Long-range structural defects by pathogenic mutations in most severe glucose-6-phosphate dehydrogenase deficiency
Naoki Horikoshi, Sunhee Hwang, Cornelius Gati, Tsutomu Matsui, Carlos Castillo-Orellana, Andrew G. Raub, Adriana A. Garcia, Fatemeh Jabbarpour, A. Batyuk, Joshua Broweleit, Xinyu Xiang, Andrew Chiang, Rachel Broweleit, Esteban Vöhringer‐Martinez, Daria Mochly‐Rosen, Soichi Wakatsuki
Abstract
Significance Mechanism of the loss of activity of the most severe patient-derived mutants of glucose-6-phosphate dehydrogenase (G6PD) deficiency has remained elusive despite the availability of the G6PD structures for decades. Structural and biophysical investigations have revealed a common mechanism and dynamics of how these mutations hinder the substrate-binding site, reducing enzymatic activity. These are triggered by a long-distance propagation of structural defects at the dimer interface and the binding site of the noncatalytic cofactor. These structural distortions are found among all of the class I mutants investigated, providing critical clues for drug design to address G6PD deficiency by correcting the structural defects.