2. Academic Validation
  3. β-N-oxalyl-L-α, β- diaminopropionic acid induces HRE expression by inhibiting HIF-prolyl hydroxylase-2 in normoxic conditions

β-N-oxalyl-L-α, β- diaminopropionic acid induces HRE expression by inhibiting HIF-prolyl hydroxylase-2 in normoxic conditions

  • Eur J Pharmacol. 2016 Nov 15;791:405-411. doi: 10.1016/j.ejphar.2016.07.007.
Ravi Kumar Eslavath 1,  Deepshikha Sharma 2,  Nabil A M Bin Omar 3,  Rajasekhar Chikati 4,  Mahesh Kumar Teli 5,  G K Rajanikant 6,  Surya S Singh 7
Affiliations

Affiliations

  • 1 Department of Biochemistry, University College of Science, Osmania University, Hyderabad, Telangana State 500007, India. Electronic address: ravikumar.biochem123@gmail.com.
  • 2 Department of Biochemistry, University College of Science, Osmania University, Hyderabad, Telangana State 500007, India. Electronic address: deepshikhagold@gmail.com.
  • 3 Department of Biochemistry, University College of Science, Osmania University, Hyderabad, Telangana State 500007, India. Electronic address: nabiloub@yahoo.com.
  • 4 Department of Biochemistry, University College of Science, Osmania University, Hyderabad, Telangana State 500007, India. Electronic address: chikati.rajasekhar@gmail.com.
  • 5 School of Biotechnology, National Institute of Technology Calicut, Calicut, Kerala, India. Electronic address: maheshkumar.teli@gmail.com.
  • 6 School of Biotechnology, National Institute of Technology Calicut, Calicut, Kerala, India. Electronic address: rajanikant@nitc.ac.in.
  • 7 Department of Biochemistry, University College of Science, Osmania University, Hyderabad, Telangana State 500007, India. Electronic address: suryasingh.oubioc@gmail.com.
PMID: 27393459 DOI: 10.1016/j.ejphar.2016.07.007
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.

Keywords

Hypoxia response elements; Prolyl hydroxylase-2; β-ODAP.

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