Target type: molecularfunction
Catalysis of the initiation of the NEDD8 (RUB1) conjugation cascade. [PMID:12646924]
NEDD8 activating enzyme (NAE) activity is a critical step in the ubiquitin-like NEDD8 conjugation pathway. This pathway involves the covalent attachment of NEDD8, a ubiquitin-like protein, to a specific lysine residue on target proteins. The NAE, also known as the E1 enzyme, plays a crucial role in this process by catalyzing the activation of NEDD8.
The NAE is a heterodimer composed of two subunits, NAE1 and NAE2. The NAE1 subunit possesses ATPase activity and is responsible for binding and activating NEDD8. It utilizes ATP to adenylate NEDD8, forming a NEDD8-adenylate intermediate. This activated NEDD8 molecule is then transferred to the NAE2 subunit, where it remains bound.
The NAE2 subunit plays a crucial role in the subsequent transfer of activated NEDD8 to the E2 enzyme, which acts as a carrier protein for NEDD8. This transfer process involves the formation of a thioester bond between NEDD8 and the active site cysteine residue of the E2 enzyme.
The NAE activity is essential for regulating a diverse range of cellular processes, including protein degradation, DNA replication, cell cycle progression, and signal transduction. By activating NEDD8, the NAE initiates the NEDD8 conjugation pathway, which ultimately modulates the activity of target proteins involved in these critical cellular functions.
The NAE activity can be regulated by various factors, including post-translational modifications, protein-protein interactions, and cellular stress responses. Dysregulation of NAE activity has been linked to various diseases, including cancer and neurodegenerative disorders.
In summary, NEDD8 activating enzyme activity is a crucial step in the NEDD8 conjugation pathway, which plays a vital role in regulating various cellular processes. The NAE, a heterodimeric enzyme, catalyzes the activation of NEDD8, enabling its subsequent transfer to the E2 enzyme and subsequent conjugation to target proteins.'
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| Protein | Definition | Taxonomy |
|---|---|---|
| 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-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-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) |
| 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 |
| 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 |