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	? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?
	?                                             ?
	?        WHAT  ELEMENTS  OR  COMPOUNDS        ?
	?                                             ?
	?          ACTUALLY  HOLD  OR  CARRY          ?
	?                                             ?
	?    THE  ELECTRONS  AND  HYDROGEN  ATOMS     ?
	?                                             ?
	?        IN  THE  TRANSFER  SEQUENCES         ?
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	? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?

~~~ BIOLOGICALLY IMPORTANT CARRIERS OF REDUCING EQUIVALENTS ~~~
	METALS:
		Fe, Fe2S2, Fe4S4, Cu, Mn, Mo 
	HYDROXYL  GROUPS:
		alcohols, sugars, hydroxycarboxylic acids, 
		enediols, phenols, polyphenols, quinols 
	SULFHYDRYL GROUPS:
		glutathione, protein thiols, lipoic acid 
	IMINES:
		pyridiniums, flavins, pyrroles, 
		phenazines, biopterin, folates 

		~~~  TRANSITION  METALS  ~~~
So named according to their position in the periodic table, 
   transition metals produce cations of various valences. 
Because fairly low voltage changes are associated with 
   these valence changes, this characteristic is useful 
   to pick up and hold electrons under the relatively 
   mild reaction conditions associated with life. 
Iron, copper, and manganese activate numerous enzymes for 
   purposes of oxidatizing substrates, holding electrons, 
   moving electrons, or reducing substrates. 

     ELEMENT:     METAL:     VALENCES:
      iron         Fe         Fe++ , Fe+++ 
                              Fe++++ , Fe++++++ 
      copper       Cu         Cu+ , Cu++ , Cu+++ 
      manganese    Mn         Mn++ , Mn+++ , Mn++++ 
                              Mn++++++ , Mn+++++++ 

	~~~  FUNCTIONS  OF  COPPER  ~~~

CYTOCHROME  A 
	utilizes oxygen in mitochondria 
SUPEROXIDE DISMUTASE 
	removes -OO* and produces H2O2 
CERULOPLASMIN   
	carries copper to tissues 
	eliminates superoxide from the blood 
	recycles enediols and paraquinones 
AMINE OXIDASES 
	remove: ptomaines, polyamines, histamine, 
		neurotransmitters, vasopressors 
LYSYL OXIDASE 
	converts lysine to aldehyde to crosslink elastin 
CHOLESTEROL OXIDATION 
	oxidative elimination of cholesterol 

		~~~  ORGANIC  SULFUR  OXIDES  ~~~
Due to its size and outer orbital characteristics,
sulfur is highly versatile in its covalent bonding
capabilities with other sulfur molecules and with oxygen.
   NAMES: elemental sulfur        FORMULAE: S8
          thiol                             RSH
          alkyl disulfide                   RSSR'
          disulfide monoxide                RSSOR'
          disulfide dioxide                 RSSO2R'
          disulfide trioxide                RSOSO2R'
          disulfide tetraoxide              RSO2SO2R'
          dialkyl sulfide                   RSR'
          dialkyl sulfoxide                 RSOR'
          dialkyl sulfone                   RSO2R'
          sulfenic acid                     RSOH
          sulfinic acid                     RSO2H
          sulfonic acid                     RSO3H
          sulfonamide                       RSO2NH2
          alcohol sulfate ester             ROSO3H

	~~~ THIOLS / SULFHYDRYL  COMPOUNDS ~~~
Thiols have the general formula RSH. 

Thiols are readily oxidized by a variety of oxidants 
to produce the relatively stable thiyl radical (RS*). 
	RSH   +   [O]    --->   RS*   +   H[O]*   

Thiyl radicals readily couple to produce disulfides (RSSR'). 
	RS*   +   R'S*   --->   RSSR' 

These actions make thiols such as glutathione, 
thioredoxin, and other peptides containing the 
amino acid cysteine handy carriers of hydrogen atoms. 

