scholarly journals Studies on the Substrate Selectivity of the Hypoxia-Inducible Factor Prolyl Hydroxylase 2 Catalytic Domain

ChemBioChem ◽  
2018 ◽  
Vol 19 (21) ◽  
pp. 2262-2267 ◽  
Author(s):  
Martine I. Abboud ◽  
Rasheduzzaman Chowdhury ◽  
Ivanhoe K. H. Leung ◽  
Kerstin Lippl ◽  
Christoph Loenarz ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Substrate Selectivity

scholarly journals Enhancement of Angiogenesis Through Stabilization of Hypoxia-inducible Factor-1 by Silencing Prolyl Hydroxylase Domain-2 Gene

2008 ◽  
Vol 16 (7) ◽  
pp. 1227-1234 ◽  
Author(s):  
Shourong Wu ◽  
Nobuhiro Nishiyama ◽  
Mitsunobu R Kano ◽  
Yasuyuki Morishita ◽  
Kohei Miyazono ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Hypoxia Inducible Factor 1 ◽  
Prolyl Hydroxylase Domain

scholarly journals A Novel Hypoxia-Inducible Factor−Prolyl Hydroxylase Inhibitor (GSK1278863) for Anemia in CKD: A 28-Day, Phase 2A Randomized Trial

2016 ◽  
Vol 67 (6) ◽  
pp. 861-871 ◽  
Author(s):  
Richard A. Brigandi ◽  
Brendan Johnson ◽  
Coreen Oei ◽  
Mark Westerman ◽  
Gordana Olbina ◽  
...  
Keyword(s):  
Randomized Trial ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Prolyl Hydroxylase Inhibitor

Biochemical characterization of human HIF hydroxylases using HIF protein substrates that contain all three hydroxylation sites

2011 ◽  
Vol 436 (2) ◽  
pp. 363-369 ◽  
Author(s):  
Melissa B. Pappalardi ◽  
Dean E. McNulty ◽  
John D. Martin ◽  
Kelly E. Fisher ◽  
Yong Jiang ◽  
...  
Keyword(s):  
Biochemical Characterization ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Transactivation Domain ◽  
Prolyl Hydroxylases ◽  
Proline Residue ◽  
Protein Substrates ◽  
Steady State Kinetic ◽  
Asparaginyl Hydroxylase

The HIF (hypoxia-inducible factor) plays a central regulatory role in oxygen homoeostasis. HIF proteins are regulated by three Fe(II)- and α-KG (α-ketoglutarate)-dependent prolyl hydroxylase enzymes [PHD (prolyl hydroxylase domain) isoenzymes 1–3 or PHD1, PHD2 and PHD3] and one asparaginyl hydroxylase [FIH (factor inhibiting HIF)]. The prolyl hydroxylases control the abundance of HIF through oxygen-dependent hydroxylation of specific proline residues in HIF proteins, triggering subsequent ubiquitination and proteasomal degradation. FIH inhibits the HIF transcription activation through asparagine hydroxylation. Understanding the precise roles and regulation of these four Fe(II)- and α-KG-dependent hydroxylases is of great importance. In the present paper, we report the biochemical characterization of the first HIF protein substrates that contain the CODDD (C-terminal oxygen-dependent degradation domain), the NODDD (N-terminal oxygen-dependent degradation domain) and the CAD (C-terminal transactivation domain). Using LC-MS/MS (liquid chromatography–tandem MS) detection, we show that all three PHD isoenzymes have a strong preference for hydroxylation of the CODDD proline residue over the NODDD proline residue and the preference is observed for both HIF1α and HIF2α protein substrates. In addition, steady-state kinetic analyses show differential substrate selectivity for HIF and α-KG in reference to the three PHD isoforms and FIH.

In vitro studies of Hypoxia Inducible Factor‐ Prolyl Hydroxylase Inhibitors Daprodustat, Desidustat and Vadadustat for equine doping control

2021 ◽  
Author(s):  
Moses Philip ◽  
Abdul Khader Karakka Kal ◽  
Michael Benedict Subhahar ◽  
Tajudheen K. Karatt ◽  
Binoy Mathew ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Doping Control ◽  
In Vitro Studies

scholarly journals Beyond Traditional Structure-Based Drug Design: The Role of Iron Complexation, Strain, and Water in the Binding of Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylase 2

ACS Omega ◽  
2019 ◽  
Vol 4 (4) ◽  
pp. 6703-6708
Author(s):  
Scott D. Bembenek ◽  
Hariharan Venkatesan ◽  
Hillary M. Peltier ◽  
Mark D. Rosen ◽  
Terrance D. Barrett ◽  
...  
Keyword(s):  
Drug Design ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Structure Based Drug Design ◽  
Traditional Structure ◽  
Iron Complexation

scholarly journals Discovery of Orally Bioavailable and Liver-Targeted Hypoxia-Inducible Factor Prolyl Hydroxylase (HIF-PHD) Inhibitors for the Treatment of Anemia

2018 ◽  
Vol 9 (12) ◽  
pp. 1193-1198 ◽  
Author(s):  
Ping Liu ◽  
Liping Wang ◽  
Byron G. DuBois ◽  
Vincent J. Colandrea ◽  
Rongqiang Liu ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Orally Bioavailable

scholarly journals Hypoxia-Inducible Factor Stabilizers in End Stage Kidney Disease: “Can the Promise Be Kept?”

2021 ◽  
Vol 22 (22) ◽  
pp. 12590
Author(s):  
Giuseppina Crugliano ◽  
Raffaele Serra ◽  
Nicola Ielapi ◽  
Yuri Battaglia ◽  
Giuseppe Coppolino ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Cardiovascular Events ◽  
Iron Supplementation ◽  
Hypoxia Inducible Factor ◽  
Current Treatment ◽  
Prolyl Hydroxylase ◽  
Individual Risk ◽  
Increased Risk ◽  
Gastrointestinal Side Effects ◽  
Iv Iron

Anemia is a common complication of chronic kidney disease (CKD). The prevalence of anemia in CKD strongly increases as the estimated Glomerular Filtration Rate (eGFR) decreases. The pathophysiology of anemia in CKD is complex. The main causes are erythropoietin (EPO) deficiency and functional iron deficiency (FID). The administration of injectable preparations of recombinant erythropoiesis-stimulating agents (ESAs), especially epoetin and darbepoetin, coupled with oral or intravenous(iv) iron supplementation, is the current treatment for anemia in CKD for both dialysis and non-dialysis patients. This approach reduces patients’ dependence on transfusion, ensuring the achievement of optimal hemoglobin target levels. However, there is still no evidence that treating anemia with ESAs can significantly reduce the risk of cardiovascular events. Meanwhile, iv iron supplementation causes an increased risk of allergic reactions, gastrointestinal side effects, infection, and cardiovascular events. Currently, there are no studies defining the best strategy for using ESAs to minimize possible risks. One class of agents under evaluation, known as prolyl hydroxylase inhibitors (PHIs), acts to stabilize hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylase (PH) enzymes. Several randomized controlled trials showed that HIF-PHIs are almost comparable to ESAs. In the era of personalized medicine, it is possible to envisage and investigate specific contexts of the application of HIF stabilizers based on the individual risk profile and mechanism of action.

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