Koutmos Lab

RNA  |  enzymology  structural biology  |  biocatalysis

 

Mission

We are interested in understanding how the 3D structure and dynamics of proteins and RNAs drive their biological function. Our lab combines chemistry, biophysics and biology to build a foundation of basic knowledge for understanding the remarkable chemistries catalyzed by nature’s best enzymes, re-designing the catalytic properties of enzymes, uncovering the roles of biomacromolecules in disease, and discovering new classes of therapeutic targets. The Koutmos Lab is a diverse community of scientific peers that that values differences as an asset to create a highly interdisciplinary environment for scientific discovery. Please contact Prof. Koutmos (mkoutmos@umich.edu) to learn more.

 

Projects

RNA Modifications and RNA/Protein Interactions

There are over 100 different nucleoside modifications found throughout RNA that are key determinants of RNA structure and function. Mutations in RNA modifying enzymes have been linked to a number of diseases including mitochondrial encephalomyopathy, heart disease, cancers, and delayed neurological development. As the study of post transcriptional modifications has exploded over the past decade with the discovery of modifications in mRNAs, many of the proteins that carry out post transcriptional modifications remain under studied. My lab studies three classes of RNA modifying enzymes: Pseudouridine Synthases, RNA methyltransferases, and demethylases. We use a combination of orthogonal approaches including x-ray crystallography, cryo-EM, and kinetics assays to characterize the structure, substrate selection and function of these proteins. We aim to translate this fundamental knowledge to important biological insights and the potential development of therapeutics or bio-applications.

Collaborators: Kristin Koutmou (UMich) and Dragony Fu (URochester)

Metalloenzymes

We are interested in discovering how biological catalysts accomplish “unusual” or “improbable” chemistries. One of our targets is vitamin B12 (cobalamin)-dependent methionine synthase (MS).  MS is a multi-modular enzyme essential for folate one-carbon metabolism. The enzyme catalyzes the methyl transfer reaction from methyltetrahydrofolate to homocysteine to form methionine and tetrahydrofolate.  The reaction is hard to accomplish at physiological pH because the methyl group binds the N5 position of folate, which is a tertiary amine, and homocysteine is thiol, making the reaction unlikely. MS accomplishes the reaction using two metals, Co (in cobalamin) and Zn.  Our interest in MS stems not only from the chemically improbable methylation that it catalyzes but also from the unique capabilities of its cobalamin cofactor. The goal of our work is to uncover fundamental principles regarding how enzyme dynamics facilitate challenging chemistries.  Furthermore, these principles could ultimately be used to reprogram MS (and/or cobalamin cofactor) to catalyze new reactions.

Collaborators: Alison Narayan (UMich) and Ruma Banerjee (UMich)

Mitochondrial RNA Biology and Processing

​Ribonuclease P is the biological catalyst responsible for maturing the 5’ end of transfer RNAs (tRNAs), the essential molecules that carry amino acids to the ribosome. We use a combination of biochemistry (kinetic and binding assays), structural biology (x-ray crystallography, Cryo-EM), and in vivo studies to uncover the structure, mechanism, and physiological role of RNase Ps first discovered in human mitochondria (protein only RNase Ps (PRORPs)). PRORPs are essential to human health, and disruption of their action is directly linked to a number of mitochondrial diseases. Our studies provide the molecular-level understanding of PRORPs required to eventually develop treatments for diseases caused by disruptions in mitochondrial tRNA 5’ end processing.

Collaborators: Carol Fierke (Texas A&M)

RNA Crystallography and Dynamics

​​Riboswitches are genetic regulatory elements present in the 5’ UTRs many bacterial mRNAs. These structured elements bind small metabolites to control essential cellular metabolic processes. While riboswitches are essential for many pathogenic bacteria, they are not present in humans, making them a promising alternative target for drug design. We are working to develop high throughput methods to screen for small molecules that inhibit riboswitches using x-ray crystallography, ligand-RNA characterization and molecular dynamics simulations.

Collaborators: Aaron Frank (UMich) and Sarah Keane (UMich)

 

Lab Members

 
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Markos Koutmos

Assistant Professor of Chemistry, Biophysics

I earned my Diploma in chemistry at the University of Athens, Greece, then trained in synthetic inorganic chemistry and protein crystallography with Professors Dimitri Coucouvanis, Martha Ludwig and Janet Smith at the University of Michigan. I began my independent career at the Uniformed University of the Health Sciences before moving back to the University of Michigan in 2018.

Kazuhiro Yamada

Research Lab Specialist Senior

My work focuses on studies to understand the role of key higher eukaryotic proteins in the vitamin B12, homocysteine, and folate metabolisms. In my spare time, I enjoy playing video games.

Leena Mallik

Research Specialist

I work on understanding the structure, function and mechanism of action of protein-only RNase P. Outside of lab, I love to travel and explore new places.

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Meredith Purchal

PhD Candidate

I earned a BS in Biology from the University of Texas at Austin. At Michigan, I joined the labs of Markos Koutmos and Kristin Koutmou, where I use protein crystallography and enzymology to study Pseudouridine Synthases (PUS enzymes), which install pseudouridine, one of the most abundant post-transcriptional RNA modifications. In my free time, I enjoy spending time with friends, cross stitching, and watching Bon Appétit cooking videos of things I will never actually cook.

Samantha Rudin-Rush

PhD Candidate, Chemistry

I focus on characterizing post-transcriptional RNA methyltransferases. Methyl groups are the most prominent post-transcriptional RNA modification. These methyl groups can have a large effect on how tRNA interacts chemically, and several diseases are linked to mutations in these methyltransferases. When not in the lab I like to go hiking, write, and go over to friends’ places to play with their cats.

Liz Tidwell

PhD Candidate, Biophysics

I got my BA in biochemistry & molecular biology at Hastings College. I am currently starting a project investigating alternative conformations of RNA molecules in existing crystallographic densities. Outside of lab I cook, hike, and read fantasy/scifi novels!

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Catherine Wilhelm

PhD Candidate, Chemistry

My project focuses on the kinetics of RNA modifications in mitochondrial RNA. These modifications affect the stability of RNA and impacts translation. In my free time, I love to read, play video games, and spend time with my cats.

Hari Sharma

Undergraduate, Senior

Cellular & Molecular Biology

In the Koutmos Lab I am working on the purifying and crystallizing a human homolog of a pseudouridine synthase, hPUS7. I enjoy playing tennis, rowing, wake surfing, cooking and traveling.

Contact

Student Office:
Room CHEM 2537

930 N University Ave

Ann Arbor, MI 48109, USA

 

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