	~~~ THIOL OXIDATION BY OXYRADICALS ~~~
	Hydroxyl Radical:
		HO*   +   RSH   --->   HOH   +   RS*
	Hydroperoxyl Radical:
		HOO*  +   RSH   --->   HOOH  +   RS*
	Alkoxyl Radical:
		RO*   +   RSH   --->   ROH   +   RS*
	Alkylperoxyl Radical:
		ROO*  +   RSH   --->   ROOH  +   RS*

    ~~~ THIOL OXIDATION BY TRANSITION METALS ~~~
	    RSH  +  Fe+++  --->  RS*  +  Fe++  +  H+ 

	~~~  THIOL  OXIDATION  BY  QUINONES  ~~~
		RSH  +  Q  --->  RS*  +  HQ* 

	~~~   THIOLS   AS   WEAK   ACIDS   ~~~
	 RSH   +   B-   --->   RS-   +   HB 
	-  Thiols can deprotonate at pH = 8. 
	-  This produces the "thiolate anion" (RS-). 
	-  Thiolate can function as a nucleophile. 
	-  Thiolate is more sensitive to oxidation 
	   than the corresponding thiol was. 

	~~~  THIOL  ALDEHYDE  ADDITIONS  ~~~
                     O                 OH 
         R-S-H   +   C-R'  <--->   R-S-C-R' 
                     H                 H 
	Thiols and aldehydes react by nucleophilic 
	  addition to produce "thiohemiacetals". 
	By this mechanism, many enzymes having 
	  thiol(s) as part of the active center are 
	  reversibly inhibited by aldehydes. 
	Also by this mechanism, certain aldehydes 
	  are detoxified by thiols. 

  ~~~  THIOL / DISULFIDE  EXCHANGE  REACTIONS  ~~~
 Such reactions are catalized by thiolate anion and are 
   therefore facilitated by mildly alkaline conditions. 
 Thiols acting as nucleophiles can undergo 
   exchanges with disulfides:
	RSH  +  R'SSR"  --->  R'SSR  +  HSR" 
 Hydrogen sulfide similarly adds to disulfides 
   displacing a thiol:
	HSH  +  R'SSR"  --->  R'SSH  +  HSR" 
 Disulfides can exchange bound thyil groups:
	RSSR'  +  R"SSR'''  --->  RSSR'''  +  R"SSR' 

	~~~ THIOL OXIDATION TO DISULFIDE 
	BY NON-FREE-RADICAL MECHANISMS ~~~

	RSH  +  R'SH  +  [O]  --->  RSSR'  +  H[O]H 
   Examples below show the ubiquitous thiol glutathione 
   (GSH) being oxidized by: 

sulfur:      S8    + 16 GSH  --->  8 H2S  + 8 GSSG 
disulfide:   RSSR  +  2 GSH  --->  2 RSH  +   GSSG 
sulfoxide:   RSOR  +  2 GSH  --->  R-S-R  +   GSSG + H2O 
disulfide monoxide:
             RSSOR +  4 GSH  --->  2 RSH  + 2 GSSG + H2O 
diamide:     D     +  2 GSH  --->    DH2  +   GSSG 
enzyme:      Enz   +  2 GSH  --->  EnzH2  +   GSSG 

   ~~~  DISULFIDE-MONOXIDE  AND  THIOL  REACTIONS  ~~~

	Disulfide-monoxides (RSOSR') first exchange
	  with thiols and then oxidize them.
	    RSOSR' +  R"SH  --->  RSOH   +  R'SSR"
	    RSOH   +  R"SH  --->  HOH    +  RSSR"
	The end result is two oxidized disulfides,
	  capable of absorbing four hydrogen atoms.
	Allicin is a disulfide monoxide, a mild
	  oxidant, and an antibacterial agent.
                 H      H  O     H      H
                  C==C--C--S--S--C--C==C
                 H   H  H        H  H   H

	~~~  THIOL  OXIDATION  BY  DIAMIDE  ~~~

	R'SH  +  R"SH  +  D  --->  R'SSR"  +  DH2 

	-  Diamide is a specific oxidant for thiols. 
	-  It acts most rapidly upon low molecular 
	   weight thiols such as glutathione. 
	-  It works by a combined nucleophilic addition 
	   & displacement mechanism, which cleanly 
	   converts thiols to disulfides. 
	-  It penetrates all compartments rapidly 
	   and is effective both in vivo & in vitro. 
	-  These features make diamide a useful probe 
	   to study thiol to disulfide conversions. 
	------------------------------------------------
                H3C     O           O     CH3 
                   \    ||         ||    / 
                    N---C---N===N---C---N 
                   /                     \ 
                H3C                       CH3 
        ---------------------------------------------
            R'--SH                   R'--S 
                            --->          \   H 
               --N==N--                  --N--N-- 
        ---------------------------------------------
                   HS--R"             R'--S--S--R" 
            R'--S 
                 \   H      --->          H  H 
                --N--N--                --N--N-- 
        ---------------------------------------------

