Category Archives: Biochemistry

Caltech Professor of Chemistry and Biochemistry Decodes a Key Part of the Cell, Atom by Atom Pasadena Now – Pasadena Now

Credit: Valerie Altounian

Whatever you are doing, whether it is driving a car, going for a jog, or even at your laziest, eating chips and watching TV on the couch, there is an entire suite of molecular machinery inside each of your cells hard at work. That machinery, far too small to see with the naked eye or even with many microscopes, creates energy for the cell, manufactures its proteins, makes copies of its DNA, and much more.

Among those pieces of machinery, and one of the most complex, is something known as the nuclear pore complex (NPC). The NPC, which is made of more than 1,000 individual proteins, is an incredibly discriminating gatekeeper for the cells nucleus, the membrane-bound region inside a cell that holds that cells genetic material. Anything going in or out of the nucleus has to pass through the NPC on its way.

The NPCs role as a gatekeeper of the nucleus means it is vital for the operations of the cell. Within the nucleus, DNA, the cells permanent genetic code, is copied into RNA. That RNA is then carried out of the nucleus so it can be used to manufacture the proteins the cell needs. The NPC ensures the nucleus gets the materials it needs for synthesizing RNA, while also protecting the DNA from the harsh environment outside the nucleusandenabling the RNA to leave the nucleus after it has been made.

Its a little like an airplane hangar where you can repair 747s, and the door opens to let the 747 come in, but theres a person standing there who can keep a single marble from getting out while the doors are open, says CaltechsAndr Hoelz, professor of chemistry and biochemistry and a Faculty Scholar of the Howard Hughes Medical Institute. For more than two decades, Hoelz has been studying and deciphering the structure of the NPC in relation to its function. Over the years, he has steadily chipped away at its secrets, unraveling thempiecebypiecebypiecebypiece.

The implications of this research are potentially huge. Not only is the NPC central to the operations of the cell, it is also involved in many diseases. Mutations in the NPC are responsible for some incurable cancers, for neurodegenerative and autoimmune diseases such as amyotrophic lateral sclerosis (ALS) and acute necrotizing encephalopathy, and for heart conditions including atrial fibrillation and early sudden cardiac death. Additionally, many viruses, including the one responsible for COVID-19, target and shutdown the NPC during the course of their lifecycles.

Now, in a pair of papers published in the journalScience,Hoelz and his research team describe two important breakthroughs: the determination of the structure of the outer face of the NPC and the elucidation of the mechanism by which special proteins act like a molecular glue to hold the NPC together.

In their paper titled Architecture of the cytoplasmic face of the nuclear pore, Hoelz and his research team describe how they mapped the structure of the side of the NPC that faces outward from the nucleus and into the cells cytoplasm. To do this, they had to solve the equivalent of a very tiny 3-D jigsaw puzzle, using imaging techniques such as electron microscopy and X-ray crystallography on each puzzle piece.

Stefan Petrovic, a graduate student in biochemistry and molecular biophysics and one of the co-first authors of the papers, says the process began withEscherichia colibacteria (a strain of bacteria commonly used in labs) that were genetically engineered to produce the proteins that make up the human NPC.

If you walk into the lab, you can see this giant wall of flasks in which cultures are growing, Petrovic says. We express each individual protein inE. colicells, break those cells open, and chemically purify each protein component.

Once that purificationwhich can require as much as 1,500 liters of bacterial culture to get enough material for a single experimentwas complete, the research team began to painstakingly test how the pieces of the NPC fit together.

George Mobbs, a senior postdoctoral scholar research associate in chemistry and another co- first author of the paper, says the assembly happened in a stepwise fashion; rather than pouring all the proteins together into a test tube at the same time, the researchers tested pairs of proteins to see which ones would fit together, like two puzzle pieces. If a pair was found that fit together, the researchers would then test the two now-combined proteins against a third protein until they found one that fit with that pair, and then the resulting three-piece structure was tested against other proteins, and so on. Working their way through the proteins in this way eventually produced the final result of their paper: a 16-protein wedge that is repeated eight times, like slices of a pizza, to form the face of the NPC.

