Complex N-Acetylation of Triethylenetetramine
Complex N-Acetylation of Triethylenetetramine
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DOI：
10.1124/dmd.111.041798
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发表时间：
2011-12-01
影响因子：
3.9
通讯作者：
Keinanen, Tuomo A.
中科院分区：
文献类型：
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作者：
Cerrada-Gimenez, Marc;Weisell, Janne;Keinanen, Tuomo A.
三乙烯四胺 (TETA) 是一种高效的铜螯合剂，具有多种临床潜力。我们最近发现，亚精胺/精胺-N-1-乙酰转移酶 (SSAT1)（关键的多胺分解代谢酶）可在体外乙酰化 TETA。在这里，我们研究了 TETA 在三种不同小鼠系中的代谢：同源小鼠、SSAT1 过表达小鼠和 SSAT1 缺陷小鼠 (SSAT1-KO)。注射 TETA（300 mg/kg i.p.）后 1、2 或 4 小时处死小鼠。我们在肝脏、肾脏和血浆样本中仅发现 N-1-乙酰三乙烯四胺 (N(1)AcTETA) 和/或 TETA。正如预期的那样，与同源小鼠和 SSAT1-KO 小鼠相比，SSAT1 过表达小鼠乙酰化 TETA 的速度更快。值得注意的是，SSAT1-KO 小鼠与同源小鼠一样代谢 TETA，可能是通过硫赖氨酸乙酰转移酶进行代谢，当用人重组酶进行体外测试时，TETA 的 K-m 值为 2.5 +/- 0.3 mM，k(cat) 值为 1.3 s(-1)。因此，目前的结果表明至少有两种 N-乙酰酶可能代谢 TETA。然而，它们对 TETA 乙酰化的生理意义需要进一步研究。此外，我们在酸化的高效液相色谱样品基质中检测到 N(1)AcTETA 和 N-1,N-8-二乙酰基三亚乙基四胺从 N-1 位置到 N-3 位置的化学分子内 N-乙酰基迁移。 TETA 复杂的代谢以及分子内 N-乙酰基迁移可能解释了先前报道的 TETA 乙酰化率的巨大个体差异。
Triethylenetetramine (TETA) is an efficient copper chelator that has versatile clinical potential. We have recently shown that spermidine/spermine-N-1-acetyltransferase (SSAT1), the key polyamine catabolic enzyme, acetylates TETA in vitro. Here, we studied the metabolism of TETA in three different mouse lines: syngenic, SSAT1-overexpressing, and SSAT1-deficient (SSAT1-KO) mice. The mice were sacrificed at 1, 2, or 4 h after TETA injection (300 mg/kg i.p.). We found only N-1-acetyltriethylenetetramine (N(1)AcTETA) and/or TETA in the liver, kidney, and plasma samples. As expected, SSAT1-overexpressing mice acetylated TETA at an accelerated rate compared with syngenic and SSAT1-KO mice. It is noteworthy that SSAT1-KO mice metabolized TETA as syngenic mice did, probably by thialysine acetyltransferase, which had a K-m value of 2.5 +/- 0.3 mM and a k(cat) value of 1.3 s(-1) for TETA when tested in vitro with the human recombinant enzyme. Thus, the present results suggest that there are at least two N-acetylases potentially metabolizing TETA. However, their physiological significance for TETA acetylation requires further studies. Furthermore, we detected chemical intramolecular N-acetyl migration from the N-1 to N-3 position of N(1)AcTETA and N-1,N-8-diacetyltriethylenetetramine in an acidified high-performance liquid chromatography sample matrix. The complex metabolism of TETA together with the intramolecular N-acetyl migration may explain the huge individual variations in the acetylation rate of TETA reported earlier.