Гликолиз: Биохимический путь преобразования глюкозы

Series of interconnected biochemical reactionsGlycolysis is the metabolic pathway that converts glucose (|C6H12O6) into pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The free energy released in this process is used to form the high energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes. The wide occurrence of glycolysis in other species indicates that it is an ancient metabolic pathway. Indeed, the reactions that make up glycolysis and its parallel pathway, the pentose phosphate pathway, can occur in the oxygen free conditions of the Archean oceans, also in the absence of enzymes, catalyzed by metal ions, meaning this is a plausible prebiotic pathway for abiogenesis. The most common type of glycolysis is the Embden–Meyerhof–Parnas (EMP) pathway, which was discovered by Gustav Embden, Otto Meyerhof, and Jakub Karol Parnas. Glycolysis also refers to other pathways, such as the Entner–Doudoroff pathway and various heterofermentative and homofermentative pathways. However, the discussion here will be limited to the Embden–Meyerhof–Parnas pathway. The glycolysis pathway can be separated into two phases:
Investment phase – wherein ATP is consumed
Yield phase – wherein more ATP is produced than originally consumed

The existence of more than one point of regulation indicates that intermediates between those points enter and leave the glycolysis pathway by other processes. For example, in the first regulated step, hexokinase converts glucose into glucose 6 phosphate. Instead of continuing through the glycolysis pathway, this intermediate can be converted into glucose storage molecules, such as glycogen or starch. The reverse reaction, breaking down, e. g., glycogen, produces mainly glucose 6 phosphate; very little free glucose is formed in the reaction. The glucose 6 phosphate so produced can enter glycolysis after the first control point. In the second regulated step (the third step of glycolysis), phosphofructokinase converts fructose 6 phosphate into fructose 1,6 bisphosphate, which then is converted into glyceraldehyde 3 phosphate and dihydroxyacetone phosphate. The dihydroxyacetone phosphate can be removed from glycolysis by conversion into glycerol 3 phosphate, which can be used to form triglycerides. Conversely, triglycerides can be broken down into fatty acids and glycerol; the latter, in turn, can be converted into dihydroxyacetone phosphate, which can enter glycolysis after the second control point.

All cells contain the enzyme hexokinase, which catalyzes the conversion of glucose that has entered the cell into glucose 6 phosphate (G6P). Since the cell membrane is impervious to G6P, hexokinase essentially acts to transport glucose into the cells from which it can then no longer escape. Hexokinase is inhibited by high levels of G6P in the cell. Thus the rate of entry of glucose into cells partially depends on how fast G6P can be disposed of by glycolysis, and by glycogen synthesis (in the cells which store glycogen, namely liver and muscles). Glucokinase, unlike hexokinase, is not inhibited by G6P. It occurs in liver cells, and will only phosphorylate the glucose entering the cell to form glucose 6 phosphate (G6P), when the glucose in the blood is abundant. This being the first step in the glycolytic pathway in the liver, it therefore imparts an additional layer of control of the glycolytic pathway in this organ. but the concentration of ATP does not change more than about 10% under physiological conditions, whereas a 10% drop in ATP results in a 6 fold increase in AMP. Thus, the relevance of ATP as an allosteric effector is questionable. An increase in AMP is a consequence of a decrease in energy charge in the cell. Citrate inhibits phosphofructokinase when tested in vitro by enhancing the inhibitory effect of ATP. However, it is doubtful that this is a meaningful effect in vivo, because citrate in the cytosol is utilized mainly for conversion to acetyl CoA for fatty acid and cholesterol synthesis. TIGAR, a p53 induced enzyme, is responsible for the regulation of phosphofructokinase and acts to protect against oxidative stress. TIGAR is a single enzyme with dual function that regulates F2,6BP. It can behave as a phosphatase (fructuose 2,6 bisphosphatase) which cleaves the phosphate at carbon 2 producing F6P. It can also behave as a kinase (PFK2) adding a phosphate onto carbon 2 of F6P which produces F2,6BP. In humans, the TIGAR protein is encoded by C12orf5 gene. The TIGAR enzyme will hinder the forward progression of glycolysis, by creating a build up of fructose 6 phosphate (F6P) which is isomerized into glucose 6 phosphate (G6P). The accumulation of G6P will shunt carbons into the pentose phosphate pathway.

Glycolytic mutations are generally rare due to importance of the metabolic pathway; the majority of occurring mutations result in an inability of the cell to respire, and therefore cause the death of the cell at an early stage. However, some mutations (glycogen storage diseases and other inborn errors of carbohydrate metabolism) are seen with one notable example being pyruvate kinase deficiency, leading to chronic hemolytic anemia.

Malignant tumor cells perform glycolysis at a rate that is ten times faster than their noncancerous tissue counterparts. During their genesis, limited capillary support often results in hypoxia (decreased O2 supply) within the tumor cells. Thus, these cells rely on anaerobic metabolic processes such as glycolysis for ATP (adenosine triphosphate). Some tumor cells overexpress specific glycolytic enzymes which result in higher rates of glycolysis. Often these enzymes are Isoenzymes, of traditional glycolysis enzymes, that vary in their susceptibility to traditional feedback inhibition. The increase in glycolytic activity ultimately counteracts the effects of hypoxia by generating sufficient ATP from this anaerobic pathway. This phenomenon was first described in 1930 by Otto Warburg and is referred to as the Warburg effect. The Warburg hypothesis claims that cancer is primarily caused by dysfunctionality in mitochondrial metabolism, rather than because of the uncontrolled growth of cells. A number of theories have been advanced to explain the Warburg effect. One such theory suggests that the increased glycolysis is a normal protective process of the body and that malignant change could be primarily caused by energy metabolism. This high glycolysis rate has important medical applications, as high aerobic glycolysis by malignant tumors is utilized clinically to diagnose and monitor treatment responses of cancers by imaging uptake of 2 18F 2 deoxyglucose (FDG) (a radioactive modified hexokinase substrate) with positron emission tomography (PET). There is ongoing research to affect mitochondrial metabolism and treat cancer by reducing glycolysis and thus starving cancerous cells in various new ways, including a ketogenic diet.

The diagram below shows human protein names. Names in other organisms may be different and the number of isozymes (such as HK1, HK2, ) is likely to be different too.

The intermediates of glycolysis depicted in Fischer projections show the chemical changing step by step. Such image can be compared to polygonal model representation. Another comparation of Fischer projections and Poligonal Model in glycolysis is shown in a video. Video animations in the same channel in YouTube can be seen for another metabolic pathway (Krebs Cycle) and the representation and applying of Polygonal Model in Organic Chemistry