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標題: 探討人類鳥胺酸脫羧酶第117至140處序列與抗酶結合所扮演之角色
The Role of Sequence 117-140 of Human Ornithine Decarboxylase in Antizyme Inhibition
作者: 蘇家暘
Su, Jia-Yang
關鍵字: ornithine decarboxylase;鳥胺酸脫羧酶多元胺;polyamine;ornithine;putrescineantizyme;Antizyme inhibitor;鳥胺酸;腐胺;抗酶抗酶抑制因子
出版社: 生命科學系所
引用: Almrud JJ, Oliveira MA, Kern AD, Grishin NV, Phillips MA, Hackert ML (2000) Crystal structure of human ornithine decarboxylase at 2.1Å resolution: structure insight to antizyme binding. J Mol Biol 295: 7-16 Auvinen M, Paasinen A, Andersson LC, Hölttä E (1992) Ornithine decarboxylase activity is critical for cell transformation. Nature 360: 355-358 Balbo PB, Patel CN, Sell KG, Adcock RS, Neelakantan S, Crooks PA, Oliveira MA (2003) Spectrophotometric and steady-state kinetic analysis of the biosynthetic arginine decarboxylase of Yersinia pestis utilizing arginine analogues as inhibitors and alternative substrates. Biochemistry 42: 15189-15196 Brown PH, Schuck P (2006) Macromolecular size-and-shape distributions by sedimentation velocity analytical ultracentrifugation. Biophys J 90: 4651-4661 Chen H, MacDonald A, Coffino P (2002) Structure elements of antizymes 1 and 2 are required for proteasomal degradation of ornithine decarboxylase. J Biol Chem 277: 45957-45961 Coffino P (2001) Antizyme, a mediator of ubiquitin-independent proteasomal degradation. Biochimie 83: 319-323 Fujita K, Murakami Y, Hayashi S (1982) A macromolecular inhibitor of the antizyme to ornithine decarboxylase. Biochem J 204: 647-652 Hayashi S, Murakami Y (1995) Rapid and regulated degradation of ornithine decarboxylase. Biochem J 306: 1-10 Heller JS, Fong WF, Canellakis ES (1976) Induction of a protein inhibitor to ornithine decarboxylase by the end products of its reaction. Proc Natl Acad Sci USA 73: 1858-1862 Howlett GJ, Minton AP, Rivas G (2006) Analytical ultracentrifugation for the study of protein association and assembly. Curr Opin Chem Biol 10: 430-436 Ivanov IP, Rohrwasser A, Terreros DA, Gesteland RF, Atkins JF (2000) Discovery of a spermatogenesis stage-specific ornithine decarboxylase antizyme: antizyme 3. Proc Natl Acad Sci USA 97: 4808-4813 Jackson LK, Brooks HB, Osterman AL, Goldsmith EJ, Phillips MA (2000) Altering the reaction specificity of eukaryotic ornithine decarboxylase. Biochemistry 39: 11247-11257 Kitani T, Fujisawa H. (1989) Purification and characterization of antizyme inhibitor of ornithine decarboxylase from rat liver. Biochim Biophys Acta 991: 44-49 Keren-Paz A, Bercovich Z, Porat Z, Erez O, Brener O, Kahana C (2006) Overexpression of antizyme-inhibitor in NIH3T3 fibroblasts provides growth advantage through neutralization of antizyme functions. Oncogene 25: 5163-5172 Kern AD, Oliveira MA, Coffino P, Hackert ML (1999) Structure of mammalian ornithine decarboxylase at 1.6Å resolution: stereochemical implications of PLP-dependent amino acid decarboxylsae. Structure 7: 567-581 Li X, Coffino P (1992) Regulated degradation of ornithine decarboxylase requires interaction with the polyamine-inducible protein antizyme. Mol Cell Biol 12: 3556-3562 Li X, Coffino P (1993) Degradation of ornithine decarboxylase: exposure of the C-terminal target by a polyamine-inducible inhibitory protein. Mol Cell Biol 13: 2377-2383 Matsufuji S, Matsufuji T, Miyazaki Y, Murakami Y, Atkins JF, Gesteland RF, Hayashi S (1995) Autoregulatory frameshifting in decoding mammalian