Evaluación de la calidad del problema

Glycolysis in Cancer Cells

Glucose is a very important energy source for the human body, and the body can use many sources for producing glucose. Glucose is a monosaccharide which can be generated from the hydrolysis of polysaccharides and disaccharides, such as starch and lactose. In some tissues, such as brain cells, glucose is the only available energy source, under non-starvation conditions. Glucose can also be synthesized from non-carbohydrate precursors, such as lactate, amino acids and glycerol. The formation of glucose from other non-cabohydrate carbon substrates, such as glycerol, lactate and glucogenic amino acides is called gluconeogenesis. The gluconeogenic pathway occuring in mitochondrial and cytosol, converts pyruvate into glucose. Gluconeogenesis is not simply the reverse process of glycolysis, as it takes two steps to convert pyruvate into PEP. The first step is the carboxylation of pyruvate to generate oxaloacetate catalyzed by pyruvate carboxylase at an expense of one molecule of ATP. The second step is under the function of phosphoenolpyruvate carboxykinase to generate PEP from oxaloacetat at the expense of one molecule of GTP.

Glycolysis is the metabolic process for cells to catalyze one molecule of glucose to produce two molecules of pyruvate, with a net energy production of two molecules of ATP. There are 10 reaction steps in this process carried out by 10 distinct enzymes. In mammals, glucose is first taken into cells with a family of glucose transporters (GLUT).

The sequence of glucose transporters is 500 amino acids long and consists of 12 transmembrane α helices. There are five members of GLUT family presented in specific tissues. GLUT1 and GLUT3 are responsible for controlling basal glucose uptake. GLUT2 exists in liver and pancreatic β cells to control glucose uptake from the blood with a very high Km value. GLUT4 is present in muscle and fat cells. GLUT5 exists in the small intestine. Once glucose is transported into the cells through GLUT, hexokinase, the first enzyme in the glycolysis process, phosphorylates glucose to form glucose 6-phosphate. Once phosphorylated, glucose 6-phosphate can not diffuse through the cell membrane and is trapped in the cytosol. Glucose 6-phosphate is further converted into fructose-6- phosphate through the function of phosphoglucose isomerase. In the next stage, the six- carbon fructose is cleaved by aldolase to generate two molecules of three-carbon fructose, glyceraldehyde 3-phosphate (GAP) and dihydroxyacerone phosphate (DHAP). GAP is the only form of the two, three-carbon molecules that can be used in the glycolysis process. Triose phosphate isomerase converts one molecule of DHAP into one molecule of GAP. Next, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) catalyzes the formation of 1,3-bisphosphoglycerate (1,3-BPG) from GAP with the production of NADH. In this step, phosphorylation is coupled to the oxidation of three-carbon molecules. 1,3-BPG is an acyl phosphate, which has a high phosphoryl-transfer potential. The phosphate is transferred to ADP in the next step under the catalytic function of phsophglycerate kinase with the production of ATP. In the next step, the phosphoryl group is shifted with the conversion of 3-phosphoglycerate to 2-phosphoglycerate by phosphoglycerate mutase. Enolase catalyzes the conversion from 2-phosphoglycerate to phosphoenolpyruvate (PEP) with the formation of an enol in PEP and the production of a

molecule of H2O. The enol phosphate in PEP has a high potential to transfer phosphate. In the final step, pyruvate kinase catalyzes this reaction and a phosphate is transferred to ADP with the production of a molecule of ATP committed with the formation of pyruvate.

The fates of pyruvate are diverse in different living organisms. In yeast and some other microorganisms, pyruvate is converted into ethanol catalyzed by pyruvate decarboxylase. In mammalian cells pyruvate is catalyzed into lactate by lactate dehydrogenase when oxygen is lacking. Most pyruvate produced in the glycolysis process enters into the citric acid cycle and the electron-transport chain in mitochondria to generate energy needed for higher organisms.

The pace of glycolysis is tightly regulated by the catalytic enzymes. Three glycolytic enzymes, which catalyze these irreversible glycolytic reactions, are involved in the regulatory process; they are hexokinase, phosphofructokinase and pyruvate kinase (Weber, Convery et al. 1966). Among these three enzymes, phosphofructokinase is the predominant regulator in the glycolytic pathway whose enzymatic activity is tightly controlled by the ATP/AMP ratio in mammalian cells. Phosphofrucokinase catalyzes the third step in the glycolysis process, which is the conversion from fuctose 6-phosphate to fructose-1,6-bisphosphate (FBP). During this process, fructose 2,6-bisphosphate formed from the phosphorylation of fructose 6-phosphate by phosphofuctokinase 2, regulates the activity of phosphofuctokinase. Fructose 2,6-bisphosphate activates phosphofructoskinase by increasing the affinity for fructose 6-phosphate as well as decreasing the ATP inhibitory effect to phosphofructokinase. Meanwhile, as an important regulator in the glycolytic pathway, the concentration of fructose 2,6-bisphosphate is

tightly controlled by its phosphorylation status. Fructose 2,6-bisphosphate can be dephosphorylated by fructose bisphosphatase 2 (FBPase 2). Phosphofuctokinase 2 and FBPase 2 are in a single peptide chain as a bi-functional enzyme. This bi-functional enzyme has five isoforms presenting as tissue specific. Overexpression of fructose 2,6- bisphosphatase decreases glycolysis flux and delays cell cycle progression (Perez, Roig et al. 2000).

Hexokinase is the second control element for the glycolytic pathway and it phosphorylates glucose to phospholate-6-glucose in the first step of the glycolysis process. Hexokinase activity is inhibited by its catalytic product, phospholate-6-glucose. Under these circumstances in which cells have enough energy production or high sources for macromolecule biosynthesis, phospholate-6-glucose will pass these signals to decrease the glycolysis process. In livers hexokinase has another isozyme, glycokinase, whose affinity to glucose is 50 folds lower than that of hexokinase. The function of glycokinase in liver is to provide phospholate-6-glucose for glycogen synthesis as well as fatty acid synthesis.