor Christopher N. Bowman received his B.S. and Ph.D. in Chemical Engineering from Purdue University in 1988 and 1991, respectively. After receiving his Ph.D., he began his academic career at the University of Colorado in January of 1992 as an Assistant Professor. Since that time Professor Bowman has built a program focused on the fundamentals and applications of crosslinked polymers formed via photopolymerization reactions. He works in the broad areas of the fundamentals of polymerization reaction engineering, polymer chemistry, crosslinked polymers, photopolymerizations and biomaterials. Professor Bowman has remained at Colorado throughout his academic career and is currently the Patten Endowed Chair of the Department of Chemical and Biological Engineering as well as a Clinical Professor of Restorative Dentistry at the University of Colorado at Denver.

Our Fall Seminar Series starts today! We welcome Dr. Steven Firestine from Wayne State University. The virtual seminar will begin at 3 p.m. today (Sept. 18) via Zoom.

Adventures in Antimicrobial Drug Discovery: Purine Biosynthesis and Spore Germination

Abstract: Antibiotics are arguably one of the greatest achievements in medical science, yet their utility is slowly being eroded by the rise of antibiotic-resistant bacteria. To combat this problem, new antibiotics focused on novel targets are desperately needed. Unfortunately, the pharmaceutical industry has divested from antimicrobial drug discovery leaving only small biotechnology companies and academia to find the next generation of antibiotics. One approach is to focus on underexplored pathways that are different between microbes and humans. Previous research has shown that the de novo purine biosynthetic pathway is different in bacteria, yeast and fungi than it is in humans. The difference is centered on the synthesis of the intermediate carboxyaminoimidazole ribonucleotide (CAIR). CAIR is synthesized from aminoimidazole ribonucleotide (AIR) and in microbes, two enzymes are required. In contrast, humans need only one enzyme. Genetic studies have shown that deleting the genes necessary for CAIR synthesis in microbes renders them avirulent. The Firestine laboratory has been focused on the interesting biochemical differences in the enzymes responsible for CAIR synthesis as well as exploiting this dissimilarity in drug discovery. The laboratory has also been exploring agents to prevent the germination of C. difficile spores. C. difficile is a challenging infection that is commonly found in hospitals and nursing homes. Spore germination is regulated by bile salts and we have discovered potent bile salt analogs which prevent germination in the nanomolar range even while in the presence of millimolar concentrations of the germinate. This seminar will outline our research on these projects.

Bio: Steve was born in Kalamazoo, MI, and attended the University of Michigan where he majored in chemistry.  While at UM, Steve conducted undergraduate research in the laboratory of Dr. James Coward working on the synthesis of fluorinated leucovorin. Steve graduated UM with high honors in chemistry and joined the Department of Medicinal Chemistry and Pharmacognosy at Purdue University where he studied medicinal chemistry and biochemistry under the direction of Dr. V. Jo Davisson. His doctoral studies focused on the study of AIR carboxylase and his research showed that this enzyme was different in microbes versus humans. Steve synthesized numerous nucleoside and nucleotide analogs including NAIR, which is the most potent inhibitor of AIR carboxylase known to date. Steve graduate in 1996 and conducted a Damon Runyon Walter Winchell Postdoctoral Fellowship in the laboratory of Dr. Stephen J. Benkovic at the Pennsylvania State University.  Steve conduct research into protein engineering and the generation of artificial transcriptional switches.  In 2000, Steve began his independent academic career as an assistant professor of medicinal chemistry at Duquesne University in Pittsburgh, PA.  There, his research focused on DNA bending agents as a mechanism to control gene expression. In 2005, Steve moved to Wayne State University and he was promoted to full professor in 2016. Since his arrival at WSU, Steve has been continuously funded by the National Institutes of Health where his research has focused on antimicrobial drug discovery.