We reported the first complete structure of the entire cytoplasmic face of the human NPC, along with rigorous validation, instead of reporting a series of incremental advances of fragments or portions based on partial, incomplete, or low-resolution observation, says Si Nie, postdoctoral scholar research associate in chemistry and also a co-first author of the paper. We decided to patiently wait until we had acquired all necessary data, reporting a humungous amount of new information.

Their work complemented research conducted by Martin Beck of the Max Planck Institute of Biophysics in Frankfurt, Germany, whose team used cryo-electron tomography to generate a map that provided the contours of a puzzle into which the researchers had to place the pieces. To accelerate the completion of the puzzle of the human NPC structure, Hoelz and Beck exchanged data more than two years ago and then independently built structures of the entire NPC. The substantially improved Beck map showed much more clearly where each piece of the NPCfor which we determined the atomic structureshad to be placed, akin to a wooden frame that defines the edge of a puzzle, Hoelz says.

The experimentally determined structures of the NPC pieces from the Hoelz group served to validate the modeling by the Beck group. We placed the structures into the map independently, using different approaches, but the final results completely agreed. It was very satisfying to see that, Petrovic says.

We built a framework on which a lot of experiments can now be done, says Christopher Bley, a senior postdoctoral scholar research associate in chemistry and also co-first author. We have this composite structure now, and it enables and informs future experiments on NPC function, or even diseases. There are a lot of mutations in the NPC that are associated with terrible diseases, and knowing where they are in the structure and how they come together can help design the next set of experiments to try and answer the questions of what these mutations are doing.

This elegant arrangement of spaghetti noodles

In the other paper, titled Architecture of the linker-scaffold in the nuclear pore, the research team describes how it determined the entire structure of what is known as the NPCs linker-scaffoldthe collection of proteins that help hold the NPC together while also providing it with the flexibility it needs to open and close and to adjust itself to fit the molecules that pass through.

Hoelz likens the NPC to something built out of Lego bricks that fit together without locking together and are instead lashed together by rubber bands that keep them mostly in place while still allowing them to move around a bit.

I call these unstructured glue pieces the dark matter of the pore,' Hoelz says. This elegant arrangement of spaghetti noodles holds everything together.

The process for characterizing the structure of the linker-scaffold was much the same as the process used to characterize the other parts of the NPC. The team manufactured and purified large amounts of the many types linker and scaffold proteins, used a variety of biochemical experiments and imaging techniques to examine individual interactions, and tested them piece by piece to see how they fit together in the intact NPC.

To check their work, they introduced mutations into the genes that code for each of those linker proteins in a living cell. Since they knew how those mutations would change the chemical properties and shape of a specific linker protein, making it defective, they could predict what would happen to the structure of the cells NPCs when those defective proteins were introduced. If the cells NPCs were functionally and structurally defective in the way they expected, they knew they had the correct arrangement of the linker proteins.

A cell is much more complicated than the simple system we create in a test tube, so it is necessary to verify that results obtained from in vitro experiments hold up in vivo, Petrovic says.

The assembly of the NPCs outer face also helped solve a longtime mystery about the nuclear envelope, the double membrane system that surrounds the nucleus. Like the membrane of the cell within which the nucleus resides, the nuclear membrane is not perfectly smooth. Rather, it is studded with molecules called integral membrane proteins (IMPs) that serve in a variety of roles, including acting as receptors and helping to catalyze biochemical reactions.

Although IMPs can be found on both the inner and outer sides of the nuclear envelope, it had been unclear how they actually traveled from one side to the other. Indeed, because IMPs are stuck inside of the membrane, they cannot just glide through the central transport channel of the NPC as do free-floating molecules.

Once Hoelzs team understood the structure of the NPCs linker-scaffold, they realized that it allows for the formation of little gutters around its outside edge that allow the IMPs to slip past the NPC from one side of the nuclear envelope to the other while always staying embedded in the membrane itself.

It explains a lot of things that have been enigmatic in the field. I am very happy to see that the central transport channel indeed has the ability to dilate and form lateral gates for these IMPs, as we had originally proposed more than a decade ago, Hoelz says.

Taken together, the findings of the two papers represent a leap forward in scientists understanding of how the human NPC is built and how it works. The teams discoveries open the door for much more research. Having determined its structure, we can now focus on working out the molecular bases for the NPCs functions, such as how mRNA gets exported and the underlying causes for the many NPC-associated diseases with the goal of developing novel therapies, Hoelz says.

