Acetylcholinesterase Inhibitors - PowerPoint by HC121106042135

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									    Chapter 19:
Acetylcholinesterase
     Inhibitors
     Bruce A. Hathaway
          CH234


                         1
Types of Enzyme Inhibitors

 Competitive   Reversible Inhibitors
 Irreversible Inhibitors
 Non-Competitive Inhibitors




                                        2
Competitive Inhibitors
   Bind to the active site of the enzyme.
   Exhibit concentration-dependent inhibition: the
    more inhibitor, the greater the inhibition of the
    enzyme.
   Inhibition can be reversed by adding more
    substrate.
   Usually resemble the substrate in chemical
    structure.

                                                        3
ACHE Competitive Inhibitors:
Edrophonium
   Has a quaternary
    ammonium group like
    acetylcholine.
   O-H group can
    hydrogen bond to the            CH3
                           O   N
                                +




    serine O-H group.               CH3
                           H   CH3


                                      4
ACHE Competitive Inhibitors:
Edrophonium
                                                          CH3
                          O                   N
                                                +




                                                          CH3
                          H                   CH3
                          O        H                  -
                                                  O             O
                    H
                                       Acid                C
          Base            CH 2
                                                           (CH2)2

      Basic Group       Serine   Acidic Group       Glutamic Acid

                    Protein "Backbone" of ACHE


                                                                    5
ACHE Competitive Inhibitors:
Neostigmine
   Has a quaternary            Carbamate group
    ammonium group like
    acetylcholine.
                                        O
   Carbamate is similar
                                        C              CH3
    to ester of ACH, but is   (H3C)2N       O     N
                                                   +




                                                       CH3
    harder to hydrolyze.                          CH3




                                                        6
ACHE Competitive Inhibitors:
Neostigmine
                         O
                         C                                     CH3
            (H3C)2N             O                  N
                                                       +




                                                               CH3
                                                   CH3
                         O          H              -
                                               O                O
                   H
                                        Acid               C
         Base            CH 2
                                                           (CH2)2

     Basic Group       Serine   Acidic Group   Glutamic Acid

                   Protein "Backbone" of ACHE

                                                                     7
Neostigmine reacts with the ACHE active
site the same way as ACH does initially.
                       O
                       C                                       CH3
          (H3C)2N              O                  N
                                                          +




                                                               CH3
                                                  CH3
                        O            H                -
                                                  O                O
                  H
                                         Acid                 C
        Base            CH 2
                                                              (CH2)2

    Basic Group       Serine       Acidic Group   Glutamic Acid

                  Protein "Backbone" of ACHE

                                                                       8
The serine OH has now been carbamylated.
Edrophonium drifts away, and water comes
into the active site.
                        O                      Edrophonium
                                                            CH3
        (H3C) 2N        C       O                      N
                                                        +




                                                            CH3
                         O      H              O
                                                   -   CH3 O
                 H
                                                       C
       Base              CH 2       Acid
                                                       (CH2)2

   Basic Group         Serine   Acidic Group   Glutamic Acid

                     Protein "Backbone" of ACHE

                                                                  9
The serine now has a carbamate group.
                        O
                                        H
        (H3C) 2N        C       O

                                    H
                         O                         -
                 H                             O            O
                                                       C
       Base              CH 2       Acid
                                                       (CH2)2

   Basic Group         Serine   Acidic Group   Glutamic Acid

                     Protein "Backbone" of ACHE

                                                                10
The water cleaves the carbamate group
more slowly than an ester group. Therefore,
the ACHE cannot be regenerated as quickly.
                         O
                                         H
         (H3C) 2N        C       O

                                     H
                          O                         -
                  H                             O            O
                                                        C
        Base              CH 2       Acid
                                                        (CH2)2

    Basic Group         Serine   Acidic Group   Glutamic Acid

                      Protein "Backbone" of ACHE

                                                                 11
Irreversible Inhibitors
   Bind to the active site of the enzyme.
   Exhibit concentration-dependent inhibition: the
    more inhibitor, the greater the inhibition of the
    enzyme.
   Inhibition cannot be reversed by adding more
    substrate.
   Usually resemble the substrate in chemical
    structure somewhat.

                                                        12
ACHE Irreversible Inhibitors: Sarin and
Diisopropylfluorophosphate (DFP)
                                             O
   Have phosphate ester H3C
    groups.                         CH   O   P    CH3
   Serine O(-) displaces
                              H3C            F
    the fluorine rather                          Sarin
    than an alcohol
    group.                H3C            O           CH3

                  DFP     H     C   O    P   O   C      H

                          H3C            F           CH3


                                                            13
Sarin reacts with the Serine in the
ACHE active site.
        H3C              O

              CH   O     P      CH3

        H3C              F
                         O        H                -
                                               O            O
                   H
                                      Acid             C
         Base            CH 2
                                                       (CH2)2

     Basic Group       Serine   Acidic Group   Glutamic Acid

                   Protein "Backbone" of ACHE

                                                                14
Water cannot hydrolyze the phosphate
ester bond, so ACHE is inactivated.

        H3C                  O

              CH       O     P      CH3         -
                                            F
        H3C
                             O        H                 -
                   H                                O            O
                                          Acid              C
         Base                CH 2
                                                            (CH2)2

     Basic Group           Serine   Acidic Group    Glutamic Acid

                       Protein "Backbone" of ACHE

                                                                     15
An Antidote for Sarin and DFP
inhibition of ACHE: 2-PAM
   Has a positive N, like
    a quaternary salt.            Oxime
   Oxime OH is more
    basic than water, so it
                                   N
    can react faster with a                     +
                              O           CH   N
    phosphate ester.
                              H
                                               CH3



                                                     16
2-PAM cleaves the phosphate ester bond to
the serine, which reactivates the enzyme.
                      -
                  F
       H3C                  O
                                   CH3
                                          N
                                                               +
             CH       O     P        O          CH            N
                                     H
       H3C                                                    CH3
                            O        H                -
                  H                               O             O
                                         Acid             C
        Base                CH 2
                                                          (CH2)2

    Basic Group           Serine   Acidic Group      Glutamic Acid

                      Protein "Backbone" of ACHE
                                                                     17
2-PAM is now bonded to the Sarin, and the
enzyme active site is now back in action.


        H3C                O
                                    CH3
                                              N
                                                                   +
              CH     O     P          O           CH           N

        H3C                                                    CH3
                               OH         H                -
                                                       O               O
                                              Acid             C
           Base                CH 2
                                                               (CH2)2

       Basic Group         Serine     Acidic Group     Glutamic Acid

                         Protein "Backbone" of ACHE

                                                                           18
Non-Competitive Inhibitors
   Do not bind to the active site.
   Bind to another site (the allosteric site), which
    changes the enzyme shape, or blocks access to
    the active site. This makes it harder for the
    substrate to bind to the active site.
   Inhibition cannot be reversed by adding more
    substrate.
   Often do not look like the substrate.

                                                    19
Non-Competitive Inhibition of ACHE:
A Schematic of the Enzyme
               Allosteric Site

                    Channel
      Enzyme


                Active Site

                     O
                         -




               OH             O




                                  20
 A Non-Competitive Inhibitor of
 ACHE: Propidium Iodide
                                               Propidium iodide is
                    NH2
                                                too big to get through
                                                the channel to the
            I
                -




                          CH2CH3    I
                                        -


                                                active site, and binds
        N
        +




H2N                       N
                           +




                                CH2CH3          to the allosteric site.
                          CH3
                                               Propidium iodide
                                                blocks ACH and
                                                nerve gases from
                                                getting to the active
                                                site.

                                                                      21

								
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