History of the Pasteur effect and its pathobiology

Abstract

Long before the mechanism of fermentation was understood, PASTEUR discovered an important regulatory phenomenon of carbohydrate metabolism. He observed that yeast consumes more sugar anaerobically than aerobically. This so-called Pasteur effect has been subject of many controversies and an analysis of the development of the concepts has been presented. Among the key errors made in the early evaluations was to emphasize the control of end product formation rather than of hexose utilization.The Pasteur phenomenon as understood at present is a complex coordinated control mechanism which operates at several levels. The basic phenomenon is a competition between glycolysis and oxidative phosphorylation for the available ADP and inorganic phosphate. Superimposed are allosteric controls of hexokinase (glucose-6-phosphate) and of phosphofructokinase (ATP). However, in some cells glucose-6-phosphate is not an inhibitor of hexokinase and ATP levels do not change significantly during transition from aerobic to anaerobic conditions. It is therefore clear that other secondary allosteric effectors such as inorganic phosphate play a significant role. The major conclusion is that there are multiple and different control mechanisms participating in the Pasteur effect in different cells.A loss of control in tumor cells gives rise to a high aerobic glycolysis. The history and possible significance of this in malignancy is described.In 18611 PASTEUR reported that the utilization of glucose by yeast is much more rapid in the absence than in the presence of oxygen. This phenomenon was called the "Pasteur reaction" by WARBURG in 19262 and later it became the "Pasteur effect". When I decided to write this article on the history of the Pasteur effect I was fully aware of the difficulties confronting me. There are few subjects in biochemistry which can compete with the confusion created in the students' mind by the Pasteur effect. Dean BURK 3 reviewed the vast number of hypotheses proposed before 1938. The period since then was masterfully analyzed in a recent review by KREBS 4. Moreover, FRUTON 5 in his fascinating book on "Molecules and Life" has given special attention to the background of PASTEUR'S research and the controversies arising from his views.

Homeostasis and the glycogen shunt explains aerobic ethanol production in yeast

“…This question originated in the mid-1920s when Otto Warburg (19) measured in yeast the fermentation of glucose to ethanol in fully oxidized, respiratorycompetent yeast. Warburg also found that tumors, metabolizing glucose aerobically, similarly fermented most of their glucose to lactate, which, like the ethanol produced by yeast, is a measure of the yield of pyruvate by aerobic glycolysis (20)(21)(22). We find that the production of ethanol is driven by a coupling of the metabolic pathways of glycolysis, futile cycling, and glycogen/trehalose synthesis (which we refer to as the glycogen shunt).…”

“…they were exposed to a high level of glucose in a nongrowth medium. These conditions are a variation of the conditions studied by Pasteur (20), often referred to as the Crabtree effect (22) or simply as the Warburg effect in yeast. The addition of glucose triggers both transcriptional and posttranscriptional changes in yeast that drastically affect metabolism (26).…”

Interactions between glucose metabolism and oxidative phosphorylations on respiratory‐competent Saccharomyces cerevisiae cells

“…Under glucose + ethanol supply, the ATP/ADP ratio and the NADH level are high, the glycolytic flux decreases and glycogen and trehalose synthesis increase. These results seem to indicate that the glycolytic flux is mainly controlled by thermodynamic constraints at the level of glyceraldehyde-3-phosphate dehydrogenase/3-phosphoglycerate kinase enzymes (Racker, 1974;Gosalvez et al, 1974), governed by oxidative phosphorylation activity. This explanation does not exclude the role of certain effectors, i.e.…”

“…ATP, ADP, P, and fructose 2,6-bisphosphate, in determining the glycolytic rate and futile cycling at the level of the phosphofructo-1-kinase/fructose-l,6-bisphosphatase couple (Lagunas and Gancedo, 1983;den Hollander et al, 1986a,b;Reibstein et al, 1986;Campbell-Burk et al, 1987). b) Thermodynamic constraints due to competition between glycolysis and oxidative phosphorylations for ADP and P, (Racker, 1974;Gosalvez et al, 1974) and for reducing equivalents. In this explanation, mitochondrial metabolism in imposing intracellular ATP/ADP.P, and NADH/NAD ratios controls glyceraldehyde-3-phosphate dehydrogenase/3-phosphoglycerate kinase activities by their mass action ratios.…”

Towards Biological Target Volumes Definition for Radiotherapy Treatment Planning: Quo Vadis PET/CT?

“…Glycolysis involves the conversion of glucose to pyruvate and then to lactic acid, the waste product. In non-cancerous cells, mitochondrias oxidize pyruvate to carbon dioxide and water in the presence of oxygen and the glycolytic reaction is inhibited (Pasteur Effect) [74] Conversion of glucose to lactic acid, even in the presence of oxygen is known as aerobic glycolysis or the Warburg effect [75] and represents a hallmark of invasive cancers. Warburg's hypothesis that cancer results from impaired mitochondrial metabolism has been shown to be incorrect, but the observation of increased glycolysis in tumors, even in the presence of oxygen, has been repeatedly verified [76].…”