The papers describing the work appear in the June 10 issue of the journalScience.

Additional co-authors of the paper, Architecture of the cytoplasmic face of the nuclear pore, are Anna T. Gres; now of Worldwide Clinical Trials; Xiaoyu Liu, now of UCLA; Sho Harvey, a former grad student in Hoelzs lab; Ferdinand M. Huber, now of Odyssey Therapeutics; Daniel H. Lin, now of the Whitehead Institute for Biomedical Research; Bonnie Brown, a former research technician in Hoelzs lab; Aaron W. Tang, a former research technician in Hoelzs lab; Emily J. Rundlet, now of St. Jude Childrens Research Hospital and Weill Cornell Medicine; Ana R. Correia, now of Amgen; Taylor A. Stevens, graduate student in biochemistry and molecular biophysics; Claudia A. Jette, graduate student in biochemistry and molecular biophysics; Alina Patke, research assistant professor of biology; Somnath Mukherjee and Anthony A. Kossiakoff of the University of Chicago; Shane Chen, Saroj G. Regmi, and Mary Dasso of the National Institute of Child Health and Human Development; and Alexander F. Palazzo of the University of Toronto.

Additional co-authors of the paper, Architecture of the linker-scaffold in the nuclear pore, are Dipanjan Samanta, postdoctoral scholar fellowship trainee in chemical engineering; Thibaud Perriches, now of Care Partners; Christopher J. Bley; Karsten Thierbach; now of Odyssey Therapeutics; Bonnie Brown, Si Nie, George W. Mobbs, Taylor A. Stevens, Xiaoyu Liu, now of UCLA; Giovani Pinton Tomaleri, graduate student in biochemistry and molecular biophysics; and Lucas Schaus, graduate student in biochemistry and molecular biophysics.

Funding for the research was provided by the National Institutes of Health, the Howard Hughes Medical Institute, and the Heritage Medical Research Institute.

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Caltech Professor of Chemistry and Biochemistry Decodes a Key Part of the Cell, Atom by Atom Pasadena Now - Pasadena Now

New cryo-electron microscopy centers help UW researchers uncover mysteries of life – University of Wisconsin-Madison

At the Steenbock Symposium on June 7 and 8, 2022, the University of WisconsinMadison Department of Biochemistry opened its doors in celebration of two new research centers that bring to campus advanced biomolecular imaging technology called cryo-electron microscopy.

The technology allows scientists to capture detailed information about the smallest components of living cells to understand everything from more effective drug development to how viruses infect cells. It relies on ultra-cold temperatures during biomolecular specimen preservation and imaging and requires the right combination of expertise and highly specialized equipment.

The UWMadison Cryo-Electron Microscopy Research Center and the NIH-sponsored Midwest Center for Cryo-Electron Tomography represent a continuation of UWMadisons long history of contributions to structural biology. The event featured tours of the centers and scientific talks and posters about cryo-EM.

Both centers provide instrumentation, training, technical assistance and support to UWMadison researchers, as well as access to cryo-EM. The centers are also open to other universities and to private industry.

1 Thomas Anderson, a cellular and molecular biology graduate student working in the lab of biochemistry professor Robert Kirchdoerfer, and Anil Kumar, a research specialist in the cryo-EM centers, explain the inner workings of the Titan Krios cryo-electron microscope to their tour group at the Cryo-Electron Microscopy Research Center. Photo by Michael P. King/UW-Madison CALS

2 Industry and campus partnerships are critical to the centers' construction and operation. Zoltan Metlagel, a senior applications engineer at ThermoFisher Scientific, shared his knowledge about tomographic imaging alongside Parrell during one of five interactive workshops held during the open house. Photo by Michael P. King/UW-Madison CALS

3 Joseph Kim, a graduate student in the chemistry department, leads scientists through one of five interactive workshops held during the open house. Dedicated on-site training by center users and staff is available to scientists across campus and beyond. Photo by Michael P. King/UW-Madison CALS

