Glycolysis Gluconeogenesis

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  • Glycolysis and Gluconeogenesis

  • GlycolysisWhat is glycolysis?sequence of reactions that converts one molecule of glucose to two molecules of pyruvate with the formation of two ATP moleculesanaerobic

  • GlycolysisWhy is glucose such a commonly used fuel?tends to exist in ring form, very stable, doesnt generally glycosylate proteinsformed from formaldehyde under prebiotic conditions

  • GlycolysisWhat are the possible fates of glucose?

  • GlycolysisWhats the difference between a facultative anaerobe and an obligate anaerobe?Can you give an example of habitat-dependent anaerobiosis?What about activity-dependent anaerobiosis?

  • GlycolysisAll the intermediates in glycolysis have either 3 or 6 carbon atomsAll of the reactions fall into one of 5 categoriesphosphoryl transferphosphoryl shiftisomerizationdehydrationaldol cleavage

  • GlycolysisEntire reaction sequence may be divided into three stagesglucose is trapped and destabilizedsix carbon molecule is split into two three carbon moleculesATP is generated

  • Glycolysis Stage 1glucose converted to glucose-6-PO4ATP is neededcatalyzed by hexokinase or glucokinaseinduced fit G01= -4.0 kcal/mole

  • Glycolysis Stage 1phosphoglucoisomerasealdose is converted to ketoseG01=+0.4 kcal/mole

  • Glycolysis Stage 1rate limiting enzyme allostericinhibited by high ATP, citric acid, long-chain fatty acidsstimulated by ADP or AMPG01= - 3.4 kcal/mole

  • Glycolysis

  • Glycolysis Stage 2six carbon molecule split into 2- 3 carbon moleculesaldose and ketoseG01=+ 5.73 kcal/mole

  • Glycolysis Stage 3At equilibrium most mixture exists as dihydroxyacetone phosphateG01=+ 1.83 kcal/mole

  • Triose Phosphate Isomerase

  • Glycolysis Stage 3redox reactionenergy from redox used to form acyl phosphateG01= +1.5 kcal/mole

  • Glycolysis Stage 3Consists of two coupled processes

  • Glycolysis Stage 3formation of ATP substrate level phosphorylation

  • Glycolysis Stage 3phosphoryl shift uses 2,3 bisphosphoglycerate G01= +1.1 kcal/moledehydration G01 = +.44 kcal/molephosphoryl transfer G01 = -7.5 kcal/mole

  • Glycolysis

  • Fate of Pyruvate

  • Alcoholic FermentationWhich organisms carry out this process?yeastother microorganismsPDC requires thiamine pyrophosphate as coenzymeNAD+ is regenerated

  • Lactic Acid FermentationOccurs in muscle cells, microorganismsRegenerates NAD+

  • NAD+ and DehydrogenasesVarious dehydrogenases have a similar binding domain for NAD+ showing their common originRossman fold

  • GlycolysisHow can fructose be used for energy?

  • GlycolysisTo use galactose it must be converted to glucose-6-PO4

  • Glycolysis

  • GlycolysisWhat causes lactose intolerance?

  • GlycolysisWhat is galactosemia?inability to metabolize galactosemissing galactose 1-phosphate uridyl transferaseliver diseasedevelopment of cataractsCNS malfunction

  • Control of GlycolysisOf what value is glycolysis for cells?provides energy in form of ATPprovides building blocks for synthetic reactions

    Where are most control points found?enzymes that catalyze irreversible reactionshexokinasephosphofructokinasepyruvate kinase

  • PhosphofructokinaseMost important control point in mammalian glycolytic pathwayallosteric enzymeactivated by AMP and fructose 2,6 bisphosphateinhibited by high levels of ATP, citrate, fatty acids

  • Phosphofructokinase

  • HexokinaseHexokinase is inhibited by its product glucose-6-PO4glucose remains in bloodGlucokinase, an isozyme of hexokinase is not inhibited by glucose-6-PO4found in liverhas lower affinity for glucose

