Chapter 4   |   Journeys can change

To maintain homeostasis and overall function, metabolic flux is always in a dynamic state responding and adjusting to external/ internal stimuli and other regulatory factors to maintain optimal levels of key metabolites or molecules. As a consequence of regulation, carbon flux through certain pathways in central carbon metabolism can increase or decrease. In this chapter, we will see how metabolic flux can be altered in different states.

 

1. This chapter can be viewed after students have completed chapters 1-3 and are familiar with central carbon metabolism and its regulation in Biochemistry and Metabolism. Students should also be familiar with hypoxia and cancer. Students can view the animations in the 'PATHWAYS' section at their own pace. Alternatively, since the animations do not have audio the instructor can describe the pathway while the students watch the animations in class.

2. These animations focus only on metabolites and do not contain any enzyme or cofactor information. This chapter does not provide information on where high energy electrons are used or released so the viewers can focus on carbon flux. The instructor needs to provide these details if desired.

3. Some sample discussion questions have been provided in the 'QUESTIONS' section at the bottom of this page. Students are encouraged to engage with these questions either on their own or in a group after viewing the animations. This could be guided by the instructor.

4. The fluxes visualized in these animations are derived from data in research publications listed in the 'REFERENCES' section at the end. The depicted fluxes are net fluxes in mammalian cells, so it is key to remember that forward and reverse fluxes for reversible reactions are not shown. The instructor may need to indicate that.

5. HOW TO READ THE ANIMATIONS? Each blue spherical particle you see in the animation represents a metabolite. This simplified representation has been used to clearly visualize the amount of flux. The unit of flux is nmoles/(h*µl of cells). In the animation, what occurs in 1 µl of cells in one hour has been shown in 1 cell in one second. It has been shown in one cell to show compartmentalization within a cell.

PATHWAYS

  Carbon Flux during Hypoxia

In this animation you can visualize how hypoxia promotes glycolytic flux (regular flux in blue and hypoxic flux in magenta). Flux of glucose-derived pyruvate into the TCA cycle is reduced. Fraction of glucose excreted as lactate is increased. Flux of glutamine into the TCA cycle is maintained and therefore, contributes to most of the ATP through oxidative phosporylation rather than glucose. If you look closely, you will also notice higher production of citrate from alpha-ketoglutarate. This video depicts flux in a transformed cell line subjected to low oxygen in a hypoxic chamber. Similar flux changes could be observed under high altitude conditions where concentrations of oxygen are lower. Biomass is the cellular DNA, RNA, protein and fatty acid content. The pink circle is to indicate biomass production via serine biosynthesis pathway and the yellow circle is to denote flux into fatty acid synthesis.Click here to download

 

 

  Carbon Flux during Cancer

This video visualizes how flux changes with cancer (regular flux in blue and cancer flux in rust color). A similar change is observed as during hypoxia, where glycolytic flux entering the TCA cycle is reduced and greater production of lactate occurs. In this case too, glutamine contributes more to oxidative phosphorylation than glucose. During cancer, a phenomenon called the Warburg effect occurs which causes more glucose uptake and anabolic metabolism or biomass production through glycolysis. Biomass is the cellular DNA, RNA, protein and fatty acid content. The pink circle is to indicate biomass production via serine biosynthesis pathway and the yellow circle is to denote flux into fatty acid synthesis.Click here to download

QUESTIONS

1. Why do you think glycolytic flux to the TCA cycle is reduced under hypoxic conditions and during cancer?

2. What would happen if the cell were to run out of glutamine?

REFERENCES

1. Fan et al., Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in normoxia and hypoxia. Mol Sys Biol. 9:712. 2013.

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