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					                     Chapter 26
                       Lipids




Dr. Wolf's CHM 424                26- 1
                             Lipids

       Lipids are naturally occurring substances
       grouped together on the basis of a common
       property—they are more soluble in nonpolar
       solvents than in water.
       Some of the most important of them—the ones
       in this chapter—are related in that they have
       acetic acid (acetate) as their biosynthetic origin.
       In many biosynthetic pathways a substance
       called acetyl coenzyme A serves as the source
       of acetate.
Dr. Wolf's CHM 424                                           26- 2
                             26.1
                     Acetyl Coenzyme A




Dr. Wolf's CHM 424                       26- 3
                     Structure of Coenzyme A


                              O O         OH          OH      H       H
                     HO
            O             P           P                       N       N
                      O           O       O                               SR
            P                                  H3C   CH 3 O
      HO        O                                                 O
                     O
       HO                     N
                      N
                HO
                                      NH 2
                      N
                              N


                                  R = H; Coenzyme A
                                          O

                                  R = CCH3; Acetyl coenzyme A
Dr. Wolf's CHM 424                                                             26- 4
                      Reactivity of Coenzyme A


                     Nucleophilic acyl substitution

              O                         O
                           HY •
                              •
       CH3CSCoA                     CH3C     Y • + HSCoA
                                               •


       Acetyl coenzyme A is a source of an acetyl
       group toward biological nucleophiles; it is an
       acetyl transfer agent.

Dr. Wolf's CHM 424                                         26- 5
                        Reactivity of Coenzyme A


                           can react via enol

                       O                         OH

                     CH3CSCoA              H2C   CSCoA

                                                     E+
   Acetyl coenzyme A reacts
   with biological                               O
   electrophiles at its 
   carbon atom.                        E    CH2CSCoA
Dr. Wolf's CHM 424                                        26- 6
                                 26.2
                     Fats, Oils, and Fatty Acids




Dr. Wolf's CHM 424                                 26- 7
                         Fats and Oils

                                 O

                        O CH2OCR'

                      RCOCH

                           CH2OCR"

                                 O

       Fats and oils are naturally occurring mixture of
       triacylglycerols (also called triglycerides).
       Fats are solids; oils are liquids.
Dr. Wolf's CHM 424                                        26- 8
                          Fats and Oils

                                  O

                         O CH2OC(CH2)16CH3

                CH3(CH2)16COCH

                            CH2OC(CH2)16CH3

                                  O

                      Tristearin; mp 72°C


Dr. Wolf's CHM 424                            26- 9
                                 Fats and Oils

                                                     O

                                           O CH2OC(CH2)16CH3

   CH3(CH2)6CH2                  CH2(CH2)6COCH
                         C   C                   CH2OC(CH2)16CH3
                     H           H                   O

          2-Oleyl-1,3-distearylglycerol; mp 43°C


Dr. Wolf's CHM 424                                            26- 10
                     Fats and Oils



                           2-Oleyl-1,3-distearylglycerol
                                     mp 43°C


                                            H2, Pt



                                     Tristearin
                                     mp 72°C


Dr. Wolf's CHM 424                                         26- 11
                           Fatty Acids
                     O                                        O

          O CH2OCR                  O           CH2OH     HOCR
                           H2O
       R'COCH                     R'COH     HOCH

               CH2OCR"                          CH2OH     HOCR"

                     O                                        O
   Acids obtained by the hydrolysis of fats and oils are called
   fatty acids.
   Fatty acids usually have an unbranched chain with an even
   number of carbon atoms.
   If double bonds are present, they are almost always cis.
Dr. Wolf's CHM 424                                            26- 12
                           Table 26.1

                         Systematic name Common name
                     O

   CH3(CH2)10COH          Dodecanoic acid     Lauric acid
                     O

   CH3(CH2)12COH         Tetradecanoic acid   Myristic acid

                     O

   CH3(CH2)14COH         Hexadecanoic acid Palmitic acid

Dr. Wolf's CHM 424                                       26- 13
                          Table 26.1

                         Systematic name Common name
                     O

   CH3(CH2)16COH         Octadecanoic acid    Stearic acid
                     O

   CH3(CH2)18COH          Icosanoic acid     Arachidic acid




Dr. Wolf's CHM 424                                      26- 14
                             Table 26.1

