NAD+-protein-glutamate ADP-ribosyltransferase activity

Definition

Target type: molecularfunction

Catalysis of the reaction: L-glutamyl-[protein] + NAD+ = 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] + nicotinamide. [PMID:19764761, PMID:25043379, RHEA:58224]

NAD+-protein-glutamate ADP-ribosyltransferase activity, also known as poly(ADP-ribose) polymerase (PARP) activity, is a critical molecular function involved in a wide range of cellular processes. This enzymatic activity catalyzes the transfer of ADP-ribose units from NAD+ to specific glutamate residues on target proteins. This post-translational modification, known as ADP-ribosylation, plays a crucial role in regulating cellular signaling, DNA repair, and apoptosis.

The catalytic mechanism of NAD+-protein-glutamate ADP-ribosyltransferase activity involves the following steps:

1. **NAD+ binding:** The enzyme binds to NAD+ in its active site.
2. **Glutamate recognition:** The enzyme recognizes a specific glutamate residue on the target protein.
3. **ADP-ribose transfer:** The enzyme cleaves NAD+ and transfers an ADP-ribose moiety to the glutamate residue, forming a poly(ADP-ribose) chain.
4. **Poly(ADP-ribose) chain elongation:** The enzyme can catalyze the addition of multiple ADP-ribose units to the growing chain, creating a branched structure.

The specific target proteins and the length and structure of the poly(ADP-ribose) chain vary depending on the PARP enzyme and the cellular context.

PARP enzymes are classified into three main families: PARP1/PARP2, PARP3/PARP4/PARP5a/PARP5b, and PARP6/PARP7/PARP8/PARP9/PARP10/PARP11/PARP12. Each family has distinct functions and target proteins:

* **PARP1/PARP2:** Play a key role in DNA damage response. They are recruited to sites of DNA damage, where they catalyze the formation of long and branched poly(ADP-ribose) chains. These chains serve as a scaffold for the recruitment of DNA repair proteins and regulate the activity of other enzymes involved in DNA repair.
* **PARP3/PARP4/PARP5a/PARP5b:** These PARPs are involved in various cellular processes, including chromatin regulation, transcription, and apoptosis.
* **PARP6/PARP7/PARP8/PARP9/PARP10/PARP11/PARP12:** These PARPs have more specialized roles, often involved in specific signaling pathways or cellular processes.

Dysregulation of PARP activity has been implicated in various diseases, including cancer, neurodegenerative disorders, and inflammatory diseases. Therefore, PARP inhibitors have emerged as promising therapeutic agents in these areas.

In summary, NAD+-protein-glutamate ADP-ribosyltransferase activity (PARP activity) is a crucial enzymatic function that regulates a wide range of cellular processes by post-translational modification of proteins through ADP-ribosylation. The activity and specificity of PARP enzymes are tightly regulated, and their dysregulation is associated with a range of diseases. Understanding the molecular function of NAD+-protein-glutamate ADP-ribosyltransferase activity is essential for developing novel therapeutic strategies for treating diseases related to PARP activity.'
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Proteins (5)

Compounds (55)