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Organic

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Title: Organic


1
  • Organic
  • Chemistry

William H. Brown Christopher S. Foote
2
  • The Organic
  • Chemistry of
  • Metabolism

Chapter 29
3
Introduction
  • We have now studied the typical reactions of the
    major classes of organic compounds, and the
    structure and reactions of carbohydrates and
    lipids
  • Now let us apply this background to the study of
    the organic chemistry of metabolism
  • We study two key metabolic pathways
  • ?-oxidation of fatty acids
  • glycolysis

4
Five Key Participants
  • Five of the compounds participating in these and
    a great many other metabolic pathways
  • ATP, ADP, and AMP are universal carriers of
    phosphate groups
  • NAD/NADH and FAD/FADH2 are coenzymes involved in
    the oxidation/reduction of metabolic
    intermediates
  • Coenzyme a low-molecular weight, nonprotein
    molecule or ion that binds reversibly to an
    enzyme, functions as a second substrate, and is
    regenerated by further reaction

5
Adenosine Triphosphate
  • ATP is the most important compound involved in
    the transfer of phosphate groups

6
Adenosine Triphosphate
  • hydrolysis of the terminal phosphate of ATP gives
    ADP and phosphate
  • in glycolysis, the phosphate acceptors are -OH
    groups of glucose and fructose

7
Nicotinamide adenine dinucleotide
  • a biological oxidizing agent

8
NAD/NADH
  • NAD is a two-electron oxidizing agent, and is
    reduced to NADH

9
NAD/NADH
  • NAD is involved in a variety of enzyme-catalyzed
    oxidation/reduction reactions we deal with two
    of these in this chapter

10
NAD/NADH
11
FAD/FADH2
12
FAD/FADH2
  • FAD participates in several types of
    enzyme-catalyzed oxidation/reduction reactions
  • our concern is its participation in the oxidation
    of a C-C bond in a fatty acid hydrocarbon chain
    to a CC bond as shown in these balanced
    half-reactions

13
FAD oxidation of C-C
14
Fatty Acids and Energy
  • Fatty acids in triglycerides are the principle
    storage form of energy for most organisms
  • carbon chains are in a highly reduced form
  • the energy yield per gram of fatty acid oxidized
    is greater than that per gram of carbohydrate

15
Oxidation of Fatty Acids
  • There are two major stages in the oxidation of
    fatty acids
  • activation of the free fatty acid in the
    cytoplasm and its transport across the inner
    mitochondrial membrane
  • ?-oxidation
  • ?-Oxidation a series of four enzyme-catalyzed
    reactions that cleaves carbon atoms two at a
    time, from the carboxyl end of a fatty acids

16
Activation of Fatty Acids
  • activation begins in the cytoplasm with formation
    of a thioester between the carboxyl group of the
    fatty acid and the sulfhydryl group of coenzyme A
  • formation of the acyl-CoA derivative is coupled
    with the hydrolysis of ATP to AMP and
    pyrophosphate

17
?-Oxidation
  • Reaction 1 stereospecific oxidation of a
    carbon-carbon single bond a,b to the carbonyl
    group
  • Reaction 2 regiospecific and stereospecific
    hydration of the carbon-carbon double bond only
    the R-enantiomer is formed

18
?-Oxidation
  • Reaction 3 oxidation of the ?-hydroxyl group
  • Reaction 4 cleavage of the carbon chain by a
    reverse Claisen condensation

19
?-Oxidation
  • mechanism of the reverse Claisen condensation

20
?-Oxidation
  • this series of reactions is then repeated on the
    shortened fatty acyl chain and continues until
    the entire fatty acid chain is degraded to
    acetyl-CoA

21
Glycolysis
  • Glycolysis from the Greek, glyko, sweet, and
    lysis, splitting
  • a series of 10 enzyme-catalyzed reactions by
    which glucose is oxidized to two molecules of
    pyruvate

22
Glycolysis - Rexn 1
  • phosphorylation of ?-D-glucose

23
Glycolysis - Rexn 2
  • isomerization of glucose 6-phosphate to fructose
    6-phosphate

24
Glycolysis - Rexn 2
  • this isomerization is most easily seen by
    considering the open-chain forms of each
    monosaccharide