                                              O

                     CH3(CH2)7           (CH2)7COH
                                 C   C

                            H            H

         Systematic name: (Z)-9-Octadecenoic acid

         Common name: Oleic acid

Dr. Wolf's CHM 424                                   26- 15
                             Table 26.1

                                                    O

            CH3(CH2)4            CH2           (CH2)7COH
                         C   C         C   C

                     H           H H           H

 Systematic name: (9Z, 12Z)-9,12-Octadecadienoic acid

 Common name: Linoleic acid

Dr. Wolf's CHM 424                                         26- 16
                               Table 26.1

                                                               O

    CH3CH2                   CH2            CH2           (CH2)7COH
                     C   C         C    C         C   C

                H            H H            H H           H

     Systematic name:              (9Z, 12Z, 15Z)-9,12,15-
                                   Octadecatrienoic acid
     Common name: Linolenic acid

Dr. Wolf's CHM 424                                                 26- 17
                         Table 26.1
                                             O
                                                     OH
                                 H

                                     H           H
                     H   H
                                         H
                             H       H
     Systematic name:    (5Z, 8Z, 11Z, 14Z)-5,8,11,14-
                         Icosatetraenoic acid
     Common name: Arachidonic acid
Dr. Wolf's CHM 424                                        26- 18
                      trans-Fatty Acids

       Are formed by isomerization that can occur
       when esters of cis-fatty acids are hydrogenated.


                             H                   O
                        H
                                                     OR


                                 H2, cat        O

                                                     OR
Dr. Wolf's CHM 424                                        26- 19
                             H             O

                                               OR
                         H


                         H             O
                     H
                                           OR


                             H2, cat   O

                                           OR
Dr. Wolf's CHM 424                              26- 20
                               26.3
                     Fatty Acid Biosynthesis




Dr. Wolf's CHM 424                             26- 21
                     Fatty Acid Biosynthesis

       Fatty acids are biosynthesized via acetyl
       coenzyme A.
       The group of enzymes involved in the overall
       process is called fatty acid synthetase.
       One of the key components of fatty acid
       synthetase is acyl carrier protein (ACP—SH).




Dr. Wolf's CHM 424                                    26- 22
                     Fatty Acid Biosynthesis

       An early step in fatty acid biosynthesis is the
       reaction of acyl carrier protein with acetyl
       coenzyme A.


         O                                  O

  CH3CSCoA + HS—ACP                     CH3CS—ACP

                                            + HSCoA

Dr. Wolf's CHM 424                                       26- 23
                     Fatty Acid Biosynthesis

       A second molecule of acetyl coenzyme A reacts
       at its  carbon atom with carbon dioxide (as
       HCO3–) to give malonyl coenzyme A.


         O                                O    O
                –
           + HCO3                      –
  CH3CSCoA                              OCCH2CSCoA

    Acetyl                                 Malonyl
 coenzyme A                              coenzyme A
Dr. Wolf's CHM 424                                     26- 24
                     Fatty Acid Biosynthesis

       Malonyl coenzyme A then reacts with acyl
       carrier protein.



      O         O                         O    O
 –                        ACP—SH       –
  OCCH2CS—ACP                           OCCH2CSCoA

                                           Malonyl
                                         coenzyme A
Dr. Wolf's CHM 424                                    26- 25
                         Fatty Acid Biosynthesis

         Malonyl—ACP and acetyl—ACP react by
         carbon-carbon bond formation, accompanied by
         decarboxylation.

                     O
                                             O       O
             CH3C        S—ACP
                                         CH3C      CH2CS—ACP
            O            O
 – ••                                     S-Acetoacetyl—ACP
  •O
  •         C        CH2CS—ACP
    ••
Dr. Wolf's CHM 424                                        26- 26
                         Fatty Acid Biosynthesis

       In the next step, the ketone carbonyl is reduced
       to a secondary alcohol.



       OH            O                       O       O
                                NADPH
CH3C           CH2CS—ACP                 CH3C      CH2CS—ACP

       H                                  S-Acetoacetyl—ACP

Dr. Wolf's CHM 424                                        26- 27
                         Fatty Acid Biosynthesis

       The alcohol then dehydrates.




       OH            O                              O

CH3C           CH2CS—ACP                CH3CH      CHCS—ACP

       H


Dr. Wolf's CHM 424                                      26- 28
                         Fatty Acid Biosynthesis

     Reduction of the double bond yields
     ACP bearing an attached butanoyl group.
     Repeating the process gives a 6-carbon acyl
     group, then an 8-carbon one, then 10, etc.

