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Antizymes

Dateline: 07/10/00

By Alan Bruzel

Protein Degradation

Living cells produce enzymes: specialized proteins that perform precise functions. If left alone, some enzymes would happily continue catalyzing their particular chemical reaction – not forever, but long enough to cause problems – with the resultant accumulation of more reaction products than the cell needs. One approach cells take to prevent prolonged enzymatic activity is to attach to the enzyme that has overstayed its welcome one or more molecules of a small polypeptide named ubiquitin (for its ubiquitous occurrence in all organisms). Cells contain dedicated protein-digesting structures, known as 26S proteasomes, which recognize these ubiquitinylated proteins and then degrade them.

What Is Antizyme?

However, the proteins ornithine decarboxylase and c-Jun are broken down by proteosomes without prior tagging by ubiquitin. There must consequently be other means of targeting these proteins for destruction. In the case of the enzyme ornithine decarboxylase (ODC), a specific protein known as antizyme binds to ODC, inactivates it, and marks it for removal by the 26S proteasome.

Why Should ODC Require This Special Treatment?

ODC is a key enzyme in the synthesis of the cell proliferation compounds putrescine, spermidine, and spermine, collectively known as polyamines. Cancer cells have increased levels of polyamines; inhibiting ODC activity, and thus lowering polyamine levels, has been shown to slow the growth of these cells. Fine-tuning of polyamine synthesis is of paramount importance if normal cells are to maintain a normal growth rate. Antizyme may be one way by which cells adjust their polyamine levels.

How Cells Regulate the Synthesis of Antizyme

If cells produce antizyme to hold in the reins on ODC activity, then how is the biosynthesis of antizyme, itself, controlled? As it turns out, the mRNA for antizyme is remarkable in that, unlike most mRNAs, it has two open reading frames that slightly overlap one another. Neither the first open reading frame by itself, nor the second open reading frame by itself can direct the synthesis of an active antizyme molecule. The only way of synthesizing a full-length, active antizyme protein is for the ribosome to progress along the first open reading frame and then, instead of prematurely terminating protein synthesis when it reaches a stop codon, to instead perform a +1 frameshift event, and begin reading the second open reading frame.

What Causes This Unusual Event to Take Place?

High polyamine levels. In other words, in a clever feedback mechanism, polyamines, the products of ODC activity, set in motion a ribosomal frameshift event that allows the synthesis of antizyme. The antizyme so produced leads to the destruction of ODC and shuts down synthesis of more polyamines.

Is There Only One Antizyme?

Three human antizymes have thus far been discovered. Antizyme 1 and antizyme 2 are found in all tissues examined except the testes; antizyme 3 is present only in the testes, and is believed to play a role in sperm cell development.

What the Web Has to Say about:
Antizymes

A Second Mammalian Antizyme
RNA pseudoknot loops differ between antizyme 1 and this antizyme 2. From Ivaylo P. Ivanov et al., in Genomics.

Anti-tumor Activity of Antizyme which Targets ODC
Using ectopically expressed antizyme as a tumor treatment. Oncogene article from Satoshi Iwata et al.

Antizyme 3
This ODC inhibitor is expressed during spermatogenesis. From Ivaylo P. Ivanov et al., Proceedings of the National Academy of Sciences.

Cadaverine and Putrescine
An article from this Web site describing polyamine synthesis during protein decomposition in spoiled food.

Crystal Structure of Human Ornithine Decarboxylase
Binding study of antizyme to ODC. Abstract from Jeffrey J. Almrud et al., Journal of Molecular Biology Online.

Gene Discovery Could Be Clue to Male Infertility
An antizyme found in developing sperm. From Lee Siegel, The Salt Lake Tribune.

Gesteland, Raymond F.
Research on biochemistry and molecular biology of antizyme. From the University of Utah.

Homolog of Mammalian Antizyme in Schizosaccharomyces pombe
Computer search finds a homology in S. pombe, but not in Saccharomyces cerevisiae. From Chang Zhu et al., University of California at San Francisco and University of California at Santa Cruz.

Induction of Antizyme Inhibitor
Cloning and characterization of this protein. Abstract from Jonas Nilsson et al., Biochemical Journal Online.

Investigation of the Mechanism of Antizyme mRNA Frameshifting
Regulatory elements responsible for frameshifting. From Pavel Baranov, University of Utah.

Ornithine Decarboxylase and Cancer
ODC activity is increased in cancer cells; inhibition of ODC is viewed as one treatment. Review article in The Cancer Journal from S. Kubota.

Regulation of Proteolysis and Protein Degradation
Ubiquitinylated and non-ubiquitinylated protein breakdown. From Robert A. Keates, University of Guelph.

UGA: A Dual Signal for 'Stop' and for Recoding in Protein Synthesis
Why the stop codon UGA appears at mRNA sites sensitive to frameshifting. Review article from Warren Tate et al., in Biokhimiya.

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