25
Glycolysis - Rexn 3
  • phosphorylation of fructose 6-phosphate

26
Glycolysis - Rexn 4
  • cleavage of fructose 6-phosphate to two triose
    phosphates

27
Glycolysis - Rexn 4
  • reaction 4 is a reverse aldol reaction
  • a key intermediate is an imine formed by the CO
    group of fructose 1,6-bisphosphate and an -NH2
    group of the enzyme catalyzing this reaction

28
Glycolysis - Rexn 4
  • reverse aldol reaction gives two three-carbon
    fragments, one as an imine

29
Glycolysis - Rexn 4
  • hydrolysis of the imine gives dihydroxyacetone
    phosphate and regenerates the -NH2 group of the
    enzyme

30
Glycolysis - Rexn 5
  • isomerization of triose phosphates

31
Glycolysis - Rexn 6
  • oxidation of the -CHO group of glyceraldehyde
    3-phosphate
  • the -CHO group is oxidized to a carboxyl group
  • which is in turn converted to a
    carboxylic-phosphoric mixed anhydride
  • the oxidizing agent is NAD, which is reduced to
    NADH

32
Glycolysis - Rexn 6
  • We divide this reaction into three stages
  • stage 1 formation of a thiohemiacetal
  • stage 2 oxidation of the thiohemiacetal by NAD

33
Glycolysis - Rexn 6
  • stage 3 conversion of the thioester to a mixed
    anhydride

34
Glycolysis - Rexn 7
  • transfer of a phosphate group from
    1,3-bisphosphoglycerate to ADP

35
Glycolysis - Rexn 8
  • isomerization of 3-phosphoglycerate to
    2-phosphoglycerate

36
Glycolysis - Rexn 9
  • dehydration of 2-phosphoglycerate

37
Glycolysis - Rexn 10
  • phosphate transfer to ADP

38
Glycolysis
  • Summing these 10 reactions gives the net equation
    for glycolysis

39
Fates of Pyruvate
  • Pyruvate does not accumulate in cells, but rather
    undergoes one of three enzyme-catalyzed
    reactions, depending of the type of cell and its
    state of oxygenation
  • reduction to lactate
  • reduction to ethanol
  • oxidation and decarboxylation to acetyl-CoA
  • A key to understanding the biochemical logic
    behind two of these fates is to recognize that
    glycolysis needs a continuing supply of NAD
  • if no oxygen is present to reoxidize NADH to
    NAD, then another way must be found to do it

40
Lactate Fermentation
  • in vertebrates under anaerobic conditions, the
    most important pathway for the regeneration of
    NAD is reduction of pyruvate to lactate

41
Pyruvate to Lactate
  • while lactate fermentation does allow glycolysis
    to continue, it increases the concentration of
    lactate and also of H in muscle tissue, as seen
    in this balanced half-reaction
  • when blood lactate reaches about 0.4 mg/100 mL,
    muscle tissue becomes almost completely exhausted

42
Pyruvate to Ethanol
  • Yeasts and several other organisms regenerate
    NAD by this two step pathway
  • decarboxylation of pyruvate to acetaldehyde
  • reduction of acetaldehyde to ethanol

43
Pyruvate to Acetyl-CoA
  • Under aerobic conditions pyruvate undergoes
    oxidative decarboxylation
  • the carboxylate group is converted to CO2
  • the remaining two carbons are converted to the
    acetyl group of acetyl-CoA

44
Pyruvate to Acetyl-CoA
  • Oxidative decarboxylation of pyruvate to
    acetyl-CoA is considerably more complex than the
    previous equation suggests
  • In addition to NAD (from the vitamin niacin) and
    coenzyme A (from the vitamin pantothenic acid),
    it also requires
  • FAD (from the vitamin riboflavin)
  • pyridoxal phosphate (from the vitamin pyridoxine)
  • lipoic acid

45
Pyruvate to Acetyl-CoA
46
Prob 29.21
  • Describe the type of reaction involved in this
    biochemical synthesis of b-hydroxybutyrate.

47
  • The Organic
  • Chemistry of
  • Metabolism

End Chapter 29
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