4 Postdoctoral researcher Daniel Parrell explains how to use cryo-electron tomography data to produce an image known as a 3D tomogram. The montage shows biological structures in a thin layer of human cells and was collected using remote access capabilities and a focused ion beam. Remote training and operation of equipment are both features of the new centers. Photo by Michael P. King/UW-Madison CALS

5 Biochemistry professor and Morgridge Institute for Research investigator Elizabeth Wright directs the UWMadison Cryo-Electron Microscopy Research Center, led by a coalition of campus partners, and the NIH-sponsored Midwest Center for Cryo-Electron Tomography. Photo by Robin Davies

6 Open house attendees learned what can be achieved with cryo-EM during scientific talks and poster sessions held in the Discovery Building. Approximately 200 people attended the open house in-person, while another 200 viewed talks and workshops online. Photo by Robin Davies

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New cryo-electron microscopy centers help UW researchers uncover mysteries of life - University of Wisconsin-Madison

UMass Amherst’s Up-and-coming Biochemists Are Already Recruiting the Next GenerationWith Strawberries – UMass News and Media Relations

Many students love their undergraduate major. But for students in the UMass Amherst Biochemistry Club, spending extra hours in the lab isnt enough. Thanks to a grant from the American Society for Biochemistry and Molecular Biology (ASBMB), club members spent this past spring semester working with high school students in the Holyoke Public Schools to help plant the seeds for the next generation of up-and-coming biochemists. Their secret? Strawberries.

The Holyoke Public School system is currently under state receivership after being designated in 2015 as chronically underperforming. The district has been working to increase graduation rates, and as part of this goal, Holyoke High School has been redesigned to let each student choose a pathway that will prepare them for success in college, in a career or in community leadership. One of these pathways is the Medical and Life Sciences Pathway, designed to develop problem solving, critical thinking and communication skills for students interested in the biological sciences and healthcare. The UMass Biochem Club worked specifically with this cohort, performing experiments with them and conducting Q-and-A panels.

One of these experiments involved extracting DNA from strawberries. Michael Cotto, chair of the science department at Holyoke High School, said that having the opportunity for a hands-on experiment was a great way to welcome students back from their spring vacation. Students were engaged and excited by the science!

Anna Gorfinkel 22 and Ashley Sheehan 22, co-presidents of the Biochem Club, said that Western Massachusetts is a hub of educational opportunities and STEM careers. As students at the University of Massachusetts Amherst, the commonwealths flagship public university, we have a great opportunity to use our proximity to Holyoke to serve as role models for students interested in continuing their education and pursuing careers in the life sciences.

The Biochem Club is the ASBMB Student Chapter for UMass Amherst, and their mission is to help young people foster curiosity and interest in STEM. They have done extensive outreach to local communities since their inception in 2012, including programs at the Amherst-Pelham Regional High School, Girls Inc. of the Valley, and the Holyoke High School.

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UMass Amherst's Up-and-coming Biochemists Are Already Recruiting the Next GenerationWith Strawberries - UMass News and Media Relations

Discover BMB: And the winner is… – ASBMB Today

During Experimental Biology 2022 in Philadelphia, visitors to the American Society of Biochemistry and Molecular Biology booth and lounge were invited to vote fortheir favorite logo for the societys stand-alone 2023 meeting, now called Discover BMB, to be held March 2528 in Seattle.

With the promise of fun prizes (who doesnt love T-shirts and magnets?), 607 people voted on their phones using our QR code. And the winner by a wide margin was Option #1.

More than half of the 607 voters selected the logo design with hexagons, which was the staff's favorite too.

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Discover BMB: And the winner is... - ASBMB Today

Academic All-Ohio Athletic Conference includes 11 from Alliance area – The-review

Staff report| The Alliance Review

Mount Union had 80 spring sports athletes recognized as Academic All-Ohio Conference.

To be selected an athlete must have a 3.50 cumulative grade point average and maintain varsity status.

