Glycolysis Lecture

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MetabolismGlcolysisFates of Glucose

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Eduard Buchner (1860-1917)1897 found fermentation inbroken yeast cells1907 Nobel Prize in Chemistry

The whole pathway in yeast and muscle cell were elucidated by

Arthur Harden1865-1940

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7GlycolysisGlycolysis is an almost universal central pathway of glucose catabolism, the pathway with the largest flux of carbon in most cells.In some mammalian tissues (erythrocytes, renal medulla, brain, sperm), the glycolytic breakdown of glucose is the sole source of metabolic energy.GlycolysisSome of the starch-storing tissues, like potato tubers, and some aquatic plants derive most of their energy from glycolysis.Many anaerobic microorganisms are entirely dependent on glycolysis.1. phosphorylation of glucose

102. Isomerization of glucose 6-phosphate

11Phosphohexose isomerase reaction

by an active-site His residueGlu3. Phosphorylation of fructose 6-phosphate: the first committed step in glycolysis

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PFK-1 is named so because there is another enzyme catalyzes a similar reaction14In some bacteria, protists and (all) plants, a pyrophosphate-dependent phosphofructokinase (PFP) also catalyzes this reaction in a reversible way

154. Cleavage of fructose 1,6-bisphosphate

16Class I aldolases form Schiff base intermediate during sugar cleavage reactionClass I aldolases were found in animals and plants.Class II aldolases (fungi and bacteria) do not form the Schiff base and require a zinc ion to catalyze reaction.

5. Interconversion of the triose phosphate

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Dihydroxyacetone phosphate and glyceraldehyde 3-phosphate become indistinguishable after triose phosphate isomerase reaction196. Oxidation of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate

20The glyceraldehyde 3-phosphate dehydrogenase reaction

hemiacetalHeavy metal ion such as Hg2+ will react with Cys residue, hence irreversibly inhibits the enzyme.217. Phosphoryl transfer from 1,3-bisphosphoglycerate to ADP

Glyceraldehyde 3-phosphate dehydrogenase and Phosphoglycerate kinase are coupled in vivoGlyceraldehyde 3-phosphate dehydrogenase catalyzes an endergonic reaction while phosphoglycerate kinase catalyzes an exergonic reaction.When these two reactions are coupled (which happens in vivo), the overall reaction is exergonic.Substrate-level phosphorylationsoluble enzymeschemical intermediates

Respiration-linked phosphorylationPhotophosphorylationmembrane-bound enzymestransmembrane gradients of protonsThe formation of ATP by phosphoryl group transfer from a substrate is referred to as a substrate-level phosphorylation8. Conversion of 3-phosphoglycerate to 2-phosphoglycerate

The phosphoglycerate mutase reaction262,3-Bisphosphoglycerate (BPG)The concentration of BPG is usually low in most of the tissues except erythrocytes (up to 5 mM).Function of BPG in erythrocytes is to regulate the affinity of hemoglobulin to O2.

279. Dehydration of 2-phosphoglycerate to phosphoenolpyruvate

10. Transfer of the phosphoryl group from phosphoenolpyruvate to ADP

Glucose + 2ATP + 2NAD+ + 4ADP + 2Pi 2 pyruvate + 2ADP + 2NADH + 2H+ + 4ATP + 2H2O

Glucose + 2ADP + 2NAD+ + 2Pi 2 pyruvate + 2ATP + 2NADH + 2H+

NADHmitochondriaATP

NAD+ (nicotinamide adenine dinucleotide) is the active form of niacin

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Niacin is the common name for nicotinamide and nicotinic acid.Nicotinic acid is the common precursor for NAD+ and NADP+ biosynthesis in cytosol.Niacin

Functions of NAD+ and NADP+Both NAD+ and NADP+ are coenzymes for many dehydrogenases in cytosol and mitochondriaNAD+ is involved in oxidoreduction reactions in oxidative pathways.NADP+ is involved mostly in reductive biosynthesis.

Weight loss, digestive disorders, dermatitis, dementiaNiacin deficiency: pellagraNiacin deficiencyBecause niacin is present in most of the food and NAD+ can also be produced from tryptophan (60 grams of trptophan 1 gram of NAD+), so it is not often to observe niacin deficiency.However, niacin deficiency can still be observed in areas where maize is the main carbohydrate source because maize only contain niacytin, a bound unavailable form of niacin. Pre-treated maize with base will release the niacin from niacytin.Niacin deficiencyAreas where sorghum is the main carbohydrate source will also observe niacin deficiency if niacin uptake is not being watched carefully.Sorghum contains large amount of leucine, which will inhibit quinolinate phosphoribosyl transferase (QPRT), an enzyme involved in NAD+ biosynthesis from tryptophan.Vitamin B6 deficiency can also lead to niacin deficiency because pyridoxal phosphate is a coenzyme in NAD+ biosynthesis from tryptophan.

