Antizyme 3 inhibits polyamine uptake and ornithine decarboxylase (ODC) activity, but does not stimulate ODC degradation

Snapir, Zohar; Keren-Paz, Alona; Bercovich, Z.; Kahana, Chaim

doi:10.1042/bj20081874

Cited by 28 publications

(29 citation statements)

References 35 publications

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“…The modulations of the proteasome-interacting surface explain why the alternative heterodimers cannot be recognized by the proteasome, consistent with the roles of Az 2 and Az 3 as simple catalytic inhibitors of ODC (21,25).…”

Section: Az 1 Binding Primes Odc For Ubiquitin-independent Proteasomementioning

confidence: 87%

Structural basis of antizyme-mediated regulation of polyamine homeostasis

Chen

Hsieh

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Polyamines are organic polycations essential for cell growth and differentiation; their aberrant accumulation is often associated with diseases, including many types of cancer. To maintain polyamine homeostasis, the catalytic activity and protein abundance of ornithine decarboxylase (ODC), the committed enzyme for polyamine biosynthesis, are reciprocally controlled by the regulatory proteins antizyme isoform 1 (Az 1 ) and antizyme inhibitor (AzIN). Az 1 suppresses polyamine production by inhibiting the assembly of the functional ODC homodimer and, most uniquely, by targeting ODC for ubiquitin-independent proteolytic destruction by the 26S proteasome. In contrast, AzIN positively regulates polyamine levels by competing with ODC for Az 1 binding. The structural basis of the Az 1 -mediated regulation of polyamine homeostasis has remained elusive. Here we report crystal structures of human Az 1 complexed with either ODC or AzIN. Structural analysis revealed that Az 1 sterically blocks ODC homodimerization. Moreover, Az 1 binding triggers ODC degradation by inducing the exposure of a cryptic proteasome-interacting surface of ODC, which illustrates how a substrate protein may be primed upon association with Az 1 for ubiquitin-independent proteasome recognition. Dynamic and functional analyses further indicated that the Az 1 -induced binding and degradation of ODC by proteasome can be decoupled, with the intrinsically disordered C-terminal tail fragment of ODC being required only for degradation but not binding. Finally, the AzIN-Az 1 structure suggests how AzIN may effectively compete with ODC for Az 1 to restore polyamine production. Taken together, our findings offer structural insights into the Az-mediated regulation of polyamine homeostasis and proteasomal degradation.polyamine homeostasis | ornithine decarboxylase | antizyme | antizyme inhibitor | ubiquitin-independent proteolysis P olyamines are multivalent organic cations that are ubiquitous and essential in eukaryotes (1). With their polycationic characteristics, these compounds are known to modulate the structural and functional properties of nucleic acids and proteins via electrostatic interactions, in turn affecting cell growth and differentiation by influencing the underlying cellular processes (1, 2). Consistent with their crucial regulatory roles, fluctuations in intracellular polyamine levels are rigorously controlled during cell growth and differentiation via fine-tuning the balance between the biosynthesis, degradation, and uptake of polyamines. Aberrant accumulation of polyamines is associated with pathological consequences, including many types of cancer (3-5).Regulation of polyamine homeostasis is achieved mainly by adjusting the catalytic activity and protein abundance of ornithine decarboxylase (ODC), a homodimeric and pyridoxal 5ʹ-phosphatedependent enzyme that catalyzes the committed and rate-limiting step in polyamine biosynthesis, through the actions of the regulatory proteins antizyme isoform 1 (Az 1 ) and antizyme inhibitor (AzIN) (3, 6). E...

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Section: Az 1 Binding Primes Odc For Ubiquitin-independent Proteasomementioning

confidence: 87%

Structural basis of antizyme-mediated regulation of polyamine homeostasis

Chen

Hsieh

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…HEK-293 cells were transfected using the calcium phosphate method (28). NIH3T3 cells expressing the tetracycline-responsive repressor were grown and stimulated for the expression of Az as described (29).…”

Section: Methodsmentioning

confidence: 99%

“…The ability of Az2 to stimulate protein degradation was tested only in cells, as it was demonstrated previously that Az2 does not stimulate ODC degradation in an in vitro degradation reaction (29,35). Simultaneous cotransfection of Az with all four tested proteins demonstrated that, like Az1, Az2 did not stimulate the degradation of cyclin D1, Aurora-A, and ⌬Np73 but efficiently stimulated ODC degradation (Fig.…”

Section: Inducible Az1 Expression Inhibits Proliferation Of Nih3t3 Cementioning

confidence: 99%

Antizyme Affects Cell Proliferation and Viability Solely through Regulating Cellular Polyamines

Bercovich

Snapir²,

Keren-Paz

et al. 2011

Journal of Biological Chemistry

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Background: Antizyme is a regulator of cell proliferation, inhibiting this process when overexpressed. Results: Antizyme overexpression does not attenuate cell proliferation and viability in cells whose polyamine supply is secured. Conclusion: Antizyme affects cell proliferation and viability only by modulating polyamine metabolism. Significance: This result emphasizes the functional relationship of antizyme to cellular polyamine metabolism.

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“…[35][36][37] AZ3 maintains polyamine homeostasis during spermatogenesis but does not mediate ODC degradation. [32,38] It was found that AZ3 transcription was restricted to testis germ cells, starting early in spermiogenesis and finishing in the late spermatid phase. [10] Since the AZ3 wave of expression follows the wave of high ODC expression that takes place during the early phases of spermatogenesis, it was postulated that the physiological role of AZ3 was to abolish ODC activity to avoid the detrimental effects of putrescine during spermiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Untitled

Malini

2017

AJP

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Aim: Type 2 diabetes mellitus (T2DM) represents a spectrum of metabolic disorders and affects all the physiological system including reproduction. Even though enormous research is carried out to focus the etiologies of infertility in T2DM, till date, the role of polyamines which modulate three multiple biochemical activities including nucleic acid and protein synthesis as well as cell signaling that are important for spermatogenesis are ignored. Limited studies are available on ornithine decarboxylase (ODC); an enzyme involved in the biosynthesis of polyamine and maintains the homeostasis of polyamines. Further, these studies are confined to animals only. Hence, an attempt was made to uncover the role of ODC in fertility of T2DM individuals. Materials and Methods: A total of 230 T2DM males and 50 control male subjects with proven fertility and non-diabetic aged between 25 and 50 years were recruited from different diabetic centers and clinics in and around Mysore, South India. Semen analysis and sperm function tests were carried out according to WHO guidelines. The level of ODC was estimated using enzyme-linked immunosorbent assay kit. Results: Our results demonstrate a strong association of type 2 diabetic conditions with reduced vitality of sperm, nuclear chromatin decondensation, and hypo-osmotic swelling among sperm function test along with a significant drastic reduction in the ODC levels. Reduced levels of ODC might be inadequate for homeostasis of polyamine. Conclusion: Overexpression of antizyme could have resulted in reduced level of ODC resulting in perturbation of normal spermatogenesis in T2DM individuals.

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Antizyme 3 inhibits polyamine uptake and ornithine decarboxylase (ODC) activity, but does not stimulate ODC degradation

Cited by 28 publications

References 35 publications

Structural basis of antizyme-mediated regulation of polyamine homeostasis

Structural basis of antizyme-mediated regulation of polyamine homeostasis

Antizyme Affects Cell Proliferation and Viability Solely through Regulating Cellular Polyamines

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