Dipartimento di Scienze Biochimiche A. Rossi Fanelli, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy.
Med Hypotheses. 2013 May;80(5):633-6. doi: 10.1016/j.mehy.2013.02.008. Epub 2013 Mar 6.
It was recently discovered that glycine consumption is strongly related to the rate of proliferation across cancer cells. This is very intriguing and raises the question of what is the actual role of this amino acid in cancer metabolism. Cancer cells are greedy for glycine. In particular, the mitochondrial production of glycine seems to be utterly important. Overexpression of mitochondrial serine hydroxymethyltransferase, the enzyme converting l-serine to glycine, assures an adequate supply of glycine to rapidly proliferating cancer cells. In fact, silencing of mitochondrial serine hydroxymethyltransferase was shown to halt cancer cell proliferation. Direct incorporation of glycine carbon atoms into the purine ring has been proposed to be one main reason for the importance of glycine in cancer cell metabolism. We believe that, as far as the importance of glycine in cancer is concerned, a central role of this amino acid, namely its participation to heme biosynthesis, has been neglected. In mitochondria, glycine condenses with succinyl-CoA to form 5-aminolevulinate, the universal precursor of the different forms of heme contained in cytochromes and oxidative phosphorylation complexes. Our hypothesis is that mitochondrial serine hydroxymethyltransferase is fundamental to sustain cancer metabolism since production of glycine fuels heme biosynthesis and therefore oxidative phosphorylation. Respiration of cancer cells may then ultimately rely on endogenous glycine synthesis by mitochondrial serine hydroxymethyltransferase. The link between mitochondrial serine hydroxymethyltransferase activity and heme biosynthesis represents an important and still unexplored aspect of the whole picture of cancer cell metabolism. Our hypothesis might be tested using a combination of metabolic tracing and gene silencing on different cancer cell lines. The experiments should be devised so as to assess the importance of mitochondrial serine hydroxymethyltransferase and the glycine deriving from its reaction as a precursor of heme. If the observed increase of glycine consumption in rapidly proliferating cancer cells has its basis in the need for heme biosynthesis, then mitochondrial serine hydroxymethyltransferase should be considered as a key target for the development of new chemotherapeutic agents.
最近发现，甘氨酸的消耗与癌细胞的增殖率密切相关。这非常有趣，引发了一个问题，即这种氨基酸在癌症代谢中的实际作用是什么。癌细胞非常贪婪甘氨酸。特别是，线粒体产生甘氨酸似乎非常重要。线粒体丝氨酸羟甲基转移酶（将 l-丝氨酸转化为甘氨酸的酶）的过表达确保了足够的甘氨酸供应给快速增殖的癌细胞。事实上，沉默线粒体丝氨酸羟甲基转移酶已被证明可以阻止癌细胞增殖。有人提出，甘氨酸碳原子直接掺入嘌呤环是甘氨酸在癌细胞代谢中重要性的一个主要原因。我们认为，就甘氨酸在癌症中的重要性而言，这种氨基酸的一个核心作用，即其参与血红素生物合成，一直被忽视。在线粒体中，甘氨酸与琥珀酰辅酶 A 缩合形成 5-氨基乙酰丙酸，这是细胞色素和氧化磷酸化复合物中包含的不同形式血红素的通用前体。我们的假设是，线粒体丝氨酸羟甲基转移酶对于维持癌症代谢至关重要，因为甘氨酸的产生为血红素生物合成提供燃料，从而为氧化磷酸化提供燃料。因此，癌细胞的呼吸可能最终依赖于线粒体丝氨酸羟甲基转移酶的内源性甘氨酸合成。线粒体丝氨酸羟甲基转移酶活性与血红素生物合成之间的联系代表了癌症细胞代谢整体图景中一个重要且尚未探索的方面。可以使用不同癌症细胞系的代谢追踪和基因沉默组合来测试我们的假设。实验设计应评估线粒体丝氨酸羟甲基转移酶及其反应中产生的甘氨酸作为血红素前体的重要性。如果快速增殖的癌细胞中甘氨酸消耗的增加是基于血红素生物合成的需要，那么线粒体丝氨酸羟甲基转移酶应该被视为开发新化疗药物的关键靶点。
