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Crabtree Effect : A Significant Fermentation Control
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April 22, 1929 Biochemical Journal (Bioechem. J) published a research by Herbert Grace Crabtree (From the Laboratories of the Imperial Cancer Research Fund, Queen Square, London) titled "Observations On The Carbohydrate Metabolism Of Tumours". His research led to a highly significant finding which had implications on almost every future research on fermentations. The finding was "Effect of glycolysis on respiration", which suggested that the glycolytic activity exerted a checking effect on the respiration powers of the cells (of specific kind(s)). This inhibition of respiration under high rate of glycolysis emerged as Crabtree Effect. The effect was later elaborated by R.H. De Deken (C.E.R.I.A., Brussels, Belgium, 1965) in the most common eukaryotic model organism for fermentation: Saccharomyces cerevisiae, describing it as 'a repression of an energy source (respiration) by another energy source (fermentation/glycolysis)'. Owing to it's contrary nature to Pasteur effect (which is the inhibition of fermentation by respiration), it was quoted as 'contre-effet Pasteur' ". This article will thus focus on unfolding the concept of Crabtree Effect, and it's significance in industrial/research based fermentation processes.

Crabtree Effect: The Concept

Crabtree effect refers to inhibition of respiration when glucose concentration is increased (or when glycolysis is increased). It is observed in glycolytically active cells (like those involved in fermentations e.g yeast; and tumor cells), and not in every cell (which is contrary to Pasteur effect, observed in all kinds of cells). The mechanism behind the Crabtree Effect can be well understood in terms of [ATP]/[ADP][Pi ] ratio (Sussman et al., 1979). It's the cytosolic [ATP]/[ADP][Pi ] ratio which regulates the rate of respiration and glycolysis in the cells. But, the regulatory mechanism of both the processes is entirely different, which ultimately leads to Crabtree Effect in such cells.
The regulation of respiration is controlled by free energy of hydrolysis of ATP (following equation gives an overview of Free Energy of ATP Hydrolysis):
[Image: free_energy.png]
Click here for Full Concept on Free Energy of ATP Hydrolysis
Decrease in [ATP]/[ADP][Pi ] thus leads to an increase in the respiration rate, and increase in [ATP]/[ADP][Pi ] leads to a decrease in respiration. On the other hand, regulation of Glycolysis is positively controlled by ADP (AMP) and Pi and negatively by ATP (thus again, decrease in [ATP]/[ADP][Pi] leads to increase in glycolytic rate, while increase leads to decrease in the glycolytic rate). So, as evident, both respiration and glycolysis are regulated by the same set of factors, but by entirely different mechanisms. Now, this distinguished control of respiration and glycolysis is what leads to Crabtree effect. To elaborate, since Crabtree Effect takes place only in those cells which are glycolytically active, an increase in glucose conc. will push it towards glycolytic pathway, leading to an increased ATP production (consuming ADP and Pi, from media). This would tremendously increase the [ATP]/[ADP][Pi ] ratio, seriously lowering the free energy of ATP hydrolysis, and hence decreasing the rate of respiration to huge extent! (But, the glycolysis induced increase in [ATP]/[ADP][Pi ] won't necessarily reduce the glycolytic rate itself, as it's dependent on ADP (AMP) and Pi too, which is often present in good amounts in medium, to activate the enzymes responsible for glycolysis; more over the inherent glycolytically active nature of the cells keeps the inhibition of glycolysis itself at the bay!). So, this is how in most simple terms, Crabtree Effect takes place.

Significance (where Crabtree is Observed in Real World):

Alcohol Production:
The alcohol production industry is highly dependent upon the Crabtree active Saccharomyces cerevisiae. Yeast produces alcohol only under anaerobic conditions (which must be maintained for higher alcohol output!). Under aerobic conditions, oxidative phosphorylation takes place, which stops the use of glycolytic pathway. But, if excess of glucose (substrate) is supplied to the culture, then Crabtree effect takes place, and respiration is inhibited even if aerobic condition prevails! This leads to excess production of alcohol rather than biomass production. So, Crabtree comes to a favorable use in alcohol industry.

Tumor Cell Growth:
Tumor cells are characterized by hypoxic environments, where oxygen and nutrients are greatly limited. Their ability to produce lactate (and efficient glucose use) enables them to suppress the respiratory and oxidative phosphorylation need, and still survive by active glycolysis. Again, this is an instance of Crabtree Effect!

Concluding:
The research on Crabtree Effect is still active, despite it's first citation in 1929. Major part of the research is rather focussed on zeroing-in on the exact mechanism of the effect, which has received several reviews through out the time of it's proposition. The mechanism discussed in this article is one of the widely accepted ones, and nicely explains the Crabtree activity of certain cells. It's involvement in alcohol production (a ubiquitous industry), itself makes it a topic worth research and development. And, I hope, the next time you might see some cells respiring anaerobically, despite the presence of aerobic conditions, you should reason it with "Crabtree" as one of the probable factors!

Thanks
Sunil Nagpal
MS(Research) Scholar, IIT Delhi (Alumnus)
Advisor for the Biotech Students portal (BiotechStudents.com)
Computational Researcher in BioSciences at a leading MNC


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Crabtree Effect : A Significant Fermentation Control00