抑制多胺合成对脱羧S-腺苷甲硫氨酸含量的影响

Effect of inhibition of polyamine synthesis on the content of decarboxylated S-adenosylmethionine.

作者信息

Pegg A E, Pösö H, Shuttleworth K, Bennett R A

出版信息

Biochem J. 1982 Feb 15;202(2):519-26. doi: 10.1042/bj2020519.

DOI:10.1042/bj2020519

PMID:6807294

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1158138/

Abstract

The content of decarboxylated S-adenosylmethionine (AdoMet) in transformed mouse fibroblasts (SV-3T3 cells) was increased 500-fold to about 0.4fmol/cell when ornithine decarboxylase was inhibited by alpha-difluoromethylornithine. This increase was due to the absence of putrescine and spermidine, which serve as substrates for aminopropyltransferases with decarboxylated AdoMet as an aminopropyl donor, and to the enhanced activity of AdoMet decarboxylase brought about by depletion of spermidine. The increase in decarboxylated AdoMet content was abolished by addition of putrescine, but not by 1,3-diaminopropane. 2. 5'-Methylthiotubercidin also increased decarboxylated AdoMet content, presumably by direct inhibition of aminopropyl-transferase activities, but the increase in its content and the decline in spermidine content were much less than those produced by alpha-difluoromethylornithine. 3. Decarboxylated AdoMet content of regenerating rat liver was measured in rats treated with inhibitors of ornithine decarboxylase. The content was increased by 60% 32h after partial hepatectomy in control rats, by 90% when alpha-difluoromethylornithine was given to the partially hepatectomized rats, and by 330% when 1,3-diaminopropane was used to inhibit putrescine and spermidine synthesis. After 48h of exposure to 1,3-diaminopropane, which completely prevented the increase in spermidine after partial hepatectomy, there was a 5-fold rise in hepatic decarboxylated AdoMet concentration. These increases were prevented by treatment with putrescine or with methylglyoxal bis(guanylhydrazone), an inhibitor of AdoMet decarboxylase. 4. These results show that changes in AdoMet metabolism result from the administration of specific inhibitors of polyamine synthesis. The possible consequences of the accumulation of decarboxylated AdoMet, which could, for example, interfere with normal cellular methylation or lead to depletion of cellular adenine nucleotides, should be considered in the interpretation of results obtained with such inhibitors.

摘要

当用α-二氟甲基鸟氨酸抑制鸟氨酸脱羧酶时，转化的小鼠成纤维细胞（SV - 3T3细胞）中脱羧S - 腺苷甲硫氨酸（AdoMet）的含量增加了500倍，达到约0.4fmol/细胞。这种增加是由于腐胺和亚精胺的缺乏，它们作为以脱羧AdoMet为氨丙基供体的氨丙基转移酶的底物，并且由于亚精胺的消耗导致AdoMet脱羧酶活性增强。添加腐胺可消除脱羧AdoMet含量的增加，但1,3 - 二氨基丙烷则不能。2. 5'-甲基硫代杀结核菌素也增加了脱羧AdoMet的含量，推测是通过直接抑制氨丙基转移酶活性，但它的含量增加和亚精胺含量的下降远小于α-二氟甲基鸟氨酸所产生的变化。3. 在接受鸟氨酸脱羧酶抑制剂治疗的大鼠中测量再生大鼠肝脏的脱羧AdoMet含量。在对照大鼠中，部分肝切除术后32小时，含量增加60%；当给部分肝切除的大鼠给予α-二氟甲基鸟氨酸时，增加90%；当使用1,3 - 二氨基丙烷抑制腐胺和亚精胺合成时，增加330%。在暴露于1,3 - 二氨基丙烷48小时后，这完全阻止了部分肝切除后亚精胺的增加，肝脏脱羧AdoMet浓度增加了5倍。用腐胺或用AdoMet脱羧酶抑制剂甲基乙二醛双（胍腙）处理可阻止这些增加。4. 这些结果表明，AdoMet代谢的变化是由多胺合成的特定抑制剂的给药引起的。在解释用此类抑制剂获得的结果时，应考虑脱羧AdoMet积累的可能后果，例如，它可能干扰正常的细胞甲基化或导致细胞腺嘌呤核苷酸的消耗。