MT201 CH14 glycolysis

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MT201 CH14 glycolysis Powered By Docstoc
					Eduard Buchner
1897 found fermentation in
broken yeast cells
1907 Nobel Prize in Chemistry
The whole pathway in yeast and
muscle cell were elucidated by

     Arthur Harden
• 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.
• 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.
1. phosphorylation of glucose
2. Isomerization of glucose 6-
  Phosphohexose isomerase reaction

          by an active-site His residue

 3. Phosphorylation of fructose 6-
phosphate: the first committed step
           in glycolysis
PFK-1 is named so because there
 is another enzyme catalyzes a
        similar reaction
In some bacteria, protists and (all) plants,
a pyrophosphate-dependent
phosphofructokinase (PFP) also
catalyzes this reaction in a reversible
4. Cleavage of fructose 1,6-
     Class I aldolases form Schiff base
intermediate during sugar cleavage reaction

                        • Class I aldolases were
                          found in animals and
                        • Class II aldolases
                          (fungi and bacteria) do
                          not form the Schiff
                          base and require a zinc
                          ion to catalyze
5. Interconversion of the triose
   Dihydroxyacetone phosphate and
 glyceraldehyde 3-phosphate become
indistinguishable after triose phosphate
          isomerase reaction
  6. Oxidation of glyceraldehyde 3-
phosphate to 1,3-bisphosphoglycerate
       The glyceraldehyde 3-phosphate
           dehydrogenase reaction

Heavy metal ion
such as Hg2+ will
react with Cys
residue, hence
inhibits the          hemiacetal
7. Phosphoryl transfer from 1,3-
  bisphosphoglycerate to ADP
      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.
The formation of ATP by phosphoryl group
 transfer from a substrate is referred to as a
       substrate-level phosphorylation

Substrate-level phosphorylation
     soluble enzymes
     chemical intermediates

Respiration-linked phosphorylation
     membrane-bound enzymes
     transmembrane gradients of protons
 8. Conversion of 3-
phosphoglycerate to 2-
The phosphoglycerate mutase
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.
9. Dehydration of 2-
 phosphoglycerate to
 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+

  NAD+ (nicotinamide adenine
dinucleotide) is the active form of
   • Niacin is the common
     name for nicotinamide
     and nicotinic acid.
   • Nicotinic acid is the
     common precursor for
     NAD+ and NADP+
     biosynthesis in cytosol.
 Functions of   NAD+    and   NADP+

• Both NAD+ and NADP+ are coenzymes for
  many dehydrogenases in cytosol and
• NAD+ is involved in oxidoreduction
  reactions in oxidative pathways.
• NADP+ is involved mostly in reductive
 Niacin deficiency: pellagra

Weight loss, digestive disorders, dermatitis, dementia
            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
            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.
                               A Commonly Used Medication

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Drug:             ISONIAZID

Classification:   Antimycobacterial
Indication:       Infection with, or disease from, mycobacterium tuberculosis
Feeder pathways for glycolysis
     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
  (a14) glycosidic linkage from the
  nonreducing end, generating glucose 1-
  phosphate and a polymer one glucose unit
Branch point (a16) is removed
    by debranching enzyme
Glucose 1-phosphate is converted to G-6-P by
phosphoglucomutase by the same mechanism
observed in phosphoglycerate mutase reaction
          Digestion of dietary
• 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
  a16 branch points.
         Digestion of dietary
• Disaccharides must be hydrolyzed to
  monosaccharides before entering cells.
• Dextrin + nH2O  n D-glucose
• Maltose + H2O  2 D-glucose
• Lactose + H2OlactaseD-galactose + D-glucose
• Sucrose + H2O  D-fructose + D-glucose
• Trehalose + H2O  2 D-glucose
           Lactose intolerance

• Lactose intolerance is due to the disappearance
  after childhood of most or all of the lactase
  activity of the intestinal cells.
Lactose intolerance
          • Undigested lactose
            will be converted to
            toxic products by
            bacteria in large
            intestine, causing
            abdominal cramps and
Fructose metabolism in muscle
         and kidney
    Fructose metabolism in liver


• In liver, the enzyme fructokinase
  catalyze the phosphorylation of fructose to form
  fructose 1-phosphate.
         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.
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.
inability to metabolize galactose due to lack
  1. UDP-glucose galactose 1-phosphate
  uridylyltransferase (classical galactosemia)
  2. UDP-glucose 4-epimerase
  3. Galactokinase
Among these, deficiency of either 1 or 2 is
  more severe (1 is the most severe).
      • 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.
Galactosemia patients develop cataracts
 by deposition of galactitol in the lens
         Mannose metabolism

 Mannose + ATP  mannose 6-phosphate
             hexokinase          +ADP
mannose 6-phosphate  fructose 6-phosphate
            phosphomannose isomerase
• Fermentation is referring to the process
  when no oxygen is consumed or no change
  in the concentration of NAD+ or NADH
  during energy extraction.

• 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.
      • However, the
        oxidation of
        glyceraldehyde 3-
        phosphate consumes
        NAD+ that will not be
        regenerated under
        hypoxic condition
        because oxidative
        phosphorylation is not
The purpose of fermentation is to
       regenerate NAD+
                 • In order to continue
                   regenerating NAD+,
                   cells come up a
                 • During fermentation,
                   NAD+ is regenerated
                   during the reduction of
                   pyruvate, the product
                   of glycolysis.
Lactate fermentation
Lactate is recycled in the liver
         (Cori cycle)
Carl and Gerty Cori, 1947 Nobel Prize in Physiology and
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

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.
           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.
Pyruvate decarboxylase
           • The decarboxylation
             of pyruvate by
             produces CO2, which
             is the reason why
             champagne is
  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).
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
Alcohol dehydrogenase catalyze the
second step of ethanol fermentation
                  • Alcohol
                    reduces acetaldehyde,
                    producing NAD+ and
                  • This enzyme is present
                    in many organisms
                    that metabolize
                    ethanol, including
Fermentation has commercial
              • Bacteria like
                bulgaricus (yogurt)
                freudenreichii (swiss
                cheese) ferments milk
                to produce lactic acid
                or propionic acid and
Dr. Chaim Weizmann
First President of Israel
Found butanol and acetone
fermentation in Clostridium acetobutyricum
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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