ornithine decarboxylase antizyme. Cell 80: 51-60. Murakami Y, Matsufuji S, Kameji T, Hayashi S, Igarashi K, Tamura T, Tanaka K, Ichihara Akira (1992) Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination. Nature 360: 597-599 Newman RM, Mobascher A, Mangold U, Koike C, Diah S, Schmidt M, Finley D, Zetter BR. (2004) Antizyme targets cyclin D1 for degradation. A novel mechanism for cell growth repression. J Biol Chem 279: 41504-41511 Pegg AE (2006) Regulation of ornithine decarboxylase. J Biol Chem 281: 14529-14532 Shantz LM, Coleman CS, Pegg AE (1996) Expression of an ornithine decarboxylase dominant-negative mutant reverses eukaryotic initiation factor 4E-induced cell transformation. Cancer Res 56: 5136-5140 Tosaka Y, Tanaka H, Yano Y, Masai K, Nozaki M, Yomogida K, Otani S, Nojima H, Nishimune Y (2000) Identification and characterization of testis specific ornithine decarboxylase antizyme (OAZ-t) gene: expression in haploid germ cells and polyamine-induced frameshifting. Genes Cells 5: 265-276 Tsodikov, OV, Record, MT, Jr, Sergeev, YV (2002) Novel computer program for fast exact calculation of accessible and molecular surface areas and average surface curvature. J. Comput. Chem 23: 600-609 Zhang M, MacDonald AI, Hoyt MA, Coffino P (2004) Proteasome begin ornithine decarboxylase digestion at the C terminus. J Biol Chem 279: 20959-20965 Zhang M, Pickart CM, Coffino P (2003) Determinants of proteasome recognition of ornithine decarboxyalse, a ubiquitin-independent substrate. EMBO J 22: 1488-1496 Zhu C, Lang DW, Coffino P (1999) Antizyme2 is a negative regulator of ornithine decarboxylase and polyamine transport. J Biol Chem 274: 26425-26430
人類鳥胺酸脫羧酶(ornithine decarboxylase, ODC; EC 4. 1. 1. 17)是體內多元胺(polyamines)合成起始與速率決定步驟的酵素,其功能為催化鳥胺酸(L-ornithine)形成腐胺(putrescine)及二氧化碳。具有酵素催化能力的鳥胺酸脫羧酶以雙聚體形式存在。抗酶(antizyme, AZ)能夠與鳥胺酸脫羧酶結合使其無法形成雙聚體而失去其酵素活性,在細胞內與抗酶結合的鳥胺酸脫羧酶更容易被26S proteasome分解,而不需先與泛素(ubiquitin)結合。抗酶抑制因子(Antizyme inhibitor, AZI)是序列及分子量都與鳥胺酸脫羧酶十分相似的蛋白質,但不具有酵素活性。抗酶抑制因子與抗酶的結合能力比鳥胺酸脫羧酶還強,能回復鳥胺酸脫羧酶受抗酶抑制的情形。經序列比對,鳥胺酸脫羧酶上可能影響其結合能力的胺基酸為N125、N126、F133、S135、M140。在活性抑制的結果中,以N125K、F133C及M140K受抑制的情形較明顯,解離常數分別為54、109、109 nM,代表這些位置和鳥胺酸脫羧酶與抗酶抑制因子結合能力之差異有關。實驗結果中還顯示不論是野生型或是任何一種突變型的ODC和AZ的結合都呈現正協同作用的情形,代表鳥胺酸脫羧酶是以雙聚體形式與AZ結合,且被第一個AZ結合後可能經過構形改變使第二個AZ更容易與其結合。

The human ornithine decarboxylase (ODC; EC 4. 1. 1. 17), which is the rate-limiting enzyme to polyamines synthesis, catalyzes the decarboxylation of L-ornithine to form putrescine and carbon dioxide. The active form of ODC is obligate homodimer. Antizyme (AZ) can inhibit ODC activity by dissociating dimeric ODC and enhances the degradation of the ODC by 26S proteasome without ubiquitination. Antizyme inhibitor (AZI) has similar sequence and molecular weight to ODC but has no enzyme activity. AZI, which has higher binding affinity to AZ, can rescue ODC from antizyme inhibition. The residue N125, N126, F133, S135, M140 have more difference in antizyme binding element of ODC by sequence alignment. The higher inhibited activities of mutants ODC N125K, ODC F133C, ODC M140K present higher binding affinity to AZ. The binding of AZ to ODC WT or any other mutants have high positive-cooperativity. The binding of first AZ to ODC may cause ODC conformational change, and make the ODC have higher binding affinity to second AZ.
其他識別: U0005-2908200715012500
Appears in Collections:生命科學系所

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