Identification of a Novel Substrate-Derived Spermine Oxidase Inhibitor.
Identification of a Novel Substrate-Derived Spermine Oxidase Inhibitor.
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DOI：
10.32607/actanaturae.10992
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发表时间：
2020-07
期刊：
影响因子：
2
通讯作者：
Casero RA Jr
中科院分区：
文献类型：
--
作者：
Dunston TT;Khomutov MA;Gabelli SB;Stewart TM;Foley JR;Kochetkov SN;Khomutov AR;Casero RA Jr
生物源性多胺精胺（Spm）和亚精胺（Spd）在真核细胞中以μM-mM的浓度存在，其稳态受到多胺合成、降解和转运酶的协调活动的精确调节，以维持正常的细胞生长和活力。精胺氧化酶（SMOX）是最近发现的多胺代谢的关键酶，通过催化Spm向Spd的反向转化，在调节多胺稳态中起重要作用。许多类型上皮癌的发展与炎症有关，疾病相关的炎症刺激可诱导SMOX。MDL72527作为一种不可逆的SMOX抑制剂在体外和体内广泛应用，但它对n1 -乙酰多胺氧化酶也有强效。虽然SMOX具有很高的底物特异性，但Spm类似物作为酶抑制剂尚未被系统研究。本研究证明1,12-二氨基-2,11-双（亚甲基）-4,9-二氮杂十二烷（2,11- met2 - spm）在标准测定条件下对SMOX的IC50值为169 μM，是研究多胺分解代谢的有趣工具和先导化合物。
Homeostasis of the biogenic polyamines spermine (Spm) and spermidine (Spd), present in μM-mM concentrations in all eukaryotic cells, is precisely regulated by coordinated activities of the enzymes of polyamine synthesis, degradation, and transport, in order to sustain normal cell growth and viability. Spermine oxidase (SMOX) is the key and most recently discovered enzyme of polyamine metabolism that plays an essential role in regulating polyamine homeostasis by catalyzing the back-conversion of Spm to Spd. The development of many types of epithelial cancer is associated with inflammation, and disease-related inflammatory stimuli induce SMOX. MDL72527 is widely used in vitro and in vivo as an irreversible inhibitor of SMOX, but it is also potent towards N1-acetylpolyamine oxidase. Although SMOX has high substrate specificity, Spm analogues have not been systematically studied as enzyme inhibitors. Here we demonstrate that 1,12-diamino-2,11-bis(methylidene)-4,9-diazadodecane (2,11-Met2-Spm) has, under standard assay conditions, an IC50 value of 169 μM towards SMOX and is an interesting instrument and lead compound for studying polyamine catabolism.
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影响因子：
1
作者：
Grigorenko, N. A.;Khomutov, M. A.;Khomutov, A. R.
通讯作者：
Khomutov, A. R.
影响因子：
2.5
作者：
Masuko, Takashi;Takao, Koichi;Sugita, Yoshiaki
通讯作者：
Sugita, Yoshiaki
DOI：
10.1038/s41568-018-0050-3
发表时间：
2018-11
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Casero RA Jr;Murray Stewart T;Pegg AE
通讯作者：
Pegg AE
DOI：
10.1073/pnas.1010203108
发表时间：
2011-09-13
影响因子：
11.1
作者：
Goodwin, Andrew C.;Shields, Christina E. Destefano;Casero, Robert A., Jr.
通讯作者：
Casero, Robert A., Jr.
DOI：
10.1007/978-1-61779-034-8_10
发表时间：
2011-01-01
期刊：
POLYAMINES: METHODS AND PROTOCOLS
影响因子：
--
作者：
Goodwin, Andrew C.;Murray-Stewart, Tracy R.;Casero, Robert A., Jr.
通讯作者：
Casero, Robert A., Jr.