* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Chapter 16 Glycolysis Control of glycolytic pathway
Butyric acid wikipedia , lookup
Metalloprotein wikipedia , lookup
Fatty acid synthesis wikipedia , lookup
Enzyme inhibitor wikipedia , lookup
Photosynthesis wikipedia , lookup
Biochemical cascade wikipedia , lookup
Light-dependent reactions wikipedia , lookup
Nicotinamide adenine dinucleotide wikipedia , lookup
Photosynthetic reaction centre wikipedia , lookup
Microbial metabolism wikipedia , lookup
Lactate dehydrogenase wikipedia , lookup
Fatty acid metabolism wikipedia , lookup
Biosynthesis wikipedia , lookup
Amino acid synthesis wikipedia , lookup
Blood sugar level wikipedia , lookup
Evolution of metal ions in biological systems wikipedia , lookup
Oxidative phosphorylation wikipedia , lookup
Glyceroneogenesis wikipedia , lookup
Phosphorylation wikipedia , lookup
Adenosine triphosphate wikipedia , lookup
Citric acid cycle wikipedia , lookup
Chapter 16 Glycolysis Control of glycolytic pathway Oligosaccharides digestion Pancreatic and salivary α-amylase cleave the α-1, 4-bonds of starch and glycogen to yield maltose and maltotriose. Maltase and α-glucosidase complete the digestion of the diand trisaccharides into glucose. The molecule remaining after amylase digestion is limit dextrin, which is rich in α-1, 6-bonds. α-Dextrinase degrades the limit dextran. Sucrase hydrolyzes sucrose, whereas lactase cleaves lactose. Why is glucose such a prominent fuel in all life forms? 1. Glucose may have been available for primitive biochemical systems because it can form under prebiotic conditions. 2. Glucose is the most stable hexose. 3. Glucose has a low tendency to nonenzymatically glycosylate proteins. Glycolysis Glycolysis converts one molecule of glucose into two molecules of pyruvate with the generation of two molecules of ATP. Glycolysis can be thought of as occurring in two stages: 1. Stage 1 traps glucose in the cell and modifies it so that it can be cleaved into a pair of phosphorylated 3-carbon compounds. 2. Stage 2 oxidizes the 3-carbon compounds to pyruvate while generating two molecules of ATP. Formation of glucose-6-phosphate Upon entering the cell through a specific transport protein, glucose is phosphorylated at the expense of ATP to form glucose 6-phosphate. Hexokinase, which requires Mg2+ or Mn2+ as a cofactor, catalyzes the reaction. Hexokinase, like most kinases, employs substrate-binding induced fit to minimize hydrolysis of ATP. Generation of fructose 1,6-bisphophate The conversion of glucose 6-phosphate to fructose 6-phosphate is catalyzed by phosphoglucose isomerase. The reaction is readily reversible. Synthesis of fructose 1,6-bisphosphate The carbohydrate is trapped in the fructose form by the addition of a second phosphate to form fructose 1,-6 bisphosphate. This irreversible reaction is catalyzed by the allosteric enzyme phosphofructokinase (PFK). Cleavage of six carbon sugar into three carbon fragments The first phase of glycolysis ends with the cleavage of fructose 1,6-bisphosphate into dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (GAP). This readily reversible reaction is catalyzed by the enzyme aldolase. GAP can be processed to pyruvate to yield ATP, whereas DHAP cannot. The enzyme triose phosphate isomerase interconverts GAP and DHAP, allowing the DHAP to be further metabolized. Triose phosphate isomerase is the only glycolytic enzyme whose deficiency is lethal. Phase two of glycolysis begins when a compound with high phosphoryl transfer potential, 1, 3-bisphosphoglycerate, is generated by the oxidation of GAP in a reaction catalyzed by glyceraldehyde 3-phosphate dehydrogenase. The formation of glyceraldehyde 1,3-bisphosphate can be thought of as occurring in two steps: the highly exergonic oxidation of carbon 1 in GAP to an acid, and the highly endergonic formation of glyceraldehyde 1, 3-bisphosphate from the acid. These two reaction are linked by the formation of an energy-rich thioester in the active site of glyceraldehyde 3-phosphate dehydrogenase. Formation of ATP by phosphoryl transfer from 1,3bisphosphoglycerate 1, 3-Bisphosphoglycerate has a greater