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Overview

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 Latin glyco (sugar) and lysis (breakdown). Glycolysis serves two main intracellular functions: generate ATP and intermediate metabolites to feed into other pathways. The glycolytic pathway converts one hexose (six-carbon carbohydrate such as glucose), into two triose molecules (three-carbon carbohydrate) such as pyruvate, and a net of two molecules of ATP (four produced, two consumed) and two molecules of nicotinamide adenine dinucleotide (NADH).

Elucidation of Glycolysis

Did you know that glycolysis was the first biochemical pathway discovered? 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, achieved by breaking open the cell and collecting the cytoplasm which contains the soluble molecules and organelles. Shortly thereafter in 1905, Arthur Harden and William Young discovered that the rate of fermentation decreases without the addition of inorganic phosphate (P_i) 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 pathway of glycolysis was established by Gustav Embden, Otto Meyerhof, Jakub Karol Parnas, et al. In fact, glycolysis is now known as the EMP pathway.

Destiny of Glucose

Glucose can enter cells in two ways: Facilitated diffusion via a group of integral proteins called GLUT (glucose transporter) proteins that shuttle glucose into the cytosol. Members of the GLUT protein family are present in specific tissues throughout the human body. Alternatively, secondary active transport moves glucose against its concentration gradient via a transmembrane symporter protein. The symporter uses the electrochemical energy from pumping an ion. Examples are the sodium-glucose linked transporters in the small intestine, heart, brain, and kidneys.

Under both aerobic (O₂ rich) and anaerobic (O₂ deficient) conditions, glycolysis can commence once glucose enters the cytosol of a cell. There are two main phases of glycolysis. The first phase is energy-requiring and is considered a preparatory step, trapping glucose in the cell and restructuring the six-carbon backbone so that it can be efficiently cleaved. The second phase is the pay-off phase, releasing energy and generating pyruvate.

Fate of Pyruvate

Depending on the oxygen level and 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 lack of 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.

Regulation of Glycolysis

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 substrate and products in the cell are near equilibrium. Consequently, the availability of the substrate determines the rate of the reaction. In enzyme-linked regulation, the concentration of substrate and products are far away from the equilibrium. The activity of the enzyme determines the rate of reaction, which controls the flux of the overall pathway. In glycolysis, the three regulatory enzymes are hexokinase, phosphofructokinase, and pyruvate kinase.