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Hypoxia Inducible Factor Prolyl 4-Hydroxylase Enzymes: Center Stage in the Battle Against Hypoxia, Metabolic Compromise and Oxidative Stress

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Abstract

Studies of adaptive mechanisms to hypoxia led to the discovery of the transcription factor called hypoxia inducible factor (HIF). HIF is a ubiquitously expressed, heterodimeric transcription factor that regulates a cassette of genes that can provide compensation for hypoxia, metabolic compromise, and oxidative stress including erythropoietin, vascular endothelial growth factor, or glycolytic enzymes. Diseases associated with oxygen deprivation and consequent metabolic compromise such as stroke or Alzheimer’s disease may result from inadequate engagement of adaptive signaling pathways that culminate in HIF activation. The discovery that HIF stability and activation are governed by a family of dioxygenases called HIF prolyl 4 hydroxylases (PHDs) identified a new target to augment the transcriptional activity of HIF and thus the adaptive machinery that governs neuroprotection. PHDs lose activity when cells are deprived of oxygen, iron or 2-oxoglutarate. Inhibition of PHD activity triggers the cellular homeostatic response to oxygen and glucose deprivation by stabilizing HIF and other proteins. Herein, we discuss the possible role of PHDs in regulation of both HIF-dependent and -independent cell survival pathways in the nervous system with particular attention to the co-substrate requirements for these enzymes. The emergence of neuroprotective therapies that modulate genes capable of combating metabolic compromise is an affirmation of elegant studies done by John Blass and colleagues over the past five decades implicating altered metabolism in neurodegeneration.

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Abbreviations

AP-1:

Activator protein 1

CO2 :

Carbon dioxide

CoCl2 :

Cobalt chloride

CODD:

Carboxy-terminal oxygen degradation domain

DFO:

Desferrioxamine

DMOG:

Dimethyl-oxalyl-glycine

EGR-1:

Early growth response protein-1

ERK:

Extracellular signal-regulated kinase

Fe2+ :

Ferrous

Fe3+ :

Ferric

FH:

Fumarate hydratase

HIF:

Hypoxia inducible factor

HIF-1α:

Hypoxia inducible factor-1 alpha

HIF-1β:

Hypoxia inducible factor-1 beta

HRE:

Hypoxia response elements

IRP2:

Iron regulatory protein-2

LIP:

Labile iron pool

MnSOD:

Manganese Superoxide Dismutase

MORG-1:

Mitogen-activated protein kinase organizer-1

NF-kB:

Nuclear factor kappa B

NODD:

N-terminal oxygen degradation domain

O2 :

Oxygen

ODD:

Oxygen degradation domain

ODDD:

Oxygen dependent degradation domain

PHD:

prolyl 4-hydroxylase domain

PVHL:

von Hippel-Lindau protein

RNA pol II:

RNA polymerase II

ROS:

Reactive Oxygen Species

SIAH2:

Seven in absentia homolog 2

SDH:

Succinate dehydrogenase

TCA:

Tricarboxylic acid

VEGF:

Vascular endothelial growth factor

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Authors and Affiliations

  1. Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, New York, NY, 10605, USA

    Ambreena Siddiq & Rajiv R Ratan

  2. Departments of Neurology and Neuroscience, Weil Medical College of Cornell University, New York, NY, 10021, USA

    Ambreena Siddiq & Rajiv R Ratan

  3. Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Leila R Aminova

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  1. Ambreena Siddiq
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Siddiq, A., Aminova, L.R. & Ratan, R.R. Hypoxia Inducible Factor Prolyl 4-Hydroxylase Enzymes: Center Stage in the Battle Against Hypoxia, Metabolic Compromise and Oxidative Stress. Neurochem Res 32, 931–946 (2007). https://doi.org/10.1007/s11064-006-9268-7

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