Application of metabolic-control logic to fuel utilization and its significance in tumor cells

The importance and the value of applying metabolic-control logic to the question of fuels, their rates of utilization and their significance to the process of proliferation are presented. Application of the recently developed quantitative theory of metabolic control of branched pathways provides a hypothesis to account for the high rate of both glycolysis and glutaminolysis in lymphocytes, macrophages and, in particular, in tumor cells. Both glycolysis and glutaminolysis provide metabolic intermediates for biosynthetic pathways: for example, glucose-6-phosphate for the formation of ribose-5-phosphate, and glutamine, ammonia and aspartate which are required for the synthesis of purine and pyrimidine nucleotides. However, the rates of both glycolysis and glutaminolysis are greatly in excess (greater than 400-fold) of the requirements for the biosynthetic processes. If energy formation per se was the major reason for the high rate of glutamine utilization, why is the oxidation only partial? The ability of the cell to divide will require the synthesis of all the DNA, RNA, phospholipids, etc., at precise times in the cell cycle. Hence very high and accurate sensitivity of the processes that provide the precursors for these compounds to their specific regulators will be expected. Maintenance of high rates of glycolysis and glutaminolysis at all times can be seen therefore as a device to allow intermediates to be "tapped off" at the precise rate required whenever they are needed for biosynthesis. Maximal activities of some key enzymes of glycolysis, the tricarboxylic acid cycle and glutaminolysis from a variety of normal, neoplastic and suppressed cells are presented. The relative activities of hexokinase and 6-phosphofructokinase suggest that, particularly in neoplastic cells, in which the capacity for glucose transport is high, hexokinase could approach saturation in respect to intracellular glucose; consequently, hexokinase and phosphofructokinase could play an important role in the regulation of glycolytic flux in these cells. The activity of pyruvate kinase is considerably higher in tumorigenic cells than in nontumorigenic cells and higher in metastatic cells than in tumorigenic cells: for nontumorigenic cells the activities range from 28.4 to 574, for tumorigenic cells from 899 to 1280, and for metastatic cells from 1590 to 1627 nmol/min per mg of protein. The ratio of pyruvate kinase activity to 2 x phosphofructokinase activity is very high in neoplastic cells. The mean is 22.4 for neoplastic cells, whereas for muscle from 60 different animals it is only 3.8.(ABSTRACT TRUNCATED AT 400 WORDS)