title: β-N-oxalyl-L-α, β- diaminopropionic acid induces HRE expression by inhibiting HIF-prolyl hydroxylase-2 in normoxic conditions.
abstract: Hypoxia inducible factor (HIF)-1α, a subunit of HIF transcription factor, regulates cellular response to hypoxia. In normoxic conditions, it is hydroxylated by prolyl hydroxylase (PHD)-2 and targeted for proteosomal degradation. Drugs which inhibit PHD-2 have implications in conditions arising from insufficient blood supply. β-ODAP (β-N- oxalyl-L-α, β- diaminopropionic acid), a non-protein excitatory amino acid present in Lathyrus sativus, is an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor agonist known to activate conventional protein kinase C and stabilize HIF-1α under normoxic conditions. However, the mechanism of HIF-1α stabilization by this compound is unknown. In silico approach was used to understand the mechanism of stabilization of HIF-1α which revealed β-ODAP interacts with key amino acid residues and Fe2+at the catalytic site of PHD-2. These results were further corroborated with luciferase HRE (hypoxia response element) reporter system in HeLa cells. Different chemical modulators of PHD-2 activity and HIF-1α levels were included in the study for comparison. Results obtained indicate that β-ODAP inhibits PHD-2 and facilitates HIF dependent HRE expression and hence, might be helpful in conditions arising from hypoxia.
authors.affiliation: Department of Biochemistry, University College of Science, Osmania University, Hyderabad, Telangana State 500007, India. Electronic address: ravikumar.biochem123@gmail.com.
authors.forename: Ravi Kumar
authors.initials: RK
authors.lastname: Eslavath
authors.affiliation: Department of Biochemistry, University College of Science, Osmania University, Hyderabad, Telangana State 500007, India. Electronic address: deepshikhagold@gmail.com.
authors.forename: Deepshikha
authors.initials: D
authors.lastname: Sharma
authors.affiliation: Department of Biochemistry, University College of Science, Osmania University, Hyderabad, Telangana State 500007, India. Electronic address: nabiloub@yahoo.com.
authors.forename: Nabil A M
authors.initials: NAM
authors.lastname: Bin Omar
authors.affiliation: Department of Biochemistry, University College of Science, Osmania University, Hyderabad, Telangana State 500007, India. Electronic address: chikati.rajasekhar@gmail.com.
authors.forename: Rajasekhar
authors.initials: R
authors.lastname: Chikati
authors.affiliation: School of Biotechnology, National Institute of Technology Calicut, Calicut, Kerala, India. Electronic address: maheshkumar.teli@gmail.com.
authors.forename: Mahesh Kumar
authors.initials: MK
authors.lastname: Teli
authors.affiliation: School of Biotechnology, National Institute of Technology Calicut, Calicut, Kerala, India. Electronic address: rajanikant@nitc.ac.in.
authors.forename: G K
authors.initials: GK
authors.lastname: Rajanikant
authors.affiliation: Department of Biochemistry, University College of Science, Osmania University, Hyderabad, Telangana State 500007, India. Electronic address: suryasingh.oubioc@gmail.com.
authors.forename: Surya S
authors.initials: SS
authors.lastname: Singh
mesh_terms: D000599:Amino Acids, Diamino / Q000494:pharmacology*; D020134:Catalytic Domain; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors*; D062105:Molecular Docking Simulation; D010100:Oxygen / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D020218:Response Elements / Q000235:genetics*
chemical_list: D000599:Amino Acids, Diamino; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; C100126:oxalyldiaminopropionic acid; D004247:DNA; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D010100:Oxygen
keywords: Hypoxia response elements; Prolyl hydroxylase-2; β-ODAP