Moreadith R W, Lehninger A L
J Biol Chem. 1984 May 25;259(10):6215-21.
Little evidence has been available on the oxidative pathways of glutamine and glutamate, the major respiratory substrates of cancer cells. Glutamate formed from glutamine by phosphate-dependent glutaminase undergoes quantitative transamination by aerobic tumor mitochondria to yield aspartate. However, when malate is also added there is a pronounced decrease in aspartate production and a large formation of citrate and alanine, in both state 3 and 4 conditions. In contrast, addition of malate to normal rat heart, liver, or kidney mitochondria oxidizing glutamate causes a marked increase in aspartate production. Further analysis showed that extramitochondrial malate is oxidized almost quantitatively to pyruvate + CO2 by NAD(P)+-linked malic enzyme, present in the mitochondria of all tumors tested, but absent in heart, liver, and kidney mitochondria. On the other hand intramitochondrial malate generated from glutamate is oxidized quantitatively to oxalacetate by mitochondrial malate dehydrogenase of tumors. Acetyl-CoA derived from extramitochondrial malate via pyruvate and oxalacetate derived from glutamate via intramitochondrial malate are quantitatively converted into citrate, which is extruded. No evidence was found that malic enzyme of tumor mitochondria converts glutamate-derived malate into pyruvate as postulated in other reports. Possible mechanisms for the integration of mitochondrial malic enzyme and malate dehydrogenase activities in tumors are discussed.
关于癌细胞的主要呼吸底物谷氨酰胺和谷氨酸的氧化途径，目前几乎没有相关证据。由磷酸依赖性谷氨酰胺酶从谷氨酰胺生成的谷氨酸，经有氧肿瘤线粒体进行定量转氨作用生成天冬氨酸。然而，当同时添加苹果酸时，在状态3和状态4条件下，天冬氨酸的生成量会显著减少，同时会大量生成柠檬酸和丙氨酸。相比之下，向氧化谷氨酸的正常大鼠心脏、肝脏或肾脏线粒体中添加苹果酸，会导致天冬氨酸生成量显著增加。进一步分析表明，胞外苹果酸几乎被所有测试肿瘤线粒体中存在但心脏、肝脏和肾脏线粒体中不存在的NAD(P)+连接的苹果酸酶定量氧化为丙酮酸 + CO2。另一方面，由谷氨酸生成的线粒体内苹果酸被肿瘤的线粒体苹果酸脱氢酶定量氧化为草酰乙酸。通过丙酮酸从胞外苹果酸衍生而来的乙酰辅酶A和通过线粒体内苹果酸从谷氨酸衍生而来的草酰乙酸被定量转化为柠檬酸并被排出。未发现肿瘤线粒体的苹果酸酶如其他报告所假设的那样将谷氨酸衍生的苹果酸转化为丙酮酸的证据。本文讨论了肿瘤中线粒体苹果酸酶和苹果酸脱氢酶活性整合的可能机制。
