Enzymes of creatine biosynthesis, arginine and methionine metabolism in normal and malignant cells
Enzymes of creatine biosynthesis, arginine and methionine metabolism in normal and malignant cells
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DOI：
10.1111/j.1742-4658.2008.06718.x
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发表时间：
2008-12-01
期刊：
影响因子：
5.4
通讯作者：
Ray, Manju
中科院分区：
文献类型：
--
作者：
Bera, Soumen;Wallimann, Theo;Ray, Manju
肌酸/肌酸激酶系统在肉瘤中急剧减少。在本研究中，催化活性，蛋白质印迹和mRNA表达的调查明确表明显着的表达肌酸合成酶L-精氨酸：甘氨酸脒基转移酶和N-胍乙酸甲基转移酶的肉瘤，埃利希腹水癌和肉瘤180细胞，而这两种酶几乎检测不到在正常肌肉。与正常动物相比，这些酶在荷肉瘤小鼠的肾脏或肝脏中不受影响。高活性和表达的线粒体丝氨酸蛋白酶II在肉瘤表明增加鸟氨酸的形成。与肌肉相比，在肉瘤中观察到鸟氨酸、胍基乙酸盐和肌酐水平略高或中度较高。尽管在埃利希腹水癌和肉瘤180细胞中固有地低水平肌酸，但这些细胞可以显著地摄取和释放肌酸，这表明功能性肌酸转运，如通过测量肌酸转运蛋白的mRNA水平所证实的。在肉瘤、埃利希腹水癌和肉瘤180细胞中，腺苷酸酶II、鸟氨酸脱羧酶、S-腺苷高半胱氨酸水解酶和甲硫氨酸合成酶的转录水平显著上调。总体而言，发现与肌酸和精氨酸/甲硫氨酸代谢相关的酶在恶性细胞中显著上调。然而，相同恶性细胞中肌酸激酶的低水平似乎不足以建立有效的肌酸/磷酸肌酸池。L-精氨酸：甘氨酸脒基转移酶和N-胍基乙酸甲基转移酶似乎不是支持肌酸生物合成，而是在多胺和甲硫氨酸合成的方向上支持癌细胞代谢，因为这两种化合物在增殖的癌细胞中需求量很高。
The creatine/creatine kinase system decreases drastically in sarcoma. In the present study, an investigation of catalytic activities, western blot and mRNA expression unambiguously demonstrates the prominent expression of the creatine-synthesizing enzymes l-arginine:glycine amidinotransferase and N-guanidinoacetate methyltransferase in sarcoma, Ehrlich ascites carcinoma and Sarcoma 180 cells, whereas both enzymes were virtually undetectable in normal muscle. Compared to that of normal animals, these enzymes remained unaffected in the kidney or liver of sarcoma-bearing mice. High activity and expression of mitochondrial arginase II in sarcoma indicated increased ornithine formation. Slightly or moderately higher levels of ornithine, guanidinoacetate and creatinine were observed in sarcoma compared to muscle. Despite the intrinsically low level of creatine in Ehrlich ascites carcinoma and Sarcoma 180 cells, these cells could significantly take up and release creatine, suggesting a functional creatine transport, as verified by measuring mRNA levels of creatine transporter. Transcript levels of arginase II, ornithine-decarboxylase, S-adenosyl-homocysteine hydrolase and methionine-synthase were significantly upregulated in sarcoma and in Ehrlich ascites carcinoma and Sarcoma 180 cells. Overall, the enzymes related to creatine and arginine/methionine metabolism were found to be significantly upregulated in malignant cells. However, the low levels of creatine kinase in the same malignant cells do not appear to be sufficient for the building up of an effective creatine/phosphocreatine pool. Instead of supporting creatine biosynthesis, l-arginine:glycine amidinotransferase and N-guanidinoacetate methyltransferase appear to be geared to support cancer cell metabolism in the direction of polyamine and methionine synthesis because both these compounds are in high demand in proliferating cancer cells.