ISONIAZIDA Commonly Used Medication

for HIV & AIDS Patients

Drug:ISONIAZIDClassification:AntimycobacterialIndication:Infection with, or disease from, mycobacterium tuberculosis

Feeder pathways for glycolysis41Glycogen and starch are degraded by phosphorolysisGlycogen and starch can be mobilized for use by a phosphorolytic reaction catalyzed by glycogen/starch phosphorylase. This enzyme catalyze an attack by Pi on the (a14) glycosidic linkage from the nonreducing end, generating glucose 1-phosphate and a polymer one glucose unit shorter.

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Branch point (a16) is removed by debranching enzymeGlucose 1-phosphate is converted to G-6-P by phosphoglucomutase by the same mechanism observed in phosphoglycerate mutase reaction

Digestion of dietary polysaccharidesDigestion begins in the mouth with salivary a-amylase hydrolyze (attacking by water) the internal glycosidic linkages.Salivary a-amylase is then inactivated by gastric juice; however pancreatic a-amylase will take its place at small intestine.The products are maltose, maltotriose, and limit dextrins (fragments of amylopectin containing a16 branch points.Digestion of dietary disaccharidesDisaccharides must be hydrolyzed to monosaccharides before entering cells.Dextrin + nH2O n D-glucoseMaltose + H2O 2 D-glucoseLactose + H2O D-galactose + D-glucoseSucrose + H2O D-fructose + D-glucoseTrehalose + H2O 2 D-glucosedextrinasemaltaselactasesucrasetrehalase

Lactose intoleranceLactose intolerance is due to the disappearance after childhood of most or all of the lactase activity of the intestinal cells.48Lactose intoleranceUndigested lactose will be converted to toxic products by bacteria in large intestine, causing abdominal cramps and diarrhea.

Fructose metabolism in muscle and kidneyFructose metabolism in liver

In liver, the enzyme fructokinasecatalyze the phosphorylation of fructose to form fructose 1-phosphate.Triose phosphate isomerase

Galactose metabolismGalactose is phosphorylated by galactokinase in the liver.Then galactose 1-phosphate is converted to glucose 1-phosphate by a series of reactions.

Galactose metabolismThe conversion of galactose 1-P to glucose 1-P (epimerization) requires uridine diphosphate (UDP) as a coenzyme-like carrier of hexose groups.53Galactosemia inability to metabolize galactose due to lack of1. UDP-glucose galactose 1-phosphate uridylyltransferase (classical galactosemia)2. UDP-glucose 4-epimerase3. GalactokinaseAmong these, deficiency of either 1 or 2 is more severe (1 is the most severe).

GalactosemiaDeficiency of transferase (or epimerase) will result in poor growth, speech abnormality, mental deficiency, and (fatal) liver damage even when galactose is withheld from the diet.

Galactosemia patients develop cataracts by deposition of galactitol in the lens

Mannose + ATP mannose 6-phosphate hexokinase+ADPmannose 6-phosphate fructose 6-phosphate phosphomannose isomeraseMannose metabolismFermentationFermentation is referring to the process when no oxygen is consumed or no change in the concentration of NAD+ or NADH during energy extraction.FermentationUnder hypoxic conditions, oxidative phosphorylation will be the first to stop. Then citric acid cycle will come to a halt due to inhibition effect from NADH. As a result, glycolysis will be the only metabolic pathway that is available to energy production during hypoxia.

FermenationHowever, the oxidation of glyceraldehyde 3-phosphate consumes NAD+ that will not be regenerated under hypoxic condition because oxidative phosphorylation is not available.

The purpose of fermentation is to regenerate NAD+In order to continue regenerating NAD+, cells come up a strategy. During fermentation, NAD+ is regenerated during the reduction of pyruvate, the product of glycolysis.

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Lactate fermentationglycolysis62

Lactate is recycled in the liver (Cori cycle)

Carl and Gerty Cori, 1947 Nobel Prize in Physiology and MedicineLactate fermentation only happened in larger animalsMost small vertebrates and moderate size running animals have circulatory systems that can carry oxygen to their muscles fast enough to avoid having to use muscle glycogen anaerobically.

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http://www.mountain-research.org/CV/coelacanth.jpg

http://www.anac.8m.net/Images/coelacanth.jpgDeep sea fish (below 4,000 m or more) coelacanth uses anaerobic metabolism exclusively. The lactate produced is excreted directly. Some marine vertebrates can do ethanol fermentation.Ethanol fermentationYeast and other microorganisms ferment glucose to ethanol and CO2.Pyruvate is first decarboxylated by pyruvate decarboxylase, which is absent in vertebrate tissues and in other organisms that carry out lactic acid fermentation. Acetaldehyde is the product of this reaction.

67Pyruvate decarboxylaseThe decarboxylation of pyruvate by pyruvate decarboxylase produces CO2, which is the reason why champagne is bubbling.

Thiamine pyrophosphate (TPP) is the coenzyme of pyruvate decarboxylaseThiamine pyrophosphate is derived from vitamin B1 (th