These are the area Mount Union students who were selected:

Colton Wade, Marlington, men's golf, senior, Biochemistry, 3.97

Krissy Tarter, Marlington, senior, women's track & field, Biochemistry, 3.94

Grace Heath, West Branch, junior, softball, Accounting and Finance, 3.93

Lily Bogunovich, Marlington, senior, women's track & field, History, 3.91

Jeff Joseph, West Branch, junior, men's track & field, Multi-Platform Software Development, 3.88

Brittany Bolevich, Southeast, junior, women's track & field, Middle Childhood Education, 3.75

Lauren Amodio, Southeast, sophomore, women's golf, Exercise Science, 3.69

Gianini Venuto, Southeast, sophomore, women's track & field, Sport Business, 3.62

Other students from area schools who were selected:

Brendan Stinson, Capital, Marlington, baseball, Business Management

Spencer Hall, Marietta, Louisville, men's tennis, Strategic Communications

Morgan Mullaly, Muskingum, Alliance, women's golf, Early Childhood Education, Special Education

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Academic All-Ohio Athletic Conference includes 11 from Alliance area - The-review

Cleanup duty | University of Minnesota – UMN News

When COVID-19 began surging around the world in early 2020 and physicians were confronting a deadly disease they knew little about, scientists at the University of Minnesotas Institute on the Biology of Aging and Metabolism (iBAM) swung into action to help.

Early in the pandemic it became very clear that certain people were at greatest riskthe elderly, people with diabetes, and people with obesity, says Laura Niedernhofer, professor of biochemistry in the Medical School and director of iBAM. And one common thread between those groups? They all have increased levels of senescent cells.

Senescent cells are aging cells that have stopped dividing but havent died. According to Niedernhofer, the burden of senescent cells in our body doubles with every decade of life.

Senescent cells drive inflammation, and that inflammation then puts you at greater risk for disease and aging, explains iBAM associate director Paul Robbins, also a professor of biochemistry in the Medical School. If you have a perfectly healthy, robust immune system, your body clears these cells for you. But as we age, our immune response wanes and stops clearing these cells effectively.

Niedernhofer, Robbins, and their iBAM colleagues didnt wait to be asked if their research into senescent cells could be applied to fight COVID-19 infections, too. This was really an instant reaction, recalls Niedernhofer. Were here to think about the biology of aging, but more importantly, were here to help older Minnesotans. We felt it was our obligation to do everything we could to help rescue our most vulnerable populations from the lethality of COVID-19.

What if there were a drug that could help clear senescent cells and slow the onset of not just the aging process, but of the many diseases associated with aging, such as heart disease, cancer, type 2 diabetes, and Alzheimers disease?

That question led Niedernhofer and Robbins, working with colleagues at the Mayo Clinic, to become the first scientists to describe a new class of drugs called senolytics in 2015. More recently, theyve shown that fisetin, a natural antioxidant found in various fruits and vegetables (apples, strawberries, onions, and cucumbers, for example), successfully clears senescent cells in mice.

We do have preliminary data [indicating] that fisetin clears senescent cells in humans, says Niedernhofer, and there are now many clinical trials underway to study it further.

When COVID-19 struck, iBAM scientists quickly geared up to see whether the senolytics they were developing to promote healthier aging could also be used to treat the viral infection caused by SARS-CoV-2.

In a study led by iBAM investigator Christina Camell, researchers exposed aged mice to a coronavirus closely related to SARS-CoV-2. In the control group, all of the infected mice died; mice treated with a senolytic, however, had a 5060% survival rate.

The excitement around senolytics as a COVID-19 treatment has been growing, says Camell, since the groups results were published last summer in the prestigious journal Science. Clinical studies are under way in Minnesota to evaluate the success of treating COVID-19 patients with senolytics.

Investment to outcomes

In 2015, the Minnesota Legislatures higher education funding bill included an unprecedented $30 million investment that allowed the U of Ms Medical School to establish four new Medical Discovery Teams (MDTs). The MDTs were designed to propel already strong programs into world-class research cohorts dedicated to addressing some of the states most pressing health care priorities: addiction, rural and Native American health, optical imaging and brain science, and the biology of aging.

That investment brought top researchers like Niedernhofer and Robbins to the U to continue building on their leading-edge research.

The University of Minnesota has been an incredibly rich backdrop for our work studying the biology of aging, says Niedernhofer, providing so many opportunities for collaborations with colleagues across campus to find new applications for senolytics in treating diseases in the elderly.

And with the states (and the worlds) aging population growing, theres no better time for progress.

