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

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.

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

“…The regulation of the expression of genes in response to hypoxia is due, in part, to the actions of hypoxia inducible factor 1 alpha (HIF1-α) (for example, (136)). Under normal oxygen conditions, HIF1-α protein levels are low due to the actions of O 2 -dependent, iron (non-heme) containing prolyl hydroxylases that oxidize it, leading to its degradation/elimination (for example (137)). However, under low O 2 conditions (hypoxia), the activity of the prolyl hydroxylases is decreased (due to the lack of O 2 as a co-substrate) leading to an increase in the levels of HIF1-α and, therefore, an increase in the expression of genes for the response to hypoxia (e.g.…”

Prolyl 4-hydroxylase activity-responsive transcription factors: From hydroxylation to gene expression and neuroprotection

“…The hydroxylation reaction catalyzed by the PHDs comprises of an iron-mediated incorporation of a hydroxyl group into the conserved proline residue with the consumption of a dioxygen molecule and release of carbon dioxide, whereas 2-oxoglutarate is converted to succinate (7) (for review, see Siddiq et al, 2007) (Figure 1). PHDs that selectively catalyze the formation of hydroxyproline in the HIF-1 molecule by the hydroxylation of conserved proline residues belong to a sub-group of the dioxygenases.…”

“…Central to these adaptive reorganization efforts is the change in activity of the oxygen, Fe 2+ and 2-oxoglutarate dependent dioxygenases known as the HIF prolyl 4-hydroxylases. These enzymes possess a Km for oxygen that makes them ideal oxygen sensors (7). In response to changes in iron, oxygen or 2-oxoglutarate, PHD activity decreases.…”

Benzimidazole-2-pyrazole HIF Prolyl 4-Hydroxylase Inhibitors as Oral Erythropoietin Secretagogues

“…6,7 Therefore, positive modulation of HIF transcriptional activity holds promise as a mode of treatment for a variety of debilitating ischemiaassociated diseases, including anemia, myocardial infarction, stroke, and metabolic disorders, by conducting an orchestrated response to hypoxic challenge. 8,9 Because of their key role in the regulation of HIF levels, inhibition of PHD enzymes is an attractive strategy by which to potentiate the transcriptional activity of HIF in a therapeutically relevant manner. Indeed, during the last several years, intense efforts to discover PHD inhibitors have been adumbrated primarily in the patent literature, 10 and to a much lesser degree in the peer-reviewed literature, [11][12][13][14][15][16][17][18][19] leading to four compounds entering clinical trials.…”