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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Downloads (Pure)

Abstract

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.
Original languageEnglish
Article number4614
Number of pages17
Journal International Journal of Molecular Sciences
Volume23
Issue number9
Early online date21 Apr 2022
DOIs
Publication statusPublished - 21 Apr 2022

Keywords

  • polyamines
  • antizyme
  • dimerization
  • polyamine analogues
  • ribosomal frameshifting
  • polyamine uptake
  • ornithine decarboxylase
  • α-difluoromethylornithine

Fingerprint

Dive into the research topics of 'Role of Polyamine-Induced Dimerization of Antizyme in Its Cellular Functions'. Together they form a unique fingerprint.

Cite this