Were living in a time on this planet where the elderly population is doubling, says Niedernhofer, and each of those elderly people has an average of two chronic diseases. By targeting the biology of aging itself, instead of targeting specific diseases, with this new class of drugs called senolytics, we may be able to help people live healthier for a longer time.

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Cleanup duty | University of Minnesota - UMN News

UC San Diego Atmospheric Chemist Kim Prather Elected to American Philosophical Society – University of California San Diego

Kim Prather is also director of the Center for Aerosol Impacts on Chemistry of the Environment.

A distinguished scientist and professor at the University of California San Diego has been inducted into Americas oldest learned society, joining the ranks of other noteworthy Triton faculty and alumni. Kimberly Prather, Distinguished Chair in Atmospheric Chemistry and Distinguished Professor at the Scripps Institution of Oceanography and the Department of Chemistry and Biochemistry in the School of Physical Sciences has been selected to join the American Philosophical Society. Prather is among 37 new members elected in 2022, and the first from UC San Diego since 2010.

I am honored to join the APS along with so many other academic and cultural luminaries, said Prather. Its a reflection of the efforts of my research group and support Ive received from the UC San Diego community in addressing the importance of our work in confronting the challenges of climate change head-on, using innovative strategies.

Prathers work focuses on how human emissions affect the atmosphere, climate and health. She joined the faculty of UC San Diego in 2001 and has five patents for her innovations in mass spectrometry for environmental chemistry lab and field studies. In 2019, she was elected to the National Academy of Engineering. In April 2020, she became a member of the National Academy of Sciences for her contributions to aerosol chemistry. She is an elected fellow of the American Geophysical Union, the American Association for the Advancement of Science and the American Academy of Arts and Sciences. Prather is also an advisory board member for UC San Diegos Institute for Practical Ethics.

She is the founding director of the NSF-fundedCenter for Aerosol Impacts on Chemistry of the Environment, and is currently working to understand the health and environmental impacts of ocean-derived pollutants and toxins in runoff and outfalls and the concentration of particles small enough to lodge deeply in human lungs and impact our health.

The urgency of addressing pollution and climate issues cannot be overstated, Prather said. It motivates me each day to wake up and share my findings with local, federal, and world leaders to help drive these issues into our broader conversation that will lead to solutions.

During the COVID-19 pandemic, Prather co-authored several high-profile publications, as well as a letter to the Biden Administration, calling for immediate action to address and limit airborne transmission of COVID-19 and inhalation exposure, which helped improve public-health protections for people around the world. She has advised local and federal government officials, school districts, businesses, and the public at large on how to safely reopen and remain open, with a focus on cleaning indoor air using filtration and ventilation.

Founded in 1743 by Benjamin Franklin to promote useful knowledge, the APS honors and engages distinguished scientists, humanists, social scientists and cultural leaders in a spirit of interdisciplinary intellectual fellowship. It provides the nations top intellectuals and scholars with opportunities for research, networking and public engagement. Over the years, members have included George Washington, Thomas Paine, Charles Darwin, Robert Frost and Albert Einstein. Since 1960, 22 prominent UC San Diego members have been elected including astronomer Margaret Burbridge, philosopher of science Nancy Cartwright, biologist Francis Crick, and professor of chemistry and former chancellor Marye Anne Fox.

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UC San Diego Atmospheric Chemist Kim Prather Elected to American Philosophical Society - University of California San Diego

First-in-class, anti-cancer mitochondrial drug found to be effective against most carcinoma cell lines – News-Medical.Net

A study of the lead agent (CPI-613) in a class of anticancer drugs undergoing Food and Drug Administration (FDA) approved clinical trials reveals that CPI-613 is effective against most carcinoma cell lines, and, used in combination, could have efficacy against reducing some tumors. The research, led by Paul M. Bingham, PhD, of the Department of Biochemistry and Cell Biology in the Renaissance School of Medicine at Stony Brook University, will help advance clinical testing of CPI-613 and similar agents that are designed to disrupt cancer cell mitochondrial metabolism, a complex process that feeds tumor growth. The findings are published in PLOS ONE.

