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The Role of Glutamine in the Oxidative Metabolism of Malignant Cells¹

Z. Kovaevi² and H. P. Morris

City of Hope Medical Center, Division of Neurosciences, Duarte, California 91010 [Z. K.], and Department of Biochemistry, Howard University College of Medicine, Washington, D. C. 20001 [H. P. M.]

Experimental evidence is presented indicating a very good correlation between the activity of mitochondrial glutaminase and the rate of respiration of tumor mitochondria in the presence of glutamine. K_m measurements for glutamine of glutaminase in intact, coupled mitochondria isolated from Morris hepatomas showed a correlation between the increase of the affinity of the enzyme for the substrate and the rate of growth of the tumors. Comparison of the rate of oxygen consumption by isolated mitochondria in the presence of glutamine and two other physiological substrates, glutamate and pyruvate, and the measurement of CO₂ production by intact tumor cells in the presence of glutamine and glucose indicated that glutamine is one of the most important substrates in the oxidative and energy metabolism of rapidly growing malignant cells in vivo. If the mitochondria are able to respire in the presence of low concentrations of glutamine (below 1 mM), they do not swell in the isoosmotic solution of ammonium glutamate, which indicates the relative impermeability of the mitochondrial membrane for glutamate. Measurement of the distribution of glutamate during glutaminase activity revealed a high accumulation of this metabolite in the mitochondrial compartment. Because glutamate is a good reductant for NAD(P)⁺, it was assumed that this is one of the factors in the maintenance of a great difference in the oxidation-reduction state between intra- and extramitochondrial pyridine nucleotides; this difference is important for mitochondrial respiration and energy production.

¹ This work was supported in part by USPHS Grant CA-10729 to Howard University and Grants CA-02568 (E. Roberts) and CA-5-R01-CA-11166 (J. T. Holden) from the National Cancer Institute, NIH.

² Present address: Department of Biochemistry, Medical Faculty, University of Novi Sad, Bulevar Revolucije 44, 21000 Novi Sad, Yugoslavia. Holder of USPHS International Postdoctoral Fellowship FO5 TW 1565-01.

Received 3/12/71. Accepted 10/21/71.

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