                     O                              O
  CH3CH2CH2CS—ACP                       CH3CH      CHCS—ACP




Dr. Wolf's CHM 424                                      26- 29
                         26.4
                     Phospholipids




Dr. Wolf's CHM 424                   26- 30
                      Phospholipids

       Phospholipids are intermediates in the
       biosynthesis of triacylglycerols.
       The starting materials are L-glycerol 3-
       phosphate and the appropriate acyl coenzyme
       A molecules.




Dr. Wolf's CHM 424                                   26- 31
               CH2OH           O           O
   HO                H     +   RCSCoA   + R'CSCoA

               CH2OPO3H2


   The diacylated
   species formed                  O
   in this step is             CH2OCR
                     O
   called a
   phosphatidic    R'CO            H
   acid.
Dr. Wolf's CHM 424
                               CH2OPO3H2            26- 32
                                 O

                      O      CH2OCR

                    R'CO        H

                             CH2OH

                       H2O
    The
    phosphatidic                 O
    acid then                CH2OCR
                        O
    undergoes
    hydrolysis of its R'CO      H
    phosphate ester
    function.
Dr. Wolf's CHM 424
                             CH2OPO3H2   26- 33
                                     O

                           O     CH2OCR

                          R'CO      H      Reaction with a
                                           third acyl
                                 CH2OH     coenzyme A
                      O
                                           molecule yields
                     R"CSCoA               the
                                    O
                                           triacylglycerol.
                           O     CH2OCR

                          R'CO      H
                                    O
                                 CH2OCR"
Dr. Wolf's CHM 424                                       26- 34
                            Phosphatidylcholine

    Phosphatidic acids are intermediates in the
    formation of phosphatidylcholine.
                  O                             O

     O           CH2OCR                    O      CH2OCR

  R'CO                  H                R'CO        H

                     CH2OPO3H2                          –
                                                  CH2OPO2
                                             +
                                       (CH3)3NCH2CH2O
Dr. Wolf's CHM 424                                          26- 35
                      Phosphatidylcholine

                                   O

                       O      CH2OCR hydrophobic "tail"

                    R'CO           H
  hydrophobic "tail"
                                    –
                              CH2OPO2
                           +
                     (CH3)3NCH2CH2O

                      polar "head group"
Dr. Wolf's CHM 424                                  26- 36
                       Phosphatidylcholine




                           hydrophobic
                        (lipophilic) "tails"




                     hydrophilic "head group"
Dr. Wolf's CHM 424                              26- 37
                     Cell Membranes

                                      water

    Cell membranes are
    "lipid bilayers." Each
    layer has an assembly
    of phosphatidyl
    choline molecules as
    its main structural
    component.


Dr. Wolf's CHM 424
                                      water   26- 38
                      Cell Membranes

                                       water

    The interior of the cell
    membrane is
    hydrocarbon-like.
    Polar materials cannot
    pass from one side to
    the other of the
    membrane.


Dr. Wolf's CHM 424
                                       water   26- 39
                      26.5
                     Waxes




Dr. Wolf's CHM 424           26- 40
                              Waxes

       Waxes are water-repelling solids that coat the
       leaves of plants, etc.
       Structurally, waxes are mixtures of esters. The
       esters are derived from fatty acids and long-
       chain alcohols.

                              O

                     CH3(CH2)14COCH2(CH2)28CH3

         Triacontyl hexadecanoate: occurs in beeswax
Dr. Wolf's CHM 424                                       26- 41
                          26.6
                     Prostaglandins




Dr. Wolf's CHM 424                    26- 42
                              Prostaglandins




       Prostaglandins are involved in many biological
       processes.
       Are biosynthesized from linoleic acid (C18) via
       arachidonic acid (C20). (See Table 26.1)




Dr. Wolf's CHM 424                                       26- 43
                      Examples: PGE1 and PGF1



         O                         O

                                        OH
                                                 PGE1


      HO             OH
       HO                          O

                                        OH
                                                 PGF1


     HO              OH
Dr. Wolf's CHM 424                                       26- 44
                         Prostaglandin Biosynthesis



