Target type: biologicalprocess
Covalent attachment of the ubiquitin-like protein NEDD8 (RUB1) to another protein. [PMID:11698580]
Neddylation is a post-translational modification process where a ubiquitin-like protein called NEDD8 (Neural precursor cell expressed developmentally downregulated 8) is covalently attached to the lysine residue of a target protein. This process is analogous to ubiquitination, but instead of ubiquitin, NEDD8 is used as the modifying molecule.
Neddylation is a highly regulated process that involves a cascade of enzymatic reactions. The first step involves the activation of NEDD8 by the E1 enzyme, NEDD8 activating enzyme (NAE). The activated NEDD8 is then transferred to the E2 enzyme, NEDD8-conjugating enzyme (UBE2F), forming an E2-NEDD8 thioester complex.
The E2-NEDD8 complex interacts with a specific E3 ligase, which recognizes and binds to the target protein. The E3 ligase facilitates the transfer of NEDD8 from the E2 enzyme to the lysine residue of the target protein.
Neddylation plays a critical role in regulating various cellular processes, including:
1. Cell cycle progression: Neddylation is essential for the proper assembly and function of the cullin-RING ubiquitin ligase (CRL) complex, which is responsible for ubiquitination and degradation of proteins involved in cell cycle regulation.
2. DNA damage response: Neddylation can regulate the activity of DNA repair proteins, such as the Rad18 protein, involved in the repair of DNA double-strand breaks.
3. Immune signaling: Neddylation is involved in regulating the activity of proteins involved in immune signaling pathways, such as the NF-κB pathway.
4. Transcription: Neddylation can affect the activity of transcription factors, leading to changes in gene expression.
Dysregulation of neddylation can have significant consequences for human health. Increased neddylation has been linked to cancer development and progression, while reduced neddylation has been associated with neurodegenerative disorders.
In summary, neddylation is a crucial post-translational modification that plays a critical role in regulating various cellular processes. The intricate cascade of enzymes involved in neddylation ensures its precise control, underscoring the significance of this modification in maintaining cellular homeostasis and health.'
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| Protein | Definition | Taxonomy |
|---|---|---|
| DCN1-like protein 1 | A DCN1-like protein 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q96GG9] | Homo sapiens (human) |
| NEDD8 | A NEDD8 protein that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q15843] | Homo sapiens (human) |
| COP9 signalosome complex subunit 5 | A COP9 signalosome complex subunit 5 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q92905] | Homo sapiens (human) |
| NEDD8-activating enzyme E1 catalytic subunit | A NEDD8-activating enzyme E1 catalytic subunit that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q8TBC4] | Homo sapiens (human) |
| NEDD8 | A NEDD8 protein that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q15843] | Homo sapiens (human) |
| NEDD8-activating enzyme E1 regulatory subunit | A NEDD8-activating enzyme E1 regulatory subunit that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q13564] | Homo sapiens (human) |
| NEDD8-conjugating enzyme Ubc12 | A NEDD8-conjugating enzyme Ubc12 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P61081] | Homo sapiens (human) |
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| candesartan cilexetil | candesartan cilexetil: a prodrug which is metabolized to an active form candesartan to exert its biological effects | biphenyls | |
| mitoxantrone | mitoxantrone : A dihydroxyanthraquinone that is 1,4-dihydroxy-9,10-anthraquinone which is substituted by 6-hydroxy-1,4-diazahexyl groups at positions 5 and 8. Mitoxantrone: An anthracenedione-derived antineoplastic agent. | dihydroxyanthraquinone | analgesic; antineoplastic agent |
| 8-mercaptoquinoline | 8-mercaptoquinoline: structure given in first source | ||
| 5-(4-chlorophenyl)-4h-1,2,4-triazole-3-thiol | 5-(4-chlorophenyl)-4H-1,2,4-triazole-3-thiol: a YUCCA enzyme inhibitor; structure in first source | triazoles | |
| 5-(4-methoxyphenyl)-1,2-dihydro-1,2,4-triazole-3-thione | triazoles | ||
| gartanin | gartanin : A member of the class of xanthones that is 9H-xanthen-9-one substituted by hydroxy groups at positions 1, 3, 5 and 8 and prenyl groups at positions 2 and 4. | polyphenol; xanthones | antineoplastic agent; plant metabolite |
| pevonedistat | pevonedistat : A pyrrolopyrimidine that is 7H-pyrrolo[2,3-d]pyrimidine which is substituted by a (1S)-2,3-dihydro-1H-inden-1-ylnitrilo group at position 4 and by a (1S,3S,4S)-3-hydroxy-4-[(sulfamoyloxy)methyl]cyclopentyl group at position 7. It is a potent and selective NEDD8-activating enzyme inhibitor with an IC50 of 4.7 nM, and currently under clinical investigation for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes. pevonedistat: a potent and selective inhibitor of NAE (NEDD8-activating enzyme) | cyclopentanols; indanes; pyrrolopyrimidine; secondary amino compound; sulfamidate | antineoplastic agent; apoptosis inducer |