What is HIF prolyl hydroxylase?
What is HIF prolyl hydroxylase?
1. HIF-prolyl hydroxylases (HPHs),6 also referred to as prolyl hydroxylase domain (PHD) proteins,7 form an evolutionarily conserved subfamily of dioxygenases that uses oxygen and 2-oxoglutarate (2-OG) as co-substrates, and iron and ascorbate as cofactors.
What does HIF PH used for hydroxylation?
Hypoxia-inducible factor (HIF) is an evolutionarily conserved transcription factor that allows the cell to respond physiologically to low concentrations of oxygen. A class of prolyl hydroxylases which act specifically on HIF has been identified; hydroxylation of HIF allows the protein to be targeted for degradation.
Where is prolyl hydroxylase found?
Hyp is also found in proteins with collagen-like domains, as well as elastin, conotoxins, and argonaute 2. A prolyl hydroxylase domain protein acts on the hypoxia inducible factor α, which plays a key role in sensing molecular oxygen, and could act on inhibitory κB kinase and RNA polymerase II.
What are HIF stabilizers?
This new class of drug-called HIF stabilizers, or HIF prolyl-hydroxylase inhibitors-prevents the proteasomal degradation of HIF-α, thereby inducing upregulation of the erythropoietin gene.
How does a HIF inhibitor work?
Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) enzyme inhibitors are a new class of agents for the treatment of anemia in CKD. These agents work by stabilizing the HIF complex and stimulating endogenous erythropoietin production even in patients with end-stage kidney disease.
Why is there no codon for hydroxyproline?
There is no codon for hydroxyproline. Except at high concentrations, hydrox- yproline is not recognized by prolyl-t-RNA synthetase. Only in thecase of Chlamydomonas cell wall, where the hy- droxyproline-rich glycoproteins are the cell wall, can a probable function be assigned to them.
What does prolyl hydroxylase use for hydroxylation?
Procollagen-proline dioxygenase, commonly known as prolyl hydroxylase, is a member of the class of enzymes known as alpha-ketoglutarate-dependent hydroxylases. These enzymes catalyze the incorporation of oxygen into organic substrates through a mechanism that requires alpha-Ketoglutaric acid, Fe2+, and ascorbate.
How does HIF PH work?
How do HIF stabilizers work?
In summary, HIF stabilizers increase Hb levels and TIBC, and decrease the levels of ferritin and hepcidin in NDD-CKD patients, indicating that these are safe for short-term use in the treatment of anemia in NDD-CKD patients.
How do HIF PHIs work?
HIF-PHIs simulate hypoxia in cells, stimulating endogenous EPO synthesis and improving iron metabolism. Furthermore, HIF-PHIs may indirectly reduce hepcidin levels, which increases the mobilization of iron stores and may offer benefits in addressing functional iron deficiency associated with ESA hyporesponsiveness.
What is the role of the prolyl hydroxylase domain?
The prolyl hydroxylase domain (PHD) / hypoxia-inducible factor (HIF) axis is a critically important oxygen-sensing pathway that mediates tissue adaptation to low oxygen environments primarily via the transcriptional regulation of gene expression.
Which is a key regulator of the HIF pathway?
The identification of oxygen- and iron-dependent PHD enzymes as key regulators of HIF has led to the development of novel therapeutic agents that are currently in clinical development for the treatment of anemia associated with chronic kidney disease.
What kind of transcription factor is a HIF?
HIFs are basic helix-loop-helix transcription factors and members of the PAS (PER/aryl hydrocarbon receptor nuclear translocator (ARNT)/single minded (SIM)) family of transcription factors.
How is HIF-PhD related to other dioxygenases?
HIF-PHDs belong to a large family of 2-oxoglutarate (OG)-dependent dioxygenases. These enzymes utilize molecular oxygen for hydroxylation and thus couple oxygen, intermediary and amino acid metabolism to multiple cellular processes, which include HIF responses, collagen synthesis, fatty acid metabolism and the regulation of the epigenome.