phosphoryl-transfer potential than ATP, and thus can be used to power the synthesis of ATP from ADP and Pi in a reaction catalyzed by phosphoglycerate kinase. Additional ATP is generated with the formation of pyruvate 3-Phosphoglycerate is converted into 2-phosphoglycerate by phosphoglycerate mutase. A dehydration reaction, catalyzed by enolase, results in the production of phosphoenolpyruvate (PEP). Phosphoenolpyruvate is a high phosphoryl-transfer compound because the presence of the phosphate traps the compound in the unstable enol tautomer. ADP is phosphorylated at the expense of PEP, generating ATP and pyruvate, in a reaction catalyzed by pyruvate kinase. Metabolism of pyruvate leads to the formation of two molecules of ATP The conversion of glucose into pyruvate generates ATP, but for ATP synthesis to continue, NADH must be reoxidized to NAD+. NAD+ can be regenerated by further oxidation of pyruvate to CO2, or by the formation of ethanol or lactate from pyruvate. Fermentations are ATP-generating pathways in which electrons are removed from one organic compound and passed to another organic compound. The formation of ethanol from pyruvate regenerates NAD+. Pyruvate decarboxylase requires the vitamin thiamine (B1). The regeneration of NAD+ by processing pyruvate to ethanol is called alcoholic fermentation. In lactic acid fermentation, pyruvate is reduced to lactate to regenerate NAD+. Obligate anaerobes cannot survive in the presence of O2. There are many more fermentations than just alcoholic and lactic acid fermentation. The Rossmann fold is an NAD+-binding domain common to many dehydrogenases. Fructose, from table sugar or high-fructose corn syrup, and galactose from milk sugar are converted into glycolytic intermediates. In the liver, fructose is metabolized by the fructose 1-phosphate pathway. In other tissues, such as adipose tissue, fructose is directly phosphorylated by hexokinase. Galactose is converted into glucose 6-phosphate by the galactose-glucose conversion pathway, which begins with the phosphorylation of galactose by galactokinase. The sum of the reactions of the galactose-glucose conversion pathway is: Glucose 1-phosphate can be converted into glucose 6-phosphate by phosphoglucomutase. Lactose intolerance or hypolactasia occurs because most adults lack lactase, the enzyme that degrades lactose. Northern Europeans have a mutation that prevents the decline of lactase activity after weaning. In lactase-deficient individuals, gut bacteria metabolize lactose, generating CH4 and H2, and disrupt water balance in the intestine. Enzymes catalyzing irreversible reactions in metabolic pathways are potential control sites. In glycolysis, these enzymes are 1. Hexokinase 2. Phosphofructokinase 3. Pyruvate kinase Phosphofructokinase is the key regulator of glycolysis in mammals. The enzyme is allosterically inhibited by ATP and allosterically stimulated by AMP. When ATP needs are great, adenylate kinase generates ATP from 2 ADP. AMP then becomes the signal for the low-energy state. Structure of phosphofructokinase A high level of ATP inhibits the enzyme by decreasing its affinity for fructose 6-phosphate Hexokinase is allosterically inhibited by glucose 6-phosphate. Pyruvate kinase is inhibited by the allosteric signals ATP and alanine, and stimulated by fructose 1, 6-bisphosphate, the product of the phosphofructokinase reaction. In muscle, glycolysis is regulated to meet the energy needs of contraction. At rest (left), glycolysis is not very active). The high concentration of ATP inhibits phosphofructokinase (PFK), pyruvate kinase, and hexokinase. Glucose 6-phosphate is converted into glycogen During exercise (right), the decrease in the ATP/AMP ratio resulting from muscle contraction activates phosphofructokinase and hence glycolysis. The flux down the pathway is increased, as represented by the thick arrows. Aerobic glycolysis Rapidly growing tumors obtain ATP by metabolizing glucose to lactate even in the presence of oxygen, a process termed aerobic glycolysis or the Warburg effect. When patients are infused with a nonmetabolizable analog of glucose, tumors are readily visualized by tomography.