School of Pharmacy, Biocenter Kuopio, University of Eastern Finland, Kuopio Campus, P.O. Box 1627, FI-70211 Kuopio, Finland.
Research Center of Biotechnology, Russian Academy of Sciences, 119071 Moscow, Russia.
Biomolecules. 2020 Mar 6;10(3):406. doi: 10.3390/biom10030406.
The biogenic polyamines, spermine, spermidine (Spd) and putrescine (Put) are present at micro-millimolar concentrations in eukaryotic and prokaryotic cells (many prokaryotes have no spermine), participating in the regulation of cellular proliferation and differentiation. In mammalian cells Put is formed exclusively from ornithine by ornithine decarboxylase (ODC) and many potent ODC inhibitors are known. In bacteria, plants, and fungi Put is synthesized also from agmatine, which is formed from arginine by arginine decarboxylase (ADC). Here we demonstrate that the isosteric hydroxylamine analogue of agmatine (AO-Agm) is a new and very potent ( 3•10 M) inhibitor of ADC. It was almost two orders of magnitude less potent towards ODC. AO-Agm decreased polyamine pools and inhibited the growth of DU145 prostate cancer cells only at high concentration (1 mM). Growth inhibitory analysis of the demonstrated that the wild type (WT) strain synthesized Put only from -ornithine, while the cephalosporin C high-yielding strain, in which the polyamine pool is increased, could use both ODC and ADC to produce Put. Thus, AO-Agm is an important addition to the set of existing inhibitors of the enzymes of polyamine biosynthesis, and an important instrument for investigating polyamine biochemistry.
生物源多胺，精胺、亚精胺（Spd）和腐胺（Put）在真核和原核细胞中以微毫摩尔浓度存在（许多原核生物没有精胺），参与细胞增殖和分化的调节。在哺乳动物细胞中，Put 仅由鸟氨酸通过鸟氨酸脱羧酶（ODC）形成，并且已知许多有效的 ODC 抑制剂。在细菌、植物和真菌中，Put 也可以由胍氨酸合成，胍氨酸由精氨酸通过精氨酸脱羧酶（ADC）形成。在这里，我们证明了胍氨酸的等排羟胺类似物（AO-Agm）是一种新的、非常有效的（3•10 M）ADC 抑制剂。它对 ODC 的抑制作用低两个数量级。AO-Agm 降低多胺池并仅在高浓度（1 mM）下抑制 DU145 前列腺癌细胞的生长。对 进行的生长抑制分析表明，野生型（WT）菌株仅从 -鸟氨酸合成 Put，而头孢菌素 C 高产菌株中，多胺池增加，既可以使用 ODC 也可以使用 ADC 来产生 Put。因此，AO-Agm 是现有多胺生物合成酶抑制剂的重要补充，也是研究多胺生物化学的重要工具。
