Dunston T T, Khomutov M A, Gabelli S B, Stewart T M, Foley J R, Kochetkov S N, Khomutov A R, Casero R A
Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287 USA.
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia.
Acta Naturae. 2020 Jul-Sep;12(3):140-144. doi: 10.32607/actanaturae.10992.
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 and as an irreversible inhibitor of SMOX, but it is also potent towards 1-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 IC value of 169 μM towards SMOX and is an interesting instrument and lead compound for studying polyamine catabolism.
生物源多胺精胺（Spm）和亚精胺（Spd）在所有真核细胞中的浓度为μM - mM，其稳态由多胺合成、降解和转运酶的协同活动精确调节，以维持正常细胞生长和活力。精胺氧化酶（SMOX）是多胺代谢中关键且最新发现的酶，通过催化Spm逆向转化为Spd在调节多胺稳态中起重要作用。多种上皮癌的发展与炎症相关，疾病相关的炎症刺激会诱导SMOX。MDL72527被广泛用作SMOX的不可逆抑制剂，但它对1 - 乙酰多胺氧化酶也有活性。尽管SMOX具有高底物特异性，但尚未对Spm类似物作为酶抑制剂进行系统研究。在此我们证明，在标准测定条件下，1,12 - 二氨基 - 2,11 - 双（亚甲基）- 4,9 - 二氮杂十二烷（2,11 - Met2 - Spm）对SMOX的IC值为169μM，是研究多胺分解代谢的一种有趣工具和先导化合物。