	~~~  THIOLS AS CARRIERS OF ACYL GROUPS  ~~~
                    R--S--C--R' 
                          || 
                          O 

              ~~~   BIOLOGICAL   THIOLS   ~~~
NOTE: These naturally occuring thiols participate
      in numerous physiologic functions and are readily
      and reversibly oxidizable to disulfides.
         "Co-Enzyme A"     "Thioctic (Lipoic) Acid"
      "Cysteine"      "Glutathione"   "Protein Thiols"
---------------------------------------------------------
CO-ENZYME A: 
   beta-amino-ethane-thiol                      1'adenine
           H  H  H                              /
       HS--C--C--N--pantethine--5'pyrophosphate--ribose
           H  H                                 \
                                                3'phosphate

---------------------------------------------------------
THIOCTIC (LIPOIC) ACID:
   Dihydrothioctic Acid (reduced):
            CH2-CH2-CH-CH2-CH2-CH2-CH2-C=O
            |       |                  |
            SH      SH                 OH

   Thioctic Acid (oxidized):
            CH2-CH2-CH-CH2-CH2-CH2-CH2-C=O
             \     /                   |
              S---S                    OH
---------------------------------------------------------
ANALOGUES  OF  CYSTEINE:
---------------------------------------------------------
   SERINE:           COOH 
                      \   H       oxygen as in alcohol 
                      HC--C--OH 
                      /   H  ^ 
                     NH2 
---------------------------------------------------------
   CYSTEINE:         COOH 
                      \   H       sulfur as in thiol 
                      HC--C--SH 
                      /   H  ^ 
                     NH2 
---------------------------------------------------------
   SELENOCYSTEINE:   COOH 
                      \   H       selenium as in selenol 
                      HC--C--SeH 
                      /   H  ^ 
                     NH2 
---------------------------------------------------------
GLUTATHIONE  (GSH) : 
        (gamma-glutamylcysteinylglycine) 
             COOH       O        O        O 
              \   H  H  ||    H  ||    H  || 
               C--C--C--C--N--C--C--N--C--C 
              /   H  H     H  |     H  H   \ 
             NH2             HCH            OH 
                              | 
                              SH 
GLUTATHIYL RADICAL  (GS*) : 
             [tripeptide]--S* 
GLUTATHIONE DISULFIDE  (GSSG) : 
             [tripeptide]--S--S--[tripeptide] 


		~~~   PROTEIN   THIOLS   ~~~
	These include redox active cysteine residues 
	  in their amino acid sequences. 
	They function as hydrogen carriers, physiologic 
	  triggers, redox buffers, and oxidoreductases. 
	Examples:  - Thioredoxin 
	           - Glutaredoxin 
	           - Protein Disulfide Isomerase 
	           - Ref-1 
	           - Transcription Factors 
	           - Growth Factors 
	           - Metallothionein 

---------------------------------------------------------
  PROTEIN THIOLS:
                (Note reduced condition.)
        H  H  O  H  H  O  H  H  O  H  H  O  H  H  O
       HN--C--C--N--C--C--N--C--C--N--C--C--N--C--COH
           |        |        |        |        |
          HCH       X        X       HCH      HCH
           |                          |        |
           SH                         SH       SH
                (Note oxidized condition.)
        H  H  O  H  H  O  H  H  O  H  H  O  H  H  O
       HN--C--C--N--C--C--N--C--C--N--C--C--N--C--COH
           |        |        |        |        |
          HCH       X        X       HCH      HCH
           |                           \      / 
           S--S--R                       S--S 
---------------------------------------------------------

