Modeling dioxygenase enzyme kinetics in familial paraganglioma
| Autor: | Yeng F. Her, Justin P. Peters, L. James Maher |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
QH301-705.5
Science PHD Biology General Biochemistry Genetics and Molecular Biology Paraganglioma 03 medical and health sciences 0302 clinical medicine Mathematical model Oxygen homeostasis medicine HIF Enzyme kinetics Biology (General) Hypoxia Transcription factor 030304 developmental biology Phenocopy 0303 health sciences Cell growth Succinate dehydrogenase Hypoxia (medical) Hypoxia-inducible factors Biochemistry 030220 oncology & carcinogenesis biology.protein medicine.symptom General Agricultural and Biological Sciences Research Article |
| Zdroj: | Biology Open, Vol 4, Iss 10, Pp 1281-1289 (2015) Biology Open |
| ISSN: | 2046-6390 |
| Popis: | Hypoxia inducible factors (HIFs) play vital roles in cellular maintenance of oxygen homeostasis. These transcription factors are responsible for the expression of genes involved in angiogenesis, metabolism, and cell proliferation. Here, we generate a detailed mathematical model for the enzyme kinetics of α-ketoglutarate-dependent HIF prolyl 4-hydroxylase domain (PHD) dioxygenases to simulate our in vitro data showing synergistic PHD inhibition by succinate and hypoxia in experimental models of succinate dehydrogenase loss, which phenocopy familial paraganglioma. Our mathematical model confirms the inhibitory synergy of succinate and hypoxia under physiologically-relevant conditions. In agreement with our experimental data, the model predicts that HIF1α is not stabilized under atmospheric oxygen concentrations, as observed. Further, the model confirms that addition of α-ketoglutarate can reverse PHD inhibition by succinate and hypoxia in SDH-deficient cells. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|