The drug CPI-613 and related anti-cancer compounds were developed by Bingham and Zuzana Zachar, PhD, through collaborative efforts in the Department of Biochemistry and Cell Biology. Cornerstone Pharmaceuticals, Inc., licensed the technology from The Research Foundation of the State University of New York in 2001, and after years of experimentation, the drug was brought to pre-clinical testing in 2011.

As the exclusive licensee, Cornerstone is conducting clinical trials of CPI-613. The drug targets cancer mitochondrial tricarboxylic acid (TCA) cycle metabolism with tumor selectivity and its mechanism of action also makes it a useful experimental probe of cancer metabolism.

Stony Brook University cancer researchers Bingham, Zachar, and Shawn D. Stuart lead the continued research of CPI-613. According to Bingham, this team and their co-authors created a pre-clinical study highlighted in the paper that provides new insight into the drug and carcinoma catabolism, a metabolic process that breaks down molecules into smaller units.

Clinical trials of CPI-613 have shown only some patients respond to the drug with reduction of tumors, the new research may form a new basis of using the anti-cancer agent more effectively in combination with cancer treatments, especially with difficult-to-treat tumors.

Our new pre-clinical research shows that the anti-cancer mechanisms we originally reported with CPI-613 remain intact against most cancer cell lines, which is potentially powerful for general and broad-based clinical approaches. Secondly, we also show that failures to respond to CPI-613 in clinical applications have a very simple, specific, tumor-general cause. And that is the TCA cycle metabolizes all major nutrient classes, then feeds the electrons these processes generate into the electron transport system (ETC) to complete mitochondrial energy metabolism.

While CPI-613 suppression of the TCA is sufficient to block many pathways for energy generation within tumor cells, a few pathways exist that can bypass the TCA cycle and feed electrons directly into the ETC. One of these alternative pathways is the generation of electrons by the initial fatty acid beta-oxidation process which is what we focused on."

Paul M. Bingham, PhD, Department of Biochemistry and Cell Biology, Renaissance School of Medicine, Stony Brook University

The researchers demonstrated that electron flow from fatty acids initially metabolized in the peroxisome enroute to mitochondria can bypass the CPI-613 blockade, which produces the drug resistance observed in some tumors. They further demonstrated that this resistance-producing electron flow can be targeted to substantially enhance the anticancer performance of CPI-613.

Bingham explains that this fatty acid "by-pass" resistance enables the scientists to target it with two cancer drugs that are FDA-approved for other purposes, thioridazine and crizotinib, improving CPI-613 sensitivity.

Overall, the study results indicate the potential of CPI-613 for treating many types of carcinomas is promising and can be even more effective when used in concert with other drugs to treat cancer an approach that is different from the agent's current use against a minority of tumors that respond to the current targeted therapy.

Source:

Journal reference:

Guardado Rivas, M.O.,et al.(2022) Evidence for a novel, effective approach to targeting carcinoma catabolism exploiting the first-in-class, anti-cancer mitochondrial drug, CPI-613.PLOS ONE.doi.org/10.1371/journal.pone.0269620.

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First-in-class, anti-cancer mitochondrial drug found to be effective against most carcinoma cell lines - News-Medical.Net

Unique insight into the inner workings of our cellular powerplants – EurekAlert

Using advanced microscopy techniques, researchers at Karolinska Institutet and Stockholm University in Sweden have visualized in unprecedented detail the machinery that the cells powerhouses, the mitochondria, use to form their proteins. The results, which are published in Nature, raise hopes of more specific antibiotics and new cancer drugs in the future.

The mitochondria are the cells powerhouses that convert energy locked in our food into a functional energy currency for the cells. They also have their own protein synthesis factories called ribosomes, which have a different appearance to those found in the cellular cytoplasm. However, little has been known about how the mitochondrial ribosomes are produced until now.

We were hoping to obtain a single snapshot of the mitoribosomal large subunit assembly, but our data revealed much more unexpected surprises, says the studys joint first author Anas Khawaya, postdoc at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet. These observations present opportunities to discover the full extent of crosstalk between mitoribosomal assembly and other aspects of mitochondrial function.

Using a technique called cryogenic electron microscopy, the researchers were able to depict important key players of the complex machinery that manufactures ribosomes. One finding was that a component called ribosome-binding factor A (RBFA) orchestrates the process. The ribosome is made up of two halves, not unlike a hamburger bun. The researchers analyses show that a protein called mS37 signals that these two parts can be joined and are ready to start protein synthesis.

