peptidyl-histidine dioxygenase activity

Definition

Target type: molecularfunction

Catalysis of the reaction: L-histidyl-[protein] + 2-oxoglutarate + O2 = (3S)-3-hydroxy-L-histidyl-[protein] + succinate + CO2. [PMID:21251231, RHEA:54256]

Peptidyl-histidine dioxygenase (PHD) activity is a crucial enzymatic process involved in the post-translational modification of proteins. This activity catalyzes the hydroxylation of histidine residues within proteins, specifically at the C2 position of the imidazole ring. This hydroxylation reaction introduces a hydroxyl group to the histidine residue, leading to the formation of 2-hydroxyhistidine.

The PHD enzyme utilizes molecular oxygen (O2) and a reducing agent, such as α-ketoglutarate, as essential cofactors for its catalytic activity. The reaction mechanism involves a series of steps that begin with the binding of the substrate protein and α-ketoglutarate to the enzyme's active site.

1. **Oxygen Activation:** The enzyme utilizes iron ions in its active site to bind and activate molecular oxygen. The activated oxygen molecule then reacts with α-ketoglutarate, leading to the formation of a reactive intermediate, succinate.

2. **Hydroxylation:** The activated oxygen atom is then transferred to the histidine residue in the substrate protein, resulting in the formation of 2-hydroxyhistidine. This hydroxylation reaction is highly specific for the C2 position of the histidine ring.

3. **Product Release:** After hydroxylation, the enzyme releases the modified protein, succinate, and carbon dioxide.

PHD activity plays a critical role in diverse cellular processes, including:

* **Hypoxia Sensing:** PHD enzymes are key regulators of the cellular response to low oxygen levels (hypoxia). Hydroxylation of specific histidine residues in proteins involved in oxygen homeostasis, such as hypoxia-inducible factor (HIF), alters their stability and activity, ultimately influencing gene expression and cellular adaptation to oxygen deprivation.
* **Transcriptional Regulation:** PHD enzymes regulate the activity of various transcription factors, including HIF, by modulating their stability and interactions with other proteins. This, in turn, influences gene expression and cellular responses.
* **Protein Stability:** Hydroxylation by PHD enzymes can affect the stability and degradation of target proteins. This can influence a wide range of cellular functions, including protein folding, assembly, and turnover.
* **Cellular Signaling:** PHD activity contributes to various signaling pathways by modulating the activity of signaling molecules, including kinases and phosphatases.

Overall, peptidyl-histidine dioxygenase activity is a critical enzymatic process that regulates a diverse range of cellular functions by modifying the histidine residues in proteins. Its role in hypoxia sensing, transcriptional regulation, protein stability, and cellular signaling highlights its significance in maintaining cellular homeostasis and responding to environmental changes.'
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Proteins (1)

Compounds (12)