       PGE2 is biosynthesized from arachidonic acid
       The oxygens come from O2
       The enzyme involved (prostaglandin endoperoxide
       synthase) has cyclooxygenase (COX) acitivity




Dr. Wolf's CHM 424                                       26- 45
                      Prostaglandin Biosynthesis




                              CO2H
                                                    Arachidonic acid
                                   CH3


                                               O2
                                  fatty acid cyclooxygenase

             O
                                                   CO2H   PGG2
         O
                     HOO                            CH3
Dr. Wolf's CHM 424                                               26- 46
                      Prostaglandin Biosynthesis




             O
                                                   CO2H   PGH2
         O
                      HO                            CH3

                                  reduction of
                                  hydroperoxide

             O
                                                   CO2H   PGG2
         O
                     HOO                            CH3
Dr. Wolf's CHM 424                                               26- 47
                         Prostaglandin Biosynthesis




             O
                                                      CO2H   PGH2
         O
                         HO                            CH3


                     O
                                                 CO2H


                                                       CH3   PGE2
              HO             HO
Dr. Wolf's CHM 424                                                  26- 48
                              Icosanoids



    Icosanoids are compounds related to icosanoic acid
                    CH3(CH2)18CO2H.

     Icosanoids include:
        prostaglandins
            thromboxanes
                  prostacyclins
                         leukotrienes




Dr. Wolf's CHM 424                                  26- 49
                       Thromboxane A2 (TXA2)



         Thromboxane A2 is biosynthesized from PGH2

            O
                                               CO2H   PGH2
        O
                      HO                        CH3
                                     TXA2 promotes platelet
                                  aggregation and blood clotting

         O                                     CO2H   TXA2
                 O
                      HO                        CH3
Dr. Wolf's CHM 424                                           26- 50
                              Prostacyclin I2 (PGI2)




                Like thromboxane A2, prostacyclin I2 is
                biosynthesized from PGH2

          HO2C
                                                 PGI2 inhibits platelet
                                               aggregation and relaxes
                          O                       coronary arteries



                                                              CH3

                     HO                     OH                      PGI2
Dr. Wolf's CHM 424                                                        26- 51
                          Leukotriene C4 (LTC4)



           Leukotrienes arise from arachidonic acid via
           a different biosynthetic pathway. They are the
           substances most responsible for constricting
           bronchial passages during asthma attacks.




Dr. Wolf's CHM 424                                          26- 52
                               Leukotriene C4 (LTC4)



                                     OH
                                                       CO2H
                                                   O
                                 S
                                       CH2CHCNHCH2CO2H
                           CH3
                                              NH

                     –                        C        O
                      O2CCHCH2CH2
                       + NH3
Dr. Wolf's CHM 424                                            26- 53
                                26.7
                     Terpenes: The Isoprene Rule




Dr. Wolf's CHM 424                                 26- 54
                                Terpenes

               Terpenes are natural products that are
               structurally related to isoprene.

                     CH3

              H2C    C     CH     CH2      or

                             Isoprene
                      (2-methyl-1,3-butadiene)

Dr. Wolf's CHM 424                                      26- 55
                              Terpenes

               Myrcene (isolated from oil of bayberry)
               is a typical terpene.

                       CH3            CH2

                     CH3C    CHCH2CH2CCH       CH2

                                 or



Dr. Wolf's CHM 424                                       26- 56
                      The Isoprene Unit

       An isoprene unit is the carbon skeleton of
       isoprene (ignoring the double bonds)




       Myrcene contains two isoprene units.




Dr. Wolf's CHM 424                                  26- 57
                      The Isoprene Unit

       The isoprene units of myrcene are joined "head-
       to-tail."

                     head               tail


                            tail head




Dr. Wolf's CHM 424                                       26- 58
                            Table 26.2

                     Classification of Terpenes


       Class                 Number of carbon atoms
       Monoterpene                     10
       Sesquiterpene                   15
       Diterpene                       20
       Sesterpene                      25
       Triterpene                      30
       Tetraterpene                    40

Dr. Wolf's CHM 424                                    26- 59
                             Figure 26.6

                     Representative Monoterpenes



                                 OH                        O

                                                                H



 -Phellandrene   Menthol                      Citral
  (eucalyptus)  (peppermint)               (lemon grass)

Dr. Wolf's CHM 424                                             26- 60
                             Figure 26.6

