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Structural defect leads to human severe (Class I) loss of function in glucose‐6‐phosphate dehydrogenase
Author(s) -
Horikoshi Naoki,
Hwang Sunhee,
Gati Cornelius,
Matsui Tsutomu,
Castillo-Orellana Carlos,
Garcia Adriana A.,
Raub Andrew G,
Jabbarpour Fatemeh,
Mochly-Rosen Daria,
Wakatsuki Soichi,
Vöhringer-Martinez Estevan
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.08997
Subject(s) - pentose phosphate pathway , glucose 6 phosphate dehydrogenase , dehydrogenase , oxidative stress , biology , enzyme , medicine , biochemistry , glycolysis
Oxidative stress caused by infection, medication, food, and imbalance of metabolic cycles damages DNA and organelles, which may lead to cancer, blood disorders, and other serious diseases. Glucose‐6‐phosphate dehydrogenase (G6PD) is the rate‐limiting enzyme in the pentose phosphate pathway, which is essential for nucleotide, fatty acid, cholesterol, and hormone synthesis. In addition to those roles, G6PD reduces NADP + to NADPH, which is crucial for reducing reactive oxygen species. Dysfunction of G6PD increases susceptibility to oxidative stress, especially in erythrocyte due to the lack of mitochondria, which is another source of NADPH. Interestingly, 400 million people worldwide have mutations on the g6pd gene, and the World Health Organization (WHO) has classified more than 160 missense mutations into five classes. The Class I G6PD deficiency is the most severe form; patients have less than 10% enzymatic activity of wild‐type G6PD and suffer from chronic non‐spherocytic hemolytic anemia. Here, we provide a new insight into the loss of activity in G6PD deficiency, based on the structure of the Class I pathogenic mutants of G6PD. We will discuss the structural basis of the Class I mutants of G6PD and its implications to various symptoms in G6PD deficiency. Support or Funding Information National Institutes of Health, R01 grant, HD084422; Japan Society for the Promotion of Science KAKENHI, Grant‐in Aid for Research Activity Start‐up, JP19K23713; University of Tsukuba; Stanford University; SLAC National Accelerator Laboratory