Neurochemical Research

, Volume 32, Issue 4–5, pp 931–946 | Cite as

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

  • Ambreena Siddiq
  • Leila R Aminova
  • Rajiv R Ratan
Original Paper


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.


Hypoxia inducible factor Prolyl 4-hydroxylase Transcriptional regulation Neuroprotection Iron chelation 



Activator protein 1


Carbon dioxide


Cobalt chloride


Carboxy-terminal oxygen degradation domain






Early growth response protein-1


Extracellular signal-regulated kinase






Fumarate hydratase


Hypoxia inducible factor


Hypoxia inducible factor-1 alpha


Hypoxia inducible factor-1 beta


Hypoxia response elements


Iron regulatory protein-2


Labile iron pool


Manganese Superoxide Dismutase


Mitogen-activated protein kinase organizer-1


Nuclear factor kappa B


N-terminal oxygen degradation domain




Oxygen degradation domain


Oxygen dependent degradation domain


prolyl 4-hydroxylase domain


von Hippel-Lindau protein

RNA pol II

RNA polymerase II


Reactive Oxygen Species


Seven in absentia homolog 2


Succinate dehydrogenase


Tricarboxylic acid


Vascular endothelial growth factor


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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Ambreena Siddiq
    • 1
    • 2
  • Leila R Aminova
    • 3
  • Rajiv R Ratan
    • 1
    • 2
  1. 1.Burke Medical Research InstituteNew YorkUSA
  2. 2.Departments of Neurology and NeuroscienceWeil Medical College of Cornell UniversityNew YorkUSA
  3. 3.Department of MicrobiologyUniversity of Illinois at Urbana-ChampaignUrbanaUSA

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