                     Representative Monoterpenes



                                 OH                        O

                                                                H



 -Phellandrene   Menthol                      Citral
  (eucalyptus)  (peppermint)               (lemon grass)

Dr. Wolf's CHM 424                                             26- 61
                             Figure 26.6

                     Representative Monoterpenes




 -Phellandrene   Menthol                      Citral
  (eucalyptus)  (peppermint)               (lemon grass)

Dr. Wolf's CHM 424                                         26- 62
                              Figure 26.6

                     Representative Sesquiterpenes




                                      H


                               -Selinene
                                (celery)

Dr. Wolf's CHM 424                                   26- 63
                              Figure 26.6

                     Representative Sesquiterpenes




                                      H


                               -Selinene
                                (celery)

Dr. Wolf's CHM 424                                   26- 64
                              Figure 26.6

                     Representative Sesquiterpenes




                               -Selinene
                                (celery)

Dr. Wolf's CHM 424                                   26- 65
                            Figure 26.6

                     Representative Diterpenes




                                                 OH




                             Vitamin A


Dr. Wolf's CHM 424                                    26- 66
                            Figure 26.6

                     Representative Diterpenes




                                                 OH




                             Vitamin A


Dr. Wolf's CHM 424                                    26- 67
                            Figure 26.6

                     Representative Diterpenes




                             Vitamin A


Dr. Wolf's CHM 424                               26- 68
                                 Figure 26.6

                         Representative Triterpene




                     tail-to-tail linkage of isoprene units




                                    Squalene
Dr. Wolf's CHM 424
                                 (shark liver oil)            26- 69
                                 26.8
                     Isopentenyl Pyrophosphate:
                     The Biological Isoprene Unit




Dr. Wolf's CHM 424                                  26- 70
                     The Biological Isoprene Unit

     The isoprene units in terpenes do not come from
     isoprene.
     They come from isopentenyl pyrophosphate.
     Isopentenyl pyrophosphate (5 carbons) comes
     from acetate (2 carbons) via mevalonate (6
     carbons).




Dr. Wolf's CHM 424                                     26- 71
                         The Biological Isoprene Unit

                     O                      O    CH3
           3 CH3COH                      HOCCH2CCH2CH2OH

                                                  OH

                                             Mevalonic acid
                CH3            O O

   H2C          CCH2CH2OPOPOH

   Isopentenyl pyrophosphate
Dr. Wolf's CHM 424                                            26- 72
                     Isopentenyl Pyrophosphate


               CH3       O O

  H2C          CCH2CH2OPOPOH        or           OPP

  Isopentenyl pyrophosphate




Dr. Wolf's CHM 424                                     26- 73
          Isopentenyl and Dimethylallyl Pyrophosphate


      Isopentenyl pyrophosphate is interconvertible with
      2-methylallyl pyrophosphate.


                     OPP                            OPP

   Isopentenyl pyrophosphate       Dimethylallyl pyrophosphate

       Dimethylallyl pyrophosphate has a leaving
       group (pyrophosphate) at an allylic carbon; it is
       reactive toward nucleophilic substitution at this
       position.
Dr. Wolf's CHM 424                                         26- 74
                                  26.9
                     Carbon-Carbon Bond Formation
                        in Terpene Biosynthesis




Dr. Wolf's CHM 424                                  26- 75
                     Carbon-Carbon Bond Formation

                             OPP
                               +
                                           OPP


   The key process involves the double bond of
   isopentenyl pyrophosphate acting as a nucleophile
   toward the allylic carbon of dimethylallyl
   pyrophosphate.


Dr. Wolf's CHM 424                                  26- 76
                     Carbon-Carbon Bond Formation

                             OPP
                               +
                                           OPP




                          –
                           OPP

                                 +
                                         OPP
Dr. Wolf's CHM 424                                  26- 77
                     After C—C Bond Formation...




                                               OPP
    The carbocation
    can lose a proton                    +
                                    –H
    to give a double
    bond.


                                +
                                             OPP
Dr. Wolf's CHM 424                                   26- 78
                     After C—C Bond Formation...




                                            OPP

    This compound is called geranyl pyrophosphate. It
    can undergo hydrolysis of its pyrophosphate to give
    geraniol (rose oil).




Dr. Wolf's CHM 424                                   26- 79
                     After C—C Bond Formation...