Clinical potential

The results are an example of basic cell biology research, but the new knowledge can also give rise to medical advances, such as more targeted antibiotics. Mitochondria are similar to bacteria and the antibiotics that currently attack a bacteriums ability to form proteins also affect our mitochondria.

Whilst the mechanisms of bacterial and cytosolic translation have been studied for decades, we are only now starting to uncover how mitochondria produce proteins, says Joanna Rorbach, principal researcher and group leader at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet. Understanding the differences between how bacteria and mitochondria produce their ribosomes could allow us to design better and more targeted antibiotics.

The study has been led by Joanna Rorbach together with Alexey Amunts and his research group at the Department of Biochemistry and Biophysics at Stockholm University.

Cancer is another future target. Unlike healthy cells, cancer cells grow quickly and divide often, a process that requires the formation of a large number of new proteins.

One possible approach is to actively inhibit the cancer cells mitochondrial ribosomes, Joanna Rorbach says.

The study was supported by grants from the Max Planck Society, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the European Research Council, the Swedish Foundation for Strategic Research, the Marie Sklodowska Curie Initiative and Karolinska Institutet.

Publication: Mechanism of mitoribosomal small unit biogenesis and preinitiation. Yuzuru Itoh, Anas Khawaja, Ivan Laptev, Miriam Cipullo, Ilian Atanassov, Petr Sergiev, Joanna Rorbach and Alexey Amunts. Nature, online June 8, 2022, doi: 10.1038/s41586-022-04795-x

Cells

Mechanism of mitoribosomal small unit biogenesis and preinitiation

8-Jun-2022

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Unique insight into the inner workings of our cellular powerplants - EurekAlert

Scope of Caesalpinia Spinosa Gum Industry 2022-2028: Market Analysis with Trends and Opportunities | Polygal, JRS Rettenmaier, Mibelle Biochemistry,…

The report on Caesalpinia Spinosa Gum Market added by Affluence provides a complete briefing on strategic recommendations, trends, segmentation, use case analysis, competitive intelligence, global and regional forecast to 2028. The objective of this research is to provide a 360 holistic view of the Caesalpinia Spinosa Gum market and bringing insights that can help stakeholders identify the opportunities as well as challenges. The report provides the market size in terms of value and volume of the Global Caesalpinia Spinosa Gum Market.

The analyst studied various companies like Polygal, JRS Rettenmaier, Mibelle Biochemistry, The Herbarie, Provital, Seppic, etc. to understand the products and/services relevant to the Caesalpinia Spinosa Gum market. The report includes information such as gross revenue, production and consumption, average product price, and market shares of key players. Other factors such as competitive analysis and trends, mergers & acquisitions, and expansion strategies have been included in the report. This will enable the existing competitors and new entrants to understand the competitive scenario to plan future strategies.

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The Caesalpinia Spinosa Gum Market Report Covers Major Market Players as Follows:

Caesalpinia Spinosa Gum Market Segmentation:

Detailed segmentation of the Caesalpinia Spinosa Gum market, based on type and application and a descriptive structure of trends of the segments and sub-segments are elaborated in the report. It also provides the market size and estimates a forecast from the year 2019 to 2028 with respect to five major regions, like North America, Europe, Asia-Pacific (APAC), Middle East and Africa (MEA) and South & Central America.

Breakdown by Type:

Breakdown by Application:

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Caesalpinia Spinosa Gum Market Report Provides Comprehensive Analysis as Following:

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Caesalpinia Spinosa Gum Market landscape and market scenario include:

The Caesalpinia Spinosa Gum industry development trends and marketing channels are analyzed. Finally, the feasibility of new investment projects is assessed, and overall research conclusions offered.

Chapters Covered in Caesalpinia Spinosa Gum Market Report Are as Follow:

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The Caesalpinia Spinosa Gum Market Report Addresses the Following Queries:

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Scope of Caesalpinia Spinosa Gum Industry 2022-2028: Market Analysis with Trends and Opportunities | Polygal, JRS Rettenmaier, Mibelle Biochemistry,...