By Jeanne Zheng Cellular respiration is a major process occurring in heterotrophs that provide energy to power cell metabolism. It has three main steps: glycolysis, the Krebs cycle, and the Electron Transport Chain (oxidative phosphorylation and chemiosmosis). You should know the basics of what happens in each part for the AP exam; in this article, we will further discuss the first step, glycolysis, as well as its relevance to oncology (the study of cancer and tumors). GLYCOLYSISIn this step, bonds in glucose are rearranged to create two molecules of pyruvate. 2 NADH and a net gain of 2 ATP molecules are also formed. ENERGY INVESTMENT PHASE
Since glucose has 6 carbons and G3P has 3, we can say that one glucose yields 2 G3P and so all products of glycolysis from here on out should be doubled to find the yield of one glucose molecules.
FERMENTATIONIn the absence of oxygen, glycolysis can still occur. However, a process called fermentation is used to recycle the NADHs produced by glycolysis back into NAD+ so it can be reused by glycolysis. There are two types of fermentation: alcoholic and lactic acid. In alcoholic fermentation, which mostly takes place in single-cell organisms such as yeast, the two pyruvates are converted into two acetaldehydes and two carbon dioxides; the former becomes an electron receiver for the NADH and is reduced into ethyl alcohol, and the latter is released as a byproduct. In lactic acid fermentation, the pyruvate acts as an electron receiver for the NADH and is subsequently reduced into lactate, or lactic acid. This is what happens in your muscles when you need a quick source of energy when, for example, you run; for this reason, your muscles will start to ache after you exercise for long periods of time. THE warburg effect & its relation to cancerIn this 1920s, Otto Warburg observed that mass-proliferating cells--including tumor cells-- defaulted to aerobic glycolysis even in the presence of oxygen, meaning that the cells used lactic acid fermentation (where lactic acid serves as an electron acceptor to recycle NADH) even when there was available oxygen. This led him to (erroneously) believe that cancer was a metabolic disorder; his work in this field earned him a Nobel Prize in Physiology in 1924. However, future research revealed that tumors primarily resulted from genetic irregularities. This caused oncology research to move away from the Warburg Effect for a period of time. In an article published in Nature Magazine in 2004, Robert A. Gatenby and Robert J. Gillies guides the discussion back to the Warburg Effect as they explore the reasons behind its development and possible future developments based on it. In their review, titled “Why Do Cancers Have High Aerobic Glycolysis”, Gatenby and Gillies propose that tumor cells’ preference for using glycolysis and lactic acid fermentation to make ATP even in the presence of oxygen (instead of oxidative phosphorylation, which can create more ATP) indicates that it must convey some sort of evolutionary advantage. Firstly, it is observed that tumor cells often have much higher uptake of glucose than normal body cells. Gatenby and Gillies hypothesize that the reason for tumor cells’ reliance on glycolysis lies in their development. When tumors grow, they are often deprived of oxygen because they are separated from blood vessels by a basement membrane; thus, oxygen and glucose have to diffuse across both the blood vessel membrane and the basement membrane to get to the tumor, effectively ensuring that no such cells can live more than 160 μm from the blood vessels (discovered in the 1950s by Thomlinson and Gray)--at this point, the oxygen is so minimal that its partial pressure (i.e., the pressure exerted by oxygen in a mixture of gases in the body) is practically zero. In addition, the flow of blood and the levels of oxygen carried in it tend to fluctuate in cycles, which means that tumor cells far away from blood vessels sometimes receive even less oxygen than usual. Other than simply ATP synthesis, aerobic glycolysis is also thought to confer another advantage to rapidly proliferating cells such as those of a tumor: carbon intermediates to be used in the quick construction of organic molecules such as lipids and proteins, also known as biosynthesis. According to Maria V. Liberti and Jason W. Locasale’s article “The Warburg Effect: How does It Benefit Cancer Cells?”, these molecules are taken from various steps of glycolysis (ex. part of the 3-phosphoglycerate from the “energy payoff” phase of glycolysis is taken to make nucleotides). Finally, Gatenby and Gillies suggest that researching the Warburg Effect and its role in tumor growth could be beneficial in finding new cancer treatment methods. For instance, they propose that buffering (maintaining at a normal level) the local tumor pH may be able to reduce the aggressiveness of tumor cells, and wonder if pharmaceutics that prevent tumor cells from defaulting to glycolysis even when oxygen is present could slow the growth of cancer. REFERENCESGatenby, Robert A., and Robert J. Gillies. “Why Do Cancers Have High Aerobic Glycolysis?” Nature Reviews Cancer, vol. 4, no. 11, 2004, pp. 891–899., doi:10.1038/nrc1478. Liberti, Maria V., and Jason W. Locasale. “The Warburg Effect: How Does It Benefit Cancer Cells?” Trends in biochemical sciences 41.3 (2016): 211–218. PMC. Web. 3 Oct. 2017. Reece, Jane B., et al. “Cellular Respiration and Fermentation.” Campbell Biology, 10th ed., Pearson, 2014, pp. 162–184. SUGGESTED READINGOther than exploring the works under "References", the following articles may be read to deepen your knowledge of this particular topic:
Heiden, M. G. Vander, et al. “Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation.” Science, vol. 324, no. 5930, 2009, pp. 1029–1033., doi:10.1126/science.1160809. Wikipedia. “Warburg Hypothesis.” Wikipedia, Wikimedia Foundation, 22 Sept. 2017, en.wikipedia.org/wiki/Warburg_hypothesis.
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