                                            OPP


                                   H2O




                                            OH
                              Geraniol
Dr. Wolf's CHM 424                                 26- 80
                       From 10 Carbons to 15

                                 OPP
                                   +
                                               OPP
              Geranyl pyrophosphate




                                       +
                                               OPP
Dr. Wolf's CHM 424                                   26- 81
                     From 10 Carbons to 15



                                             OPP


                                     +
                                –H



                                   +
                                             OPP
Dr. Wolf's CHM 424                                 26- 82
                     From 10 Carbons to 15



                                             OPP

       This compound is called farnesyl
       pyrophosphate.
       Hydrolysis of the pyrophosphate ester gives the
       alcohol farnesol (Figure 26.6).



Dr. Wolf's CHM 424                                       26- 83
                     From 15 Carbons to 20



                                             OPP




                                                   OPP
        Farnesyl pyrophosphate is extended by another
        isoprene unit by reaction with isopentenyl
        pyrophosphate.
Dr. Wolf's CHM 424                                      26- 84
                           Cyclization

       Rings form by intramolecular carbon-carbon
       bond formation.

                                                    +

                                         OPP

                     OPP

            E double                 Z double
            bond                     bond
Dr. Wolf's CHM 424                                      26- 85
              Limonene
                                       +
                                  –H

                                           +
                            OH

                                 H2O

              -Terpineol


Dr. Wolf's CHM 424                             26- 86
                         Bicyclic Terpenes




             +
                                  +
                                             +




                     +

          -Pinene
Dr. Wolf's CHM 424
                                 -Pinene        26- 87
                                26.10
                     The Pathway from Acetate to
                      Isopentenyl Pyrophosphate




Dr. Wolf's CHM 424                                 26- 88
                           Recall

                     O              O   CH3
           3 CH3COH             HOCCH2CCH2CH2OH

                                        OH

                                    Mevalonic acid
                CH3      O O

   H2C          CCH2CH2OPOPOH

   Isopentenyl pyrophosphate
Dr. Wolf's CHM 424                                   26- 89
                     Biosynthesis of Mevalonic Acid


       In a sequence analogous to the early steps of
       fatty acid biosynthesis, acetyl coenzyme A is
       converted to S-acetoacetyl coenzyme A.

                                O    O

                            CH3CCH2CSCoA

                             S-Acetoacetyl
                             coenzyme A
Dr. Wolf's CHM 424                                     26- 90
                     Biosynthesis of Mevalonic Acid

                     O    O               O

               CH3CCH2CSCoA + CH3CSCoA


      In the next step, S-acetoacetyl coenzyme A
      reacts with acetyl coenzyme A.
      Nucleophilic addition of acetyl coenzyme A
      (probably via its enol) to the ketone carbonyl of
      S-acetoacetyl coenzyme A occurs.


Dr. Wolf's CHM 424                                        26- 91
                     Biosynthesis of Mevalonic Acid

                     O    O               O

               CH3CCH2CSCoA + CH3CSCoA



                              HO   O
                         CH3CCH2CSCoA
                               CH2COH

                                   O
Dr. Wolf's CHM 424                                    26- 92
                     Biosynthesis of Mevalonic Acid


       Next, the acyl coenzyme A function is reduced.
       The product of this reduction is mevalonic acid.


                            HO     O
                         CH3CCH2CSCoA
                              CH2COH

                                 O
Dr. Wolf's CHM 424                                        26- 93
                       HO

                     CH3CCH2CH2OH   Mevalonic
                                      acid
                        CH2COH

                            O



                      HO    O
                     CH3CCH2CSCoA
                       CH2COH

                            O
Dr. Wolf's CHM 424                              26- 94
                         Conversion of Mevalonic Acid to
                           Isopentenyl Pyrophosphate

                                                       2–
        HO                                       OPO3

   CH3CCH2CH2OH                              CH3CCH2CH2OPP
           CH2COH                                CH2COH
                     O                               O

       The two hydroxyl groups of mevalonic acid
       undergo phosphorylation.

Dr. Wolf's CHM 424                                           26- 95
                     Conversion of Mevalonic Acid to
                       Isopentenyl Pyrophosphate
                     3–
          OPO3                                     2–
                                             OPO3

   CH3CCH2CH2OPP                         CH3CCH2CH2OPP
                                                            •• –
           CH2                               CH2        C   O• •
                                                            ••
                 O        C   O                         O
       Phosphorylation is followed by a novel
       elimination involving loss of CO2 and PO43–.


