Structural and degradative aspects of ornithine decarboxylase antizyme inhibitor 2.

摘要: Ornithine decarboxylase (ODC) is the key enzyme in polyamine biosynthetic pathway. ODC levels are controlled by polyamines through induction of antizymes (AZs), small proteins that inhibit and target it to proteasomal degradation without ubiquitination. Antizyme inhibitors (AZIN1 AZIN2) homologous bind AZs counteract their negative effect on ODC. Whereas AZIN1 well-characterized proteins, little known structure stability AZIN2, lastly discovered member this regulatory circuit. In work we first analyzed structural aspects AZIN2 combining biochemical computational approaches. We demonstrated contrast ODC, does not form homodimers, although predicted tertiary monomer was similar Furthermore, identified conserved residues antizyme-binding element, whose substitution drastically affected capacity AZ1. On other hand, also found much more labile than but highly stabilized its binding AZs. Interestingly, administration proteasome inhibitor MG132 caused differential effects three AZ-binding having no preventing AZIN1, unexpectedly increasing AZIN2. Inhibitors lysosomal function partially prevented These results suggest could be mediated an alternative route proteasome. findings provide new relevant information unique mechanism metabolism.