	~~~  MECHANISM  OF  OXIDO-REDUCTASES  ~~~

NOTE: These use the thiol / disulfide half reaction  
      as part of the reductant transfer mechanism.
   1)   Red-H2  +  Enz-SS  --->  Red  +  Enz-(SH)2
   2)   Enz-(SH)2  +  Ox   --->  Ox-H2  +  Enz-SS

    - cys -               - cys -                - cys -
       |                     |                      |
  H    S                     SH                     S   H
[Red]  |  [Ox]  --->  [Red]      [Ox]  --->  [Red]  |  [Ox]
  H    S                     SH                     S   H
       |                     |                      |
    - cys -               - cys -                - cys -

    ~~~ MECHANISM OF INACTIVATION BY MERCURY II ~~~

	Enz-(SH)2  +  Hg++   --->  Enz-SHgS  +  2H+

    - cys -            - cys -          |        - cys -
       |                  |             |           |
       SH                 S             |      H    S
          +  Hg++  --->   Hg  +  2H+    |    [Red]  Hg  [Ox]
       SH                 S             |      H    S
       |                  |             |           |
    - cys -            - cys -          |        - cys -

~~~   ENOLS   MECHANISM   OF   DEHYDROGENATION   ~~~

Enols are composed of one hydroxyl group (HO) 
  attached to the vinylic carbon of an olefin. 

              OH 
              | 
             -C==C- 

When oxidized by the abstraction of the 
  hydroxyl hydrogen, an alkoxyl radical is produced. 
It is stabilized by two point resonance 
  with the conjugated vinyl group. 

              O*                 O 
              |         <--->    |  * 
             -C==C-             -C--C- 

If this structure is further conjugated, 
  then fairly stable radicals can be produced. 

	~~~  UNPROTECTED  PHENOXYL  RADICAL  ~~~
     O*              O               O               O
     |               ||              ||              ||
     C               C               C               C
   //  \           /   \           /   \           /   \
HC       CH     HC*      CH     HC       CH     HC      *CH
 |      ||       |      ||       ||     ||       ||      |
HC       CH     HC       CH     HC       CH     HC       CH
  \\   /          \\   /           \ * /           \   //
     C               C               C               C 
     H               H               H               H
Phenoxyl radicals are stabilized well by 4 point resonance.
However, they are subject to addition reactions at each
  of the 4 exposed radical sites shown: O, C#2, C#4, C#6.

	~~~  PROTECTED  PHENOXYL  RADICALS  ~~~
NOTE: The attached groups protect the four sites 
      of resonance against addition reactions. 
-------------------------------------------------------
 butylatedhydroxytoluene                HC--C--C(CH3)3 
  RO* + BHT-OH -->                     //    \\ 
  ROH + BHT-O*                    CH3--C      C--O* 
                                        \    / 
                                        HC==C--C(CH3)3 
-------------------------------------------------------
 alpha-tocopherol             CH3   CH3--C--C--CH3 
  RO* + E-OH -->               \       //    \\ 
  ROH + E-O*         [turpene]--C---O--C      C--O* 
                                |       \    / 
                                CH2-CH2--C==C--CH3 
-------------------------------------------------------
 ubiquinol                         H3CO--C--C--OCH3 
  RO* + CoQ-OH -->                     //    \\ 
  ROH + CoQ-O*                     HO--C      C--O* 
                                        \    / 
                              [turpene]--C==C--CH3 
-------------------------------------------------------

	~~~  ENEDIOLS  MECHANISM  OF  DEHYDROGENATION  ~~~
Enediols are subject to facile one and two step 
  hydrogen abstractions. 

