Coupling between protein stability and catalytic activity determines pathogenicity of glucose-6-phosphate dehydrogenase (G6PD) variants
- G6PD deficiency, an enzymopathy affecting 7% of the world population, is caused by over 160 different amino acid variants in glucose-6-phosphate dehydrogenase (G6PD). This essential enzyme plays a critical role in maintaining redox homeostasis, and while variants that reduce activity are protective against malaria, complete loss of G6PD activity is lethal. G6PD deficiency is a major risk factor for hyperbilirubinemia and kernicterus, and may contribute to many health conditions including neurodegenerative diseases, heart disease, diabetes, and aging. The clinical presentation of G6PD deficiency is diverse, likely due to the broad distribution of variants across the protein and the potential for multidimensional biochemical effects -- previously characterized G6PD variants have been shown to affect catalytic activity, thermostability, and protein folding. However, the relationship between the structural, biochemical, and phenotypic effects of a G6PD variant remains largely unexplored. Recent developments in the fields of bioinformatics and genome sequencing have allowed us to combine existing phenotypic, biochemical, and genomic information about G6PD to develop new hypotheses about its evolution, structure, and function. In this study, we use existing databases of characterized and uncharacterized G6PD variants to interpret the importance of various structural regions of G6PD. Using biochemical analyses, we identify a trade-off between protein stability and catalytic activity as a major determinant of a G6PD variant's clinical phenotype. Additionally, we examine the evolution of G6PD using a recently developed sequence coevolution analysis method. We identify three coevolving sectors of amino acids that are enriched in different classes of G6PD variants; these three sectors also correspond to functionally characterized structural regions. Based on two sectors that span multiple structural regions, we develop novel hypotheses about conformational and allosteric regulation of G6PD. This work expands the current understanding of the structural and biochemical underpinnings of G6PD variant pathogenicity, and suggests a promising avenue for correcting G6PD deficiency by targeting essential structural features of G6PD.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|Cunningham, Anna D
|Stanford University, Department of Chemical and Systems Biology.
|Statement of responsibility
|Anna D. Cunningham.
|Submitted to the Department of Chemical and Systems Biology.
|Thesis (Ph.D.)--Stanford University, 2017.
- © 2017 by Anna Delia Cunningham
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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