Dr. Wolf's CHM 424                                            26- 96
                     Conversion of Mevalonic Acid to
                       Isopentenyl Pyrophosphate



   CH3CCH2CH2OPP
           CH2


       The product of this elimination is isopentenyl
       pyrophosphate.


Dr. Wolf's CHM 424                                      26- 97
                  Biosynthetic pathway is based on
                 experiments with 14C-labeled acetate

                     O                  O    CH3
              CH3COH                 HOCCH2CCH2CH2OH

                                              OH

                                         Mevalonic acid
                CH3        O O

   H2C          CCH2CH2OPOPOH

   Isopentenyl pyrophosphate
Dr. Wolf's CHM 424                                        26- 98
                  Biosynthetic pathway is based on
                 experiments with 14C-labeled acetate


       Citronellal biosynthesized using 14C-labeled
       acetate as the carbon source had the labeled
       carbons in the positions indicated.
                     O                           CH3    O O

             CH3COH                  H2C         CCH2CH2OPOPOH


                     •           •       O

                •
Dr. Wolf's CHM 424
                         •   •       •       H
                                                              26- 99
                             26.11
                     Steroids: Cholesterol




Dr. Wolf's CHM 424                           26- 100
                     Structure of Cholesterol




       Fundamental framework of steroids is the
       tetracyclic unit shown.

Dr. Wolf's CHM 424                                26- 101
                          Structure of Cholesterol
                                            CH3            CH3
                                             CH3

                                CH3     H            CH3


                                    H        H
                     HO


       Cholesterol has the fundamental steroid
       skeleton modified as shown.

Dr. Wolf's CHM 424                                         26- 102
                          Structure of Cholesterol

                                            CH3            CH3
                                             CH3

                                CH3     H            CH3


                                    H        H
                     HO

       Some parts of the cholesterol molecule are
       isoprenoid. But other parts don't obey the
       isoprene rule. Also, cholesterol has 27 carbons,
       which is not a multiple of 5.
Dr. Wolf's CHM 424                                         26- 103
                     Biosynthesis of Cholesterol


       Cholesterol is biosynthesized from the triterpene
       squalene. In the first step, squalene is
       converted to its 2,3-epoxide.




                                   O2, NADH, enzyme



        O
Dr. Wolf's CHM 424                                     26- 104
                         Biosynthesis of Cholesterol




         O

       To understand the second step, we need to look
       at squalene oxide in a different conformation,
       one that is in a geometry suitable for cyclization.

                     O




Dr. Wolf's CHM 424                                       26- 105
                     Biosynthesis of Cholesterol



          HO
                                         +

                                     H

       Cyclization is triggered by epoxide ring opening.


            H+ O



Dr. Wolf's CHM 424                                     26- 106
                     Biosynthesis of Cholesterol



          HO
                                         +

                                     H
   The five-membered ring expands to a six-membered
   one.
                                H


           HO
                                             +
                                                 H
Dr. Wolf's CHM 424                                   26- 107
                     Biosynthesis of Cholesterol
                                H

                                                     +
         HO

        protosteryl cation
                                         H
   Cyclization to form a tetracyclic carbocation.
                                H


           HO
                                             +
                                                 H
Dr. Wolf's CHM 424                                       26- 108
                     Biosynthesis of Cholesterol
                                ••
                               • OH
                               •   2
                               H

                                              +
         HO
                                                  H
                                        H
       Deprotonation and multiple migrations.
                                                   H

           HO
                                               H
Dr. Wolf's CHM 424                                     26- 109
                     Biosynthesis of Cholesterol




       The product of this rearrangement is a
       triterpene called lanosterol. A number of
       enzyme-catalyzed steps follow that convert
       lanosterol to cholesterol.

