Abstract
Ornithine decarboxylase (ODC) catalyzes the first and rate-limiting step of polyamine biosynthesis in humans. Polyamines are essential for cell proliferation and are implicated in cellular processes, ranging from DNA replication to apoptosis. Excessive accumulation of polyamines has a cytotoxic effect on cells and elevated level of ODC activity is associated with cancer development. To maintain normal cellular proliferation, regulation of polyamine synthesis is imposed by Antizyme1 (AZ1). The expression of AZ1 is induced by a ribosomal frameshifting mechanism in response to increased intracellular polyamines. AZ1 regulates polyamine homeostasis by inactivating ODC activity and enhancing its degradation. Here, we report the structure of human ODC in complex with N-terminally truncated AZ1 (cAZ1). The structure shows cAZ1 binding to ODC, which occludes the binding of a second molecule of ODC to form the active homodimer. Consequently, the substrate binding site is disrupted and ODC is inactivated. Structural comparison shows that the binding of cAZ1 to ODC causes a global conformational change of ODC and renders its C-terminal region flexible, therefore exposing this region for degradation by the 26S proteasome. Our structure provides the molecular basis for the inactivation of ODC by AZ1 and sheds light on how AZ1 promotes its degradation.
Highlights
Ornithine decarboxylase (ODC) is an enzyme that catalyzes the first and rate-limiting step of polyamine biosynthesis in humans: the decarboxylation of ornithine to putrescine
The crystal structure of ODC-complex with N-terminally truncated AZ1 (cAZ1) complex was solved at a resolution of 3.2 Å (Fig. 1A)
In the asymmetric unit of the crystal structure, the ODC-cAZ1 complex forms a heterodimer, which consists of one ODC monomer and one cAZ1 molecule
Summary
Ornithine decarboxylase (ODC) is an enzyme that catalyzes the first and rate-limiting step of polyamine biosynthesis in humans: the decarboxylation of ornithine to putrescine. Disruption of its function by inhibitors leaves cells non-viable and causes embryonic lethality[3,4]. This is because the products of its catalysis – polyamines – play essential roles in normal cell growth and differentiation[1]. Given its essential role in normal cell proliferation, the depletion of polyamines and the inhibition of polyamine synthesis lead to growth cessation and cell death[3,11,12]. Polyamine homeostasis is achieved by Antizymes, a class of small proteins that inhibit ODC activity and polyamine uptake into cells[15,16]. A feedback loop is established: increased level of intracellular polyamines promotes the overexpression of AZ1, which inhibits ODC and promotes its degradation. The expression of AZ1 inhibits ODC activity, exhibits anti-tumor activities and may be considered a tumor suppressor[17,27]
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