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Born to sense: biophysical analyses of the oxygen sensing prolyl hydroxylase from the simplest animal Trichoplax adhaerens

Authors Lippl K, Boleininger A, McDonough MA, Abboud MI, Tarhonskaya H, Chowdhury R, Loenarz C, Schofield CJ

Received 19 May 2018

Accepted for publication 27 July 2018

Published 9 November 2018 Volume 2018:6 Pages 57—71

DOI https://doi.org/10.2147/HP.S174655

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Andrew Yee

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Dörthe Katschinski


Kerstin Lippl, Anna Boleininger, Michael A McDonough, Martine I Abboud, Hanna Tarhonskaya, Rasheduzzaman Chowdhury, Christoph Loenarz, Christopher J Schofield

Chemistry Research Laboratory, University of Oxford, Oxford, UK

Background: In humans and other animals, the chronic hypoxic response is mediated by hypoxia inducible transcription factors (HIFs) which regulate the expression of genes that counteract the effects of limiting oxygen. Prolyl hydroxylases (PHDs) act as hypoxia sensors for the HIF system in organisms ranging from humans to the simplest animal Trichoplax adhaerens.
Methods: We report structural and biochemical studies on the T. adhaerens HIF prolyl hydroxylase (TaPHD) that inform about the evolution of hypoxia sensing in animals.
Results: High resolution crystal structures (≤1.3 Å) of TaPHD, with and without its HIFα substrate, reveal remarkable conservation of key active site elements between T. adhaerens and human PHDs, which also manifest in kinetic comparisons.
Conclusion: Conserved structural features of TaPHD and human PHDs include those apparently enabling the slow binding/reaction of oxygen with the active site Fe(II), the formation of a stable 2-oxoglutarate complex, and a stereoelectronically promoted change in conformation of the hydroxylated proline-residue. Comparison of substrate selectivity between the human PHDs and TaPHD provides insights into the selectivity determinants of HIF binding by the PHDs, and into the evolution of the multiple HIFs and PHDs present in higher animals.

Keywords: hypoxia, hypoxic response, oxygen sensing, hypoxia-inducible factor (HIF), evolution, dioxygenase, enzyme structure, PHD/EGLN prolyl hydroxylases, 2-oxoglutarate oxygenase, Trichoplax adhaerens

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