bioRxiv preprint doi: https://doi.org/10.1101/2020.04.19.049387; this version posted April 20, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Mechanisms of pH-dependent IDH1 catalysis An acidic residue buried in the dimer interface of isocitrate dehydrogenase 1 (IDH1) helps regulate catalysis and pH sensitivity Lucas A. Luna1, Zachary Lesecq1, Katharine A. White2, An Hoang1, David A. Scott3, Olga Zagnitko3, Andrey A. Bobkov3, Diane L. Barber4, Jamie M. Schiffer5, Daniel G. Isom6, and Christal D. Sohl1,‡,§ From the 1Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA, 92182; 2Harper Cancer Research Institute, Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, IN, 46617; 3Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037; 4Department of Cell and Tissue Biology, University of California, San Francisco, CA, 94143; 5Janssen Research and Development, 3210 Merryfield Row, San Diego, CA, 92121; 6Department of Pharmacology, Sylvester Comprehensive Cancer Center, and Center for Computational Sciences, University of Miami, Miami, FL, 33136 Running title: Mechanisms of pH-dependent IDH1 catalysis ‡To whom correspondence should be addressed: Christal D. Sohl, Department of Chemistry and Biochemistry, San Diego State University, CSL 328, 5500 Campanile Dr., San Diego, California 92182, Email:
[email protected]; Telephone: (619) 594-2053. §This paper is dedicated to the memory of our dear colleague and friend, Michelle Evon Scott (1990-2020). Keywords: enzyme kinetics, cancer, tumor metabolism, pH regulation, post-translational modification (PTM), buried ionizable residues ABSTRACT protonation states leading to conformational Isocitrate dehydrogenase 1 (IDH1) changes that regulate catalysis.