The Search to Unlock Protein-Metabolite Interactions
An interview with Jared Rutter, Ph.D. and Kevin Hicks, Ph.D. About Atavistik Bio’s Foundational Technology and the Inspiration
Q: What led you to focus your research/career in the area of metabolism and its integration with cell behavior?
A: Dr. Rutter: Early in my Ph.D. studies, I just became fascinated with this topic. I had come to observe, in my work and in the work of others, that metabolism had quite profound effects on how cells behave. It was also clear that this was quite important in the pathophysiology of some, perhaps many, diseases. I also felt that it was an area that wasn’t receiving the attention that was appropriate given the importance.
Q: Dr. Rutter, you joined the faculty at the University of Utah in 2003. Over the past decades, what have been some of the significant advancements in this space?
A: I am reluctant to call out a small number of specific advances because I would certainly leave some out. I am particularly excited about our ability as a scientific community to measure metabolism in increasingly sophisticated ways. As with any field, progress is only as good as the analytical tools, and ours just keep getting better. I am also excited that people simply think about metabolism now. Instead of discarding it, people now pay attention when they make an observation about a metabolic gene or protein. This is a big part of building the connectivity between our understanding of metabolism and our understanding of everything else that happens in the cell or the body.
Turning to the Science paper specifically …
Q: For context, can you describe metabolites’ function in the body and why their interactions with proteins matter?
A: Dr. Rutter: Small molecule metabolites serve as nutrients, building blocks, and the energy currency of the body. Metabolite interactions with proteins allow cells to rapidly and adaptively sense and respond to the metabolic status of the organism.
Q: Can you describe the MIDAS platform? What inspired you to develop this technology?
A: Dr. Rutter: The MIDAS platform combines a classic biochemical technique, equilibrium dialysis, a custom human metabolite compound library, and a high-throughput metabolomics platform to identify low and high affinity protein-metabolite binding interactions. Briefly, a pooled human metabolite library is dialyzed against a target protein. Once equilibrium is reached, the abundance of each metabolite in the protein and metabolite chambers are determined using mass spectrometry. Metabolites that interact with the target protein are enriched or depleted in the protein chamber relative to metabolites that do not interact and are equal in both chambers. This technology was inspired by a set of conversations that I had with my colleague Janet Lindsley in the Department of Biochemistry at the University of Utah many years ago. We were brainstorming ways that we could identify small molecules that would bind to a protein of interest where the binding was very weak. This is a difficult problem, and MIDAS is one of a relatively small number of tools that can do it.
Q: What are the key takeaways from the Science publication? What have we learned that we didn’t know previously?
A: Dr. Hicks: The key takeaways from the Science publication are four-fold. 1) We developed a new technology, MIDAS, that enables relatively high-throughput discovery of low- and high-affinity protein-metabolite interactions. 2) Using MIDAS, we analyzed thirty-three enzymes from human carbohydrate metabolism (glycolysis, gluconeogenesis, the TCA cycle, and ancillary pathways) and revealed over 800 protein-metabolite interactions, many of them unknown. These findings suggest that small molecule metabolism and proteome function maybe very highly interconnected allowing coordination of seemingly disparate cellular processes. 3) MIDAS revealed functional interactions between the enzyme lactate dehydrogenase (LDH, an important node of carbohydrate metabolism) and metabolites from energy and fatty acid metabolism (ATP and acyl-coenzyme As, respectively). These metabolites inhibit LDH function. These molecular findings support observations that fatty acids are the preferred energy source over carbs in select tissues. 4) MIDAS has the capacity to reveal endogenous allosteric modulation providing the potential for new avenues of therapeutic targeting.
Q: What was most surprising to you about the findings?
A: Dr. Hicks: The magnitude of protein-metabolite interactions in human carbohydrate metabolism was surprising (33 enzymes, 800+ interactions). When extrapolated to the proteome, the potential number of protein-metabolite interactions is immense. We have much to explore and learn about this neglected interactome, surely providing a deeper understanding of the biological network.
Q: What’s next for this technology? How can these learnings be applied therapeutically?
A: Dr. Rutter: Together with Dr. Ralph DeBeradinis, I co-founded Atavistik Bio to build on the MIDAS technology with the goal of leveraging it to develop meaningful medicines for patients. The Atavistik Bio team has industrialized this technology with the enhancement of advanced data analytics, AI and structure-based design which encompasses the Atavistik Metabolite Protein Screening (AMPS) platform. We believe that the advancements of the AMPS platform will enable the development of transformative therapeutics for patients across a broad range of diseases. In the Rutter lab, we are adapting the MIDAS platform to enable RNA-metabolite, membrane protein-metabolite, and protein-metabolome interaction discovery. Expect exciting developments soon! The more thorough our understanding of metabolite interactions with disease relevant receptors the broader the discovery potential for novel therapeutic interventions.
Q: What do you hope this technology will ultimately lead to?
A: Dr. Rutter: Ultimately, I hope this technology will enable us to comprehensively understand the extent of interactions between the small molecule metabolome and proteome and apply this information to inform our understanding of disease etiology, and, therefore better modalities of treatment.
For more information on Atavistik Bio’s approach – visit Our Science