Download - Glycolysis Lecture
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Eduard Buchner (1860-1917)1897 found fermentation inbroken yeast cells1907 Nobel Prize in Chemistry
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The whole pathway in yeast and muscle cell were elucidated by
Arthur Harden1865-1940
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Glycolysis
• Glycolysis 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.
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Glycolysis
• Some 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.
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1. phosphorylation of glucose
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2. Isomerization of glucose 6-phosphate
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Phosphohexose isomerase reaction
by an active-site His residue
Glu
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3. 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 reaction
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In some bacteria, protists and (all) plants, a pyrophosphate-dependent phosphofructokinase (PFP) also catalyzes this reaction in a reversible way
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4. Cleavage of fructose 1,6-bisphosphate
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Class I aldolases form Schiff base intermediate during sugar cleavage reaction
• Class 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.
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5. Interconversion of the triose phosphate
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Dihydroxyacetone phosphate and glyceraldehyde 3-phosphate become
indistinguishable after triose phosphate isomerase reaction
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6. Oxidation of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate
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The glyceraldehyde 3-phosphate dehydrogenase reaction
hemiacetal
Heavy metal ion such as Hg2+ will react with Cys residue, hence irreversibly inhibits the enzyme.
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7. Phosphoryl transfer from 1,3-bisphosphoglycerate to ADP
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Glyceraldehyde 3-phosphate dehydrogenase and Phosphoglycerate
kinase are coupled in vivo• Glyceraldehyde 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.
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Substrate-level phosphorylationsoluble enzymeschemical intermediates
Respiration-linked phosphorylationPhotophosphorylation
membrane-bound enzymestransmembrane gradients of protons
The formation of ATP by phosphoryl group transfer from a substrate is referred to as a
substrate-level phosphorylation
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8. Conversion of 3-phosphoglycerate to 2-
phosphoglycerate
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The phosphoglycerate mutase reaction
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2,3-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.
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9. Dehydration of 2-phosphoglycerate to
phosphoenolpyruvate
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10. Transfer of the phosphoryl group from phosphoenolpyruvate
to ADP
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Glucose + 2ATP + 2NAD+ + 4ADP + 2Pi 2 pyruvate + 2ADP + 2NADH + 2H+ +
4ATP + 2H2O
Glucose + 2ADP + 2NAD+ + 2Pi 2 pyruvate + 2ATP + 2NADH + 2H+
在有氧狀況下,產生的 NADH很快就被送到mitochondria中用來合成 ATP
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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
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Functions of NAD+ and NADP+
• Both NAD+ and NADP+ are coenzymes for many dehydrogenases in cytosol and mitochondria
• NAD+ is involved in oxidoreduction reactions in oxidative pathways.
• NADP+ is involved mostly in reductive biosynthesis.
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Weight loss, digestive disorders, dermatitis, dementia
Niacin deficiency: pellagra
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Niacin deficiency
• Because 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.
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Niacin deficiency
• Areas 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.
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ISONIAZIDA Commonly Used Medication
for HIV & AIDS Patients
Drug: ISONIAZID
Classification: Antimycobacterial
Indication: Infection with, or disease from, mycobacterium tuberculosis
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Feeder pathways for glycolysis
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Glycogen and starch are degraded by phosphorolysis
• Glycogen 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 enzyme
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Glucose 1-phosphate is converted to G-6-P by phosphoglucomutase by the same mechanism observed in phosphoglycerate mutase reaction
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Digestion of dietary polysaccharides
• Digestion 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.
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Digestion of dietary disaccharides
• Disaccharides must be hydrolyzed to monosaccharides before entering cells.
• Dextrin + nH2O n D-glucose
• Maltose + H2O 2 D-glucose
• Lactose + H2O D-galactose + D-glucose
• Sucrose + H2O D-fructose + D-glucose
• Trehalose + H2O 2 D-glucose
dextrinase
maltase
lactase
sucrase
trehalase
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Lactose intolerance
• Lactose intolerance is due to the disappearance after childhood of most or all of the lactase activity of the intestinal cells.
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Lactose intolerance
• Undigested lactose will be converted to toxic products by bacteria in large intestine, causing abdominal cramps and diarrhea.
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Fructose metabolism in muscle and kidney
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Fructose metabolism in liver
• In liver, the enzyme fructokinase
catalyze the phosphorylation of fructose to form fructose 1-phosphate.
Triose phosphate isomerase
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Galactose metabolism
• Galactose is phosphorylated by galactokinase in the liver.
• Then galactose 1-phosphate is converted to glucose 1-phosphate by a series of reactions.
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Galactose metabolism
• The conversion of galactose 1-P to glucose 1-P (epimerization) requires uridine diphosphate (UDP) as a coenzyme-like carrier of hexose groups.
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Galactosemia
inability to metabolize galactose due to lack of1. UDP-glucose galactose 1-phosphate uridylyltransferase (classical galactosemia)2. UDP-glucose 4-epimerase3. Galactokinase
Among these, deficiency of either 1 or 2 is more severe (1 is the most severe).
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Galactosemia
• Deficiency 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.
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Galactosemia patients develop cataracts by deposition of galactitol in the lens
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Mannose + ATP mannose 6-phosphate hexokinase +ADP
mannose 6-phosphate fructose 6-phosphate phosphomannose isomerase
Mannose metabolism
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Fermentation
• Fermentation is referring to the process when no oxygen is consumed or no change in the concentration of NAD+ or NADH during energy extraction.
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Fermentation
• Under 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.
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Fermenation
• However, the oxidation of glyceraldehyde 3-phosphate consumes NAD+ that will not be regenerated under hypoxic condition because oxidative phosphorylation is not available.
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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 fermentation
glycolysis
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Lactate is recycled in the liver (Cori cycle)
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Carl and Gerty Cori, 1947 Nobel Prize in Physiology and Medicine
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Lactate fermentation only happened in larger animals
• Most 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.jpg
Deep 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.
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Ethanol fermentation
• Yeast 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.
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Pyruvate decarboxylase
• The decarboxylation of pyruvate by pyruvate decarboxylase produces CO2, which is the reason why champagne is bubbling.
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Thiamine pyrophosphate (TPP) is the coenzyme of pyruvate decarboxylase
• Thiamine pyrophosphate is derived from vitamin B1 (thiamine).
• Lack of vitamine B1 will lead to beriberi (edema, pain, paralysis, death).
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TPP plays an important role in the cleavage of bonds adjacent to a carbonyl group.
• The thiazolium ring of TPP acts as an “electron sink” to facilitates decarboxylation reaction.
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Alcohol dehydrogenase catalyze the second step of ethanol fermentation
• Alcohol dehydrogeanse reduces acetaldehyde, producing NAD+ and ethanol.
• This enzyme is present in many organisms that metabolize ethanol, including human.
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Fermentation has commercial values
• Bacteria like Lactobacillus bulgaricus (yogurt) and Propionibacterium freudenreichii (swiss cheese) ferments milk to produce lactic acid or propionic acid and CO2.
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Dr. Chaim Weizmann1874-1952First President of IsraelFound butanol and acetonefermentation in Clostridium acetobutyricum
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Industrial fermentation is done in huge close vats
• Fermentors are huge closed vats in which temperature and access to air are adjusted to favor the multiplication of the desired microorganism.
• Some even immobilize the cells in an inert support so no effort is required to separate microorganisms from products after fermentation is completed.
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