  • Pyruvate KinasePyruvate kinase exists as isozymesL form predominates in liverM form mostly in muscle and brainPK is an allosteric enzymeactivated by fructose 1,6 bisphosphateinhibited by ATP, alanineL form of PK influenced by covalent modificationinhibited by phosphorylation

  • Pyruvate Kinase

  • Glucose TransportWhat is the role of glucose transporters in animal cells?facilitate movement of glucose across cell membraneWhat kind of molecule is a transporter and where is it located?small protein embedded in plasma membrane

  • Glucose Transportmammalian glucose transporter

  • Glucose Transport

  • Glycolysis and CancerWhy are rapidly growing tumor cells dependent upon glycolysis?insufficient oxygen supplyWhat is the function of HIF-1?hypoxia-inducible transcription factor stimulates synthesis of many glycolytic enzymes and GLUT-1 and 3also stimulates vascular endothelial growth factor

  • GluconeogenesisWhat is gluconeogenesis?synthesis of glucose from non-carbohydrate precursorsWhy is this an important pathway?What are some of the major precursors?lactate, amino acids, glycerolWhere does this process occur?liver, kidney

  • GluconeogenesisIf gluconeogenesis involves the conversion of pyruvate to glucose why is it not simply the reverse of glycolysis?glycolysis contains several irreversible reactionsWhich reactions in glycolysis are irreversible?phosphoenolpyruvate to pyruvatefructose 6-phosphate to fructose 1,6-bisphosphateglucose to glucose 6-phosphate

  • GluconeogenesisWhat is the first reaction?

  • GluconeogenesisWhy is pyruvate carboxylase of special interest?structural propertiescontains ATP-grasp domain at N-terminal endcontains biotin-binding domain at C-terminal end

  • GluconeogenesisWhat is the role of biotin in this reaction?prosthetic group lined to -amino group of lysine residuecarrier of activated carbon dioxide

  • GluconeogenesisPyruvate carboxylase is an allosteric enzymeactivated by acetyl CoAneeded to form carboxybiotin

  • GluconeogenesisCarboxylation of pyruvate occurs in the mitocondria but next step in reaction sequence occurs in cytosol

  • GluconeogenesisDecarboxylation of oxaloacetate is coupled withphosphorylation by GTPenzyme is phosphoenolpyruvate carboxykinase

  • GluconeogenesisWhich other steps in glycolysis are irreversible?conversion of fructose 1,6-bisphosphate to fructose 6-phosphateconversion of glucose 6-phosphate to glucose

  • GluconeogenesisG = -16.7 kJ mol-1fructose-1,6-bisphosphatase is an allosteric enzyme, inhibited by AMP and activated by ATP

  • GluconeogenesisEnzyme that catalyzes last reaction not found in all tissuesliver and kidney cortex

  • GluconeogenesisIs gluconeogenesis an energetically favorable reaction in the cell?

    What drives this reaction?

    Are glycolysis and gluconeogenesis active at the same time?

  • Regulation of Glycolysis and GluconeogenesisWhat are some of the factors that ensure the reciprocal regulation of these processes?allosteric regulators of key enzymesenergy chargefructose 2,6-bisphosphatehormones

  • Regulation of Glycolysis and Gluconeogenesis

  • Regulation of Glycolysis and Gluconeogenesisfructose 2,6-bisphosphate stimulates PFK and inhibits fructose 1,6-bisphosphasecontrolled by insulin and glucagon and reflects the nutritional status of the cell

  • Regulation of Glycolysis and GluconeogenesisHow do hormones influence the enzymes associated with these processes?influence gene expressionchange transcription rateinfluence degradation of m-RNAinsulin PFK, PKglucagon PEPCK, fructose 1,6-bisphosphatase

  • Regulation of Glycolysis and GluconeogenesisWhat are substrate cycles and why are they important?can amplify metabolic signalscan generate heat

  • Regulation of Glycolysis and GluconeogenesisWhat is the Cori cycle and why is it important?

  • Regulation of Glycolysis and Gluconeogenesis