Allosteric regulation of human ribokinase by monovalent cations

Naomi Akanmori 
MSc Student
Department of Biochemistry

Date: March 4, 2024
Time: 1:00 p.m. to 2:00 p.m. 
Room: CSF 1302

Abstract:

Ribose serves as a crucial building block for nucleotides, amino acids, and enzyme cofactors. It is an essential component of cellular energy currency and has gained significant attention as a dietary supplement. The initial step in ribose metabolism is catalyzed by ribokinase (RK), which activates ribose to ribose-5-phosphate (R5P). R5P subsequently enters various metabolic pathways, including the pentose phosphate pathway. Notably, RK exhibits a unique dependence on monovalent cations, demonstrating significantly higher catalytic activity in the presence of K⁺ compared to Na⁺. However, the molecular mechanisms underlying this disparity remain unknown. My research aims to elucidate the mechanism of RK activation by K⁺. We hypothesize that K⁺ binding induces a conformational change in the ATP binding site that optimally orients ATP for catalysis, whereas Na⁺binding cannot. To test this hypothesis, we are conducting crystallographic studies of human RK in the presence of either K⁺ or Na⁺ in different ligand-bound states. In addition, we are performing molecular dynamics (MD) simulations to uncover any conformational changes beyond those captured in the crystal structures. To date, we have obtained eight crystal structures of human RK, all bound with Na⁺, representing various stages of the enzyme’s catalytic cycle. These structures will serve as reference points for future studies on K⁺-bound structures and have also provided insights into the sequence of substrate binding and product release for the RK reaction. Particularly notable is the observation of extreme flexibility in the phosphate groups of ATP, supporting our hypothesis of inefficient ATP orientation in the presence of Na⁺. Preliminary MD simulation results are overall consistent with experimental data, with regions of flexibility aligning well with those identified in the crystal structures.