Glycolysis - Glucose oxidation

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Glucose Oxidationmajor Pathway

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I. Glycolysis

Definition:Glycolysis means oxidation of glucose to give: Pyruvate (in the presence of oxygen) or, Lactate (in the absence of oxygen)

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Site:Cytoplasm of all tissue cells, but it is of physiological importance in: 1. Tissues with no mitochondria: mature RBCs, cornea and lens. 2. Tissues with few mitochondria: Testis, leucocytes, medulla of the kidney, retina, skin and gastrointestinal tract. 3. Tissues undergo frequent oxygen lack: skeletal muscles especially during exercise.

GlycolysisWhat are the possible fates of glucose?

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 1

glucose converted to glucose-6-PO4ATP is neededcatalyzed by hexokinase or glucokinase

Glycolysis Stage 1phosphoglucoisomerasealdose is converted to ketose

Glycolysis Stage 1rate limiting enzyme phosphofructokinaseinhibited by high ATP, citric acid, long-chain fatty acidsstimulated by ADP or AMP

Glycolysis

Glycolysis Stage 2six carbon molecule split into 2- 3 carbon moleculesaldose and ketose

Glycolysis Stage 3

Glycolysis Stage 3redox reactionenergy from redox used to form acyl phosphate

Glycolysis Stage 3Consists of two coupled processes

Glycolysis Stage 3formation of ATP substrate level phosphorylation

Glycolysis Stage 3phosphoryl shift uses 2,3 bisphosphoglycerate

Glycolysis

In the energy investment phase, ATP provides activation energy by phosphorylating glucose.This requires 2 ATP per glucose.In the energy payoff phase, ATP is produced by substrate-level phosphorylation and NAD+ is reduced to NADH.2 ATP (net) and 2 NADH are produced per glucose.

Energy Investment Phase

Energy-Payoff Phase

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+

Substrate level phosphorylation:

This means phosphorylation of ADP to ATP at the reaction itself .In glycolysis, there are 2 examples: - 1.3 Bisphosphoglycerate + ADP 3 Phosphoglycerate + ATP - Phospho-enol pyruvate + ADP Enolpyruvate + ATP.

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Special features of glycolysis in RBCs 1. Mature RBCs contain no mitochondria, thus: a) They depend only upon glycolysis for energy production (=2 ATP). b) Lactate is always the end product. 2. Glucose uptake by RBCs is independent on insulin hormone. 3. Reduction of met-hemoglobin: Glycolysis produces NADH+H+, which used for reduction of met-hemoglobin in red cells

Biological importance (functions) of glycolysis:

Energy production: a) anaerobic glycolysis gives 2 ATP. b) aerobic glycolysis gives 8 ATP.Provides important intermediates: a) Dihydroxyacetone phosphate: can give glycerol-3phosphate, which is used for synthesis of triacylglycerols and phospholipids (lipogenesis). b) 3 Phosphoglycerate: which can be used for synthesis of amino acid serine. c) Pyruvate: which can be used in synthesis of amino acid alanine.

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Aerobic glycolysis provides the mitochondria with pyruvate, which gives acetyl CoA Krebs' cycle.

GlycolysisHow can fructose be used for energy?

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

Glycolysis

GlycolysisWhat causes lactose intolerance?

Reversibility of glycolysis (Gluconeoqenesis): 1. Reversible reaction means that the same enzyme can catalyzes the reaction in both directions. 2. all reactions of glycolysis -except 3- are reversible. 3. The 3 irreversible reactions (those catalyzed by kinase enzymes) can be reversed by using other enzymes.Glucose-6-p Glucose F1, 6 Bisphosphate Fructose-6-pPyruvate Phosphoenol pyruvate 4. During fasting, glycolysis is reversed for synthesis of glucose from non- carbohydrate sources e.g. lactate. This mechanism is called: gluconeogenesis.

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Importance of lactate production in anerobic glycolysis:

1. In absence of oxygen, lactate is the end product of glycolysis:

2. In absence of oxygen, NADH + H+ is not oxidized by the respiratory chain.3. The conversion of pyruvate to lactate is the mechanism for regeneration of NAD+. 4. This helps continuity of glycolysis, as the generated NAD+ will be used once more for oxidation of another glucose molecule. Glucose Pyruvate Lactate

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What 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

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

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

Gluconeogenesis

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

Gluconeogenesis

G = -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

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