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Pathways Glycolysis Pathway
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Description: Description: Glycolysis was one of the first metabolic pathways studied and is one of the best understood, in terms of the enzymes involved, their mechanisms of action, and the regulation of the pathway to meet the needs of the organism and the cell. The glycolytic pathway is extremely ancient in evolution, and is common to essentially all living organisms. The earliest biochemical studies of glycolysis over 100 years ago used cell free extracts of yeast, in which it was observed that glucose could be converted to carbon dioxide and ethanol in the same manner carried out by intact yeast cells to make beer and bread. These experiments were the first to demonstrate that the reactions of life were not inextricably tied to living cells but could occur in a cell-free system, the foundation of modern biochemistry.
In glycolysis, the six-carbon sugar glucose is oxidized and split in two halves, to create two molecules of pyruvate (3 carbons each) from each molecule of glucose. Along the way, the cell extracts a relatively small amount of energy from glucose in the form of ATP, 2 ATP molecules collected for each glucose molecule that starts down the glycolytic path. The pyruvate produced has one of three metabolic fates, to either become acetyl-CoA, ethanol, or lactate. When oxygen is available, the pyruvate can be converted to acetyl-CoA and enter the Krebs Cycle, where the acetyl-CoA will be completely oxidized and generate ATP through oxidative phosphorylation. Fermentation is much less efficient than oxidative phosphorylation in making ATP, creating only 2 ATP per glucose while oxidative phosphorylation creates 36 ATP per glucose in mammalian cells. Oxidative phosphorylation does not work in the absence of oxygen, however, and in the absence of oxygen glycolysis is forced to a halt due to a lack of NAD+, unless NAD+ is regenerated through fermentation. In yeast, fermentation allows the yeast to continue producing energy and survive in the absence of oxygen, producing ethanol and carbon dioxide from pyruvate. In mammalian muscle, strenuous exertion can create conditions in which oxygen is consumed faster than blood can provide it, forcing the muscle to use fermentation and create lactic acid in this case and make your muscles sore after a workout.
There are ten enzymes that catalyze the steps in glycolysis that convert glucose into pyruvate, and the entire pathway is located in the cytoplasm of eukaryotic cells. The activity of the pathway is regulated at key steps to ensure that glucose consumption and energy production match the needs of the cell. The steps along the pathway each involve a change in the free energy of the products and reactants, and as long as the overall change in free energy is negative, the reaction continues forward, like water flowing down hill to its lowest energy point. The key steps in the regulation of glycolysis, or any pathway, are those that catalyze the rate-limiting, irreversible steps along the pathway. In glycolysis in mammals, the key regulatory enzyme is phosphofructokinase, which catalyzes the rate-limiting committed step. Phosphofructokinase is activated by AMP and inhibited by ATP, among other regulatory mechanisms. Thus, when ATP is low (and AMP is high), phosphofructokinase will be activated and generate more ATP. Similarly, when ATP is abundant, phosphofructokinase will be inhibited to prevent wasting glucose on making energy when it is not needed.
Although the glycolytic pathway was one of the first studied, it is still relevant to many issues faced in modern biology. Failure to provide energy can have lethal consequences for cells - the absence of oxygen caused by a stroke or a heart attack that prevents ATP generation can have lethal consequences for the cells involved. Cancer cells often generate energy through glycolytic fermentation more than oxidative phosphorylation, suggesting that manipulation of metabolism may provide a therapeutic strategy. Well known glycolytic enzymes such as glyceraldehyde-3-phosphate dehydrogenase may play roles in other cellular processes such as apoptosis. Future studies may reveal additional functions of glycolytic enzymes.
Description: Description: Glenn Croston, PhD
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