                                                   H

           HO
                                               H
Dr. Wolf's CHM 424                                     26- 110
                          Cholesterol

       Cholesterol is the biosynthetic precursor to a
       large number of important steroids:
             Bile acids
             Vitamin D
             Corticosteroids
             Sex hormones




Dr. Wolf's CHM 424                                      26- 111
                       26.12
                     Vitamin D




Dr. Wolf's CHM 424               26- 112
                             Cholesterol

                                  CH3                  CH3
                                   CH3

                     CH3      H                  CH3


                         H         H
           HO
    Cholesterol is the precursor to vitamin D.
    Enzymes dehydrogenate cholesterol to introduce a second
    double bond in conjugation with the existing one. The
    product of this reaction is called 7-dehydrocholesterol.
Dr. Wolf's CHM 424                                           26- 113
                     7-Dehydrocholesterol

                            CH3                   CH3
                             CH3

                     CH3                    CH3


                        H     H
           HO

       Sunlight converts 7-dehydrocholesterol on the
       skin's surface to vitamin D3.
Dr. Wolf's CHM 424                                      26- 114
                           Vitamin D3

                              CH3                     CH3
                               CH3

                                                CH3


                                H
           HO

       Insufficient sunlight can lead to a deficiency of
       vitamin D3, interfering with Ca2+ transport and
       bone development. Rickets can result.
Dr. Wolf's CHM 424                                          26- 115
                        26.13
                     Bile Acids




Dr. Wolf's CHM 424                26- 116
                             Cholesterol

                             CH3                      CH3
                              CH3

                 CH3     H                      CH3


                     H        H
   HO

     Oxidation in the liver degrades the cholesterol side chain
     and introduces OH groups at various positions on the
     steroid skeleton. Cholic acid (next slide) is the most
     abundant of the bile acids.
Dr. Wolf's CHM 424                                                26- 117
                                 Cholic Acid
                                               O
                           HO CH3
                               CH3                 OH

                     CH3     H


                         H        H
    HO                             OH
                     H

    Salts of cholic acid amides (bile salts), such as sodium
    taurocholate (next slide), act as emulsifying agents to aid
    digestion.
Dr. Wolf's CHM 424                                                26- 118
                           Sodium Taurocholate
                                           O
                            HO CH3
                                CH3              NHCH2CH2SO3Na

                     CH3     H


                         H       H
    HO                           OH
                     H




Dr. Wolf's CHM 424                                         26- 119
                          26.14
                     Corticosteroids




Dr. Wolf's CHM 424                     26- 120
                            Cholesterol

                                  CH3                     CH3
                                   CH3

                      CH3     H                     CH3


                          H        H
           HO

    Enzymatic degradation of the side chain and oxidation of
    various positions on the steroid skeleton convert cholesterol
    to corticosteroids.
Dr. Wolf's CHM 424                                              26- 121
                              Cortisol

                                  O
                                  CH3        OH
                     HO
                                          OH
                      CH3     H


                          H       H
              O


    Cortisol is the most abundant of the corticosteroids.
    Enzyme-catalyzed oxidation of cortisol gives cortisone.
Dr. Wolf's CHM 424                                            26- 122
                                Cortisone

                                    O
                                    CH3        OH
                       O
                                            OH
                       CH3      H


                            H       H
              O

       Corticosteroids are involved in maintaining electrolyte
       levels, in the metabolism of carbohydrates, and in
       mediating the allergic response.
Dr. Wolf's CHM 424                                               26- 123
                         26.15
                     Sex Hormones




Dr. Wolf's CHM 424                  26- 124
                         Testosterone


                                            OH
                                    H3C

                          H3C       H


                                H       H
                     O

          Testosterone is the main male sex hormone.


Dr. Wolf's CHM 424                                     26- 125
                          Estradiol


                                          OH
                                  H3C

                                  H


                              H       H
                     HO

        Estradiol is a female sex hormone involved in
     regulating the menstrual cycle and in reproduction.

Dr. Wolf's CHM 424                                    26- 126
                           Progesterone

                                        O
                                      H3C

                            H3C       H


                                  H       H
                     O

               Supresses ovulation during pregnancy.


Dr. Wolf's CHM 424                                     26- 127
                        26.16
                     Carotenoids




Dr. Wolf's CHM 424                 26- 128
                        Carotenoids


       Carotenoids are naturally occurring pigments.
       Structurally, carotenoids are tetraterpenes.
       They have 40 carbons. Two C20 units are linked
       in a tail-to-tail fashion.
       Examples are lycopene and -carotene.




Dr. Wolf's CHM 424                                  26- 129
                         Carotenoids




                     Lycopene (tomatoes)




                     -Carotene (carrots)
Dr. Wolf's CHM 424                          26- 130
                     End of Chapter 26




Dr. Wolf's CHM 424                       26- 131

				
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