STEP 1:    OH OH                   O* OH            O  OH 
           |  |    +  [O]  --->    |  |    <--->   ||  | 
         --C==C--                --C==C--          -C--C-- 
                                                       * 

STEP 2:    O  OH                   O  O*            O  O 
          ||  |    +  [O]  --->   ||  |     --->   ||  || 
         --C--C--                --C--C--         --C--C-- 
              *                       * 
The first abstraction is more difficult, because the 
  strong covalent oxyhydrogen sigma bond must be broken 
  to generate an alkoxyl radical. 
However the opportunity for resonance stabilization 
  offerred by the conjugated vinyl group energetically 
  facilitates the abstraction. 
Resonance towards the second hydroxyl group facilitates 
  release of the second hydrogen atom, because all 
  electrons of the final product can be paired. 
This is an example of free radical quenching by oxidation. 

		~~~   ENEDIOL   EXAMPLES   ~~~
-------------------------------------------------
   ASCORBIC ACID                HO      OH
                                  \    /
                              H    C==C
                           H  O   /    \
                          HC--C--CH     C==O
                           O  H   \   /
                           H        O
-------------------------------------------------
   CATACHOLS/                   HO      OH
   ORTHOHYDROQUINOLS              \    /
                                   C==C
                                  /    \
                              R--C      C--R
                                 \\    //
                                R--C--C--R

~~~  PARAHYDROQUINOL  MECHANISM  OF  DEHYDROGENATION  ~~~

Parahydroquinol (QH2):
     HC==CH                       HC==CH 
     /    \                       /    \ 
 HO-C      C-OH  +  [O]  ---> *O-C      C-OH  +  *[O]H 
     \\  //                       \\  // 
     HC--CH                       HC--CH 
Semiquinone (*QH):
    HC==CH  <--->  HC==CH  <--->  HC==CH  <--->  HC--CH 
    /    \         /    \         /    \         /*  \\ 
*O-C      C-OH  O=C      C-OH  O=C     *C-OH  O=C      C-OH 
    \\  //         \*  //         \    /         \    / 
    HC--CH         HC--CH         HC==CH         HC==CH 

Paraquinone (Q):
     HC==CH                       HC==CH 
     /    \                       /    \ 
  O=C     *C-OH  +  [O]  --->  O=C      C=O   +  *[O]H 
     \    /                       \    / 
     HC==CH                       HC==CH 

		~~~  IMINES  ~~~
Imines (also known as Schiff's bases) are compounds 
  containing the carbon to nitrogen double bond. 
			C==N
They can be produced by the reaction of a carbonyl 
  group and a primary amino group at slightly acid pH. 
 \        H           \ /OH          \ 
  C=O  +  N-R   <--->  C      <--->   C=N-R  +  HOH 
 /        H           / \N-R         / 
                         H 
As indicated by the arrows, 
  this reaction is usually reversible.
Imines can also be formed by oxidation.
  \                           \
   CH-NH-R   +   [O]   --->    C=N-R   +   H[O]H
  /                           /
Oxidation is usually followed by hydrolysis, 
  unless the imine is stabilized as in a ring structure. 

~~~ CONJUGATED IMINES AS REDOX ACTIVE COMPOUNDS ~~~
	Structure Activity Relationships: 
          H        H      [O] 
       R--N--C==C--N--R'  ---> 
             H  H 

          *        H 
       R--N--C==C--N--R' <---> 
             H  H 

                *  H      [O] 
       R--N==C--C--N--R'  ---> 
             H  H 

       R--N==C--C==N--R' 
             H  H 

Note how the above is similar to the 
  dehydrogenation of enediols. 
The above steps can be reversed 
  by adding back two hydrogen atoms. 

IMPORTANT IMINE TYPE REDOX AGENTS IN BIOCHEMISTRY:
 Pyridiniums    Flavins    Phenazines    Biopterins 
 Porphins     Pyrroloquinoline-quinones     Folates

~~~ PYRIDINIUMS AS CARRIERS OF REDUCING EQUIVALENTS ~~~

            H                     H H 
   [H]      C                      C 
           / \\  O   H            / \   O   H 
         HC   C--C--N           HC   C--C--N 
          ||  |      H           || ||      H 
         HC   CH                HC   CH 
     _     \ //                   \ / 
    e       N+                     N 
            R                      R 
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