Cells make energy by breaking down macromolecules. Cellular respiration is the biochemical process that converts "food energy" (from the chemical bonds of macromolecules) into chemical energy in the form of adenosine triphosphate (ATP). The first step of this tightly regulated and intricate process is glycolysis. The word glycolysis originates from the Latin glyco (sugar) and lysis (breakdown). Glycolysis serves two main intracellular functions: generating ATP and generating intermediate metabolites to feed into other pathways. The glycolytic pathway converts one hexose (a six-carbon carbohydrate such as glucose) into two triose molecules (three-carbon carbohydrate) such as pyruvate, to produce a net total of two molecules of ATP (four produced, two consumed) and two molecules of nicotinamide adenine dinucleotide (NADH).
In the mid-1800s, Louis Pasteur determined that microorganisms cause the breakdown of glucose in the absence of oxygen (fermentation). In 1897, Eduard Buchner found that fermentation reactions can still be carried out in cell-free yeast extracts by breaking open the cell and collecting the cytoplasm containing the soluble molecules and organelles. Shortly after, in 1905, Arthur Harden and William Young discovered that the rate of fermentation decreases without the addition of inorganic phosphate (Pi) and that fermentation requires the presence of both a heat-sensitive component (later identified to contain a number of enzymes) and a low molecular weight, heat-stable fraction (inorganic ions, ATP, ADP and coenzymes like NAD). By 1940, with the effort of many individuals, the complete glycolysis pathway was established by Gustav Embden, Otto Meyerhof, Jakub Karol Parnas, and others. Now, glycolysis is known as the EMP pathway.
There are two ways that glucose can enter the cell. A group of integral GLUT (glucose transporter) proteins shuttles glucose into the cytosol via facilitated diffusion. Members of the GLUT protein family are present in specific tissues throughout the human body. Alternatively, transmembrane symporter proteins move glucose against its concentration gradient via secondary active transport. The symporter uses electrochemical energy from pumping ions. Examples are the sodium-glucose-linked transporters in the small intestine, the heart, the brain, and the kidneys.
Under aerobic (O2-rich) and anaerobic (O2-deficient) conditions, glycolysis can start once glucose enters the cell cytosol. There are two main phases of glycolysis. The first phase is an energy-requiring preparatory step that traps glucose in the cell and restructures the six-carbon backbone so that it can be efficiently cleaved. The second phase releases energy and generates pyruvate.
Depending on the oxygen level and the presence of mitochondria, pyruvate may have one of two possible fates. Under aerobic conditions with mitochondria present, pyruvate enters the mitochondria, undergoing the citric acid cycle and the electron transport chain (ETC) to be oxidized to CO2, H2O, and even more ATP. In contrast, under anaerobic conditions (i.e., working muscles) or without mitochondria (i.e., prokaryotes), pyruvate undergoes lactate fermentation (i.e., is reduced to lactate in anaerobic conditions). Interestingly, yeast and some bacteria under anaerobic conditions can convert pyruvate to ethanol through a process known as alcohol fermentation.
Tight control and regulation of enzyme-mediated metabolic pathways, such as glycolysis, is critical for the proper functioning of an organism. Control is exerted by substrate limitation or enzyme-linked regulation. Substrate limitation occurs when the concentration of the substrates and products in the cell is near equilibrium. Consequently, the availability of the substrate determines the rate of the reaction. In enzyme-linked regulation, the concentration of the substrates and products is far from equilibrium. The activity of three enzymes (hexokinase, phosphofructokinase, and pyruvate kinase) determines the rate of reaction, which controls the flux of the overall pathway.
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