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Hyvönen, Mervi T.; Smirnova, Olga A.; Mitkevich, Vladimir A.; Tunitskaya, Vera L.; Khomutov, Maxim; Karpov, Dmitry S.; Korolev, Sergey P.; Häkkinen, Merja R.; Pietilä, Marko; Gottikh, Marina B.; Vepsäläinen, Jouko; Alhonen, Leena; Makarov, Alexander A.; Kochetkov, Sergey N.; Wallace, Heather M.; Keinänen, Tuomo A.; Khomutov, Alex R.

Role of Polyamine-Induced Dimerization of Antizyme in Its Cellular Functions

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  • Media type: E-Article
  • Title: Role of Polyamine-Induced Dimerization of Antizyme in Its Cellular Functions
  • Contributor: Hyvönen, Mervi T.; Smirnova, Olga A.; Mitkevich, Vladimir A.; Tunitskaya, Vera L.; Khomutov, Maxim; Karpov, Dmitry S.; Korolev, Sergey P.; Häkkinen, Merja R.; Pietilä, Marko; Gottikh, Marina B.; Vepsäläinen, Jouko; Alhonen, Leena; Makarov, Alexander A.; Kochetkov, Sergey N.; Wallace, Heather M.; Keinänen, Tuomo A.; Khomutov, Alex R.
  • imprint: MDPI AG, 2022
  • Published in: International Journal of Molecular Sciences
  • Language: English
  • DOI: 10.3390/ijms23094614
  • ISSN: 1422-0067
  • Keywords: Inorganic Chemistry ; Organic Chemistry ; Physical and Theoretical Chemistry ; Computer Science Applications ; Spectroscopy ; Molecular Biology ; General Medicine ; Catalysis
  • Origination:
  • Footnote:
  • Description: <jats:p>The polyamines, spermine (Spm) and spermidine (Spd), are important for cell growth and function. Their homeostasis is strictly controlled, and a key downregulator of the polyamine pool is the polyamine-inducible protein, antizyme 1 (OAZ1). OAZ1 inhibits polyamine uptake and targets ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine biosynthesis, for proteasomal degradation. Here we report, for the first time, that polyamines induce dimerization of mouse recombinant full-length OAZ1, forming an (OAZ1)2-Polyamine complex. Dimerization could be modulated by functionally active C-methylated spermidine mimetics (MeSpds) by changing the position of the methyl group along the Spd backbone—2-MeSpd was a poor inducer as opposed to 1-MeSpd, 3-MeSpd, and Spd, which were good inducers. Importantly, the ability of compounds to inhibit polyamine uptake correlated with the efficiency of the (OAZ1)2-Polyamine complex formation. Thus, the (OAZ1)2-Polyamine complex may be needed to inhibit polyamine uptake. The efficiency of polyamine-induced ribosomal +1 frameshifting of OAZ1 mRNA could also be differentially modulated by MeSpds—2-MeSpd was a poor inducer of OAZ1 biosynthesis and hence a poor downregulator of ODC activity unlike the other MeSpds. These findings offer new insight into the OAZ1-mediated regulation of polyamine homeostasis and provide the chemical tools to study it.</jats:p>
  • Access State: Open Access