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Lipids-II-05

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					Terpenes: The Isoprene Rule
                 Terpenes

Terpenes are natural products that are
structurally related to isoprene.

      CH3

H2C   C     CH     CH2      or

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

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

       CH3             CH2

   CH3C      CHCH2CH2CCH        CH2

                  or
               The Isoprene Unit

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




Myrcene contains two isoprene units.
              The Isoprene Unit

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

             head               tail


                    tail head
Common Carbon Backbone
                     Terpenes

             Classification of Terpenes


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

            Representative Monoterpenes



                              OH                   O

                                                       H



a-Phellandrene   Menthol               Citral
 (eucalyptus)  (peppermint)        (lemon grass)
                       Terpenes

            Representative Monoterpenes



                              OH                   O

                                                       H



a-Phellandrene   Menthol               Citral
 (eucalyptus)  (peppermint)        (lemon grass)
                       Terpenes

            Representative Monoterpenes




a-Phellandrene   Menthol              Citral
 (eucalyptus)  (peppermint)       (lemon grass)
          Terpenes

Representative Sesquiterpenes




                 H


          a-Selinene
           (celery)
          Terpenes

Representative Sesquiterpenes




                 H


          a-Selinene
           (celery)
          Terpenes

Representative Sesquiterpenes




          a-Selinene
           (celery)
        Terpenes

Representative Diterpenes




                            OH




        Vitamin A
        Terpenes

Representative Diterpenes




                            OH




        Vitamin A
        Terpenes

Representative Diterpenes




        Vitamin A
             Common Terpenes
               OH                               OH


                               Nerol C 10H18O
  Linalool C 10 H 18 O


                         OH

                                          OH

Geraniol C 10 H18 O
                              Terpineol    C10H18O
 Limonene
CH 2




            CH 2
  Limonene



CH2
 Rearrangement



OH               OH




     Product?
               Terpenes




Camphene (H)
                          Terpinene (I)
               Terpenes




                     Carene (K)
Limonene (J)
     Isoprene / Biosynthesis



               O       O
               P       P
           O       O        O
               O       O
Isopentenyl pyrophosphate       Isoprene
Terpene Biosynthesis




Formation of geranyl pyrophosphate
Farnesyl Pyrophosphate
Formation of Squalene, the Precursor
           of Cholesterol
              Terpenes

    Representative Triterpene




tail-to-tail linkage of isoprene units




               Squalene
            (shark liver oil)
Isoprene Links
  Heads or Tails?
Squalene, a triterpene, is a precursor of steroids
      Steroids
• Many hormones are steroids
       The B, C, and D rings are trans fused




Methyl groups at C-10 and C-13 are called angular
                  methyl groups
The A and B rings are also trans fused in most naturally
                  occurring steroids




Substituents on the same side of the steroid ring system
   as the angular methyl groups are b-substituents

   Those on the opposite side of the plane of the ring
              system are a-substituents
Biosynthesis of Cholesterol
Synthetic Steroids
TERPENE BIOSYNTHESES
       in detail

Isopentenyl Pyrophosphate:
The Biological Isoprene Unit
           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).
              The Biological Isoprene Unit

          O                      O    CH3
      3 CH3COH                HOCCH2CCH2CH2OH

                                       OH

                                  Mevalonic acid
        CH3         O O

H2C     CCH2CH2OPOPOH

Isopentenyl pyrophosphate
            Isopentenyl Pyrophosphate


      CH3       O O

H2C   CCH2CH2OPOPOH         or          OPP

Isopentenyl pyrophosphate
    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.
Carbon-Carbon Bond Formation in
     Terpene Biosynthesis
         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.
Carbon-Carbon Bond Formation

        OPP
          +
                      OPP




     –
      OPP

            +
                    OPP
           After C—C Bond Formation...




The carbocation
can lose a proton
to give a double
bond.


                      +
                               OPP
           After C—C Bond Formation...




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


                      +
                                   OPP
           After C—C Bond Formation...




                                    OPP

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




                       OPP


              H2O




                       OH
         Geraniol
                         Terpenes

                        O       O
                        P       P
                    O       O        O
                        O       O
         Isopentenyl pyrophosphate       Isoprene



isoprenyl (C5) --> geranyl (C10)
geranyl (C10) --> farnesyl (C15)
farnesyl (C15) --> squalene (C30)
Generic: C10 monoterpenes,
    C15sesquiterpenes, C20 diterpenes,
     C30 triterpenes, C40 tetraterpenes
         From 10 Carbons to 15

                   OPP
                     +
                                 OPP
Geranyl pyrophosphate




                         +
                                 OPP
From 10 Carbons to 15



                        OPP


                +
           –H



              +
                        OPP
            From 10 Carbons to 15



                                     OPP

This compound is called farnesyl
pyrophosphate.
Hydrolysis of the pyrophosphate ester gives the
alcohol farnesol.
           From 15 Carbons to 20



                                   OPP




                                         OPP
Farnesyl pyrophosphate is extended by another
isoprene unit by reaction with isopentenyl
pyrophosphate.
                  Cyclization

Rings form by intramolecular carbon-carbon
bond formation.

                                             +

                                OPP

         OPP

  E double                  Z double
  bond                      bond
Limonene
                         +
                    –H

                             +
              OH

                   H2O

a-Terpineol
               Bicyclic Terpenes




 +
                        +
                                   +




           +

a-Pinene               b-Pinene
The Pathway from Acetate to
 Isopentenyl Pyrophosphate
                   Terpenes

          O                   O   CH3
      3 CH3COH              HOCCH2CCH2CH2OH

                                  OH

                              Mevalonic acid
        CH3      O O

H2C     CCH2CH2OPOPOH

Isopentenyl pyrophosphate
        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
         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.
  Biosynthesis of Mevalonic Acid
  O    O               O

CH3CCH2CSCoA + CH3CSCoA



           HO   O
      CH3CCH2CSCoA
            CH2COH

                O
        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
  HO

CH3CCH2CH2OH   Mevalonic
                 acid
   CH2COH

       O



 HO    O
CH3CCH2CSCoA
  CH2COH

       O
           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.
          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–.
         Conversion of Mevalonic Acid to
           Isopentenyl Pyrophosphate



CH3CCH2CH2OPP
   CH2


 The product of this elimination is isopentenyl
 pyrophosphate.
        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
      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

    •       •   •       •       H

				
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posted:9/14/2011
language:English
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