1
Bio-Organic Mechanism Game
Many biomolecules have a complex structure that makes it difficult to write out step-by-step
mechanisms. However, if we simplify those structures to the essential parts necessary to explain
the mechanistic chemistry of each step, it becomes much easier to consider each step through
important cycles. Just below, are proposed simplified biochemical structures for many vitamins
and co-factors that are used in later examples of biochemical metabolic cycles. Often in
biochemical cycles, the strategy is to just write names, or perhaps, names and an occasional
structure. Sometimes multiple steps are combined in a single arrow of a cycle. Occasionally a few
mechanistic steps are suggested, but rarely is a completely detailed sequence of mechanistic steps
provided. Since it is hard to find such detailed mechanistic steps anywhere (sometimes they are
not known) our proposed steps are, of necessity, somewhat speculative. In this book we are not
looking for perfection, which is not possible, but for sound organic logic that is consistent with the
biochemical examples presented below. As more is known, we can modify our proposed steps.
There is great satisfaction in blending organic knowledge with real life reactions that help
explain how life works. In working through some of the problems, you may develop an alternative
mechanism that is just as good, or even better than the one proposed here. When conflicts arise
with book examples and/or the proposed examples, either here or your own, we have discovered a
possible area of research. Speculation is part of what makes it fun and exciting. If you discover a
better mechanism than my mechanism or a book mechanism, I hope you will share it with me. If
an improved version of this book ever gets written it can be included in the next version (with
acknowledgement). It is certain that I have made some errors and I would appreciate it if you
would let me know when you find them.
Biomolecules and our simplified representation.
1. ATP – adenosine triphosphate – phosphorylation, source of high energy bonds
NH2
actual structure - adenosine triphosphate
N
O
O
O
N
O
ribose
O
P
O
ATP
=
O
O
P
O
O
simplified structure
P
O
O
P
O
CH2
O
H
H
OH
H
OH
H
triphosphate
N
O
N
adenine
NH2
actual structure - adenosine triphosphate
N
O
N
O
O
ribose
O
P
O
ADP
=
O
simplified structure
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O
P
O
O
diphosphate
P
O
CH2
O
N
O
H
H
OH
H
OH
H
N
adenine
2
NH2
actual structure - adenosine triphosphate
N
O
N
O
ribose
O
P
O
AMP
O
=
O
P
O
CH2
O
simplified structure
H
H
OH
H
OH
H
monophosphate
N
O
N
adenine
Example reaction mechanisms:
Biochemical cycles:
2. NAD+ (catabolism = breaking down) and NADP+ (anabolism = building up) - nicotinamide
adenine dinucleotide (hydride acceptors) The extra phosphate on the C3 ribose position of NADP
structures probably helps to keep the cycles separate from one another.
NH2
CONH2
N
=
N
N
H2C
O
P
O
P
O
CH2
OH HO
R
O
O
O
simplified
structure
N
O
O
N
H
H
OH
H
OH NADP+ has a
H
actual
structure
N
O
phosphate here.
Example reaction mechanisms:
Biochemical cycles:
3. NADH and NADPH - nicotinamide adenine dinucleotide (hydride donors)
H
H
H
NH2
CONH2
H
N
=
N
N
O
P
O
P
O
CH2
OH HO
O
R
simplified
structure
H2 C
O
actual
structure
Example reaction mechanisms:
Biochemical cycles:
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N
O
O
O
N
O
N
H
H
OH
H
OH NADP+ has a
H
phosphate here.
3
4. Vitamin B-6 – pyridoxal phosphate (amino acid metabolism, transamination with -ketoacids,
decarboxylation, removal of some amino acid side chains, epimerizations)
1o amine version
of Vit B-6
aldehyde version
of Vit B-6
NH2
H
1o amine version
of Vit B-6
O
H
NH2
O
H
H
interconvert
via imine,
tautomers,
hydrolysis
O
-2
O3PO
N
N
H
O
-2
O3PO
N
N
H
simplified
structure
simplified
structure
aldehyde version
of Vit B-6
H
H
actual
structure
actual
structure
5. TPP – Thiamine diphosphate (decarboxylation and enamine chemistry with proton, carbohydrates
or lipoyl amide, used to be called thiamine pyrophosphate = TPP)
N
NH2
R
R
N
N
ylid form of TPP
(we use it this way)
N
B
H
S
pKa  18
N
S
H
O
O
simplified
structure
S
R
O
P
O
O
P
CH2
OH
N
O
S
R
actual
structure
O
enamine form of TPP
(we use it this way)
6. Coenzyme A and acetyl CoA (more general acyl CoA’s are possible) (acyl transfers)
All of this is "Co-A"
OH
H
N
H
O
H
N
S
O
P
actual
structure
O
O
P
O
N
NH2
O
O
O
O
O
N
Thiol esters form here.
N
HO
H
OH
CoA
S
simplified
structure of CoA
O
O
C
CoA
This is an
H
C
S
3
acetyl group
simplified structure
of acetyl Co-A
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This is a more
general acyl
group
CoA
R
S
simplified structure
of acyl Co-A
N
4
7. FAD / FADH2 – Flavin adenine dinucleotide (oxidation – reduction) – used to deliver hydride to
C=C or take hydride from CH-CH (fatty acid metabolism, etc.). Can also be used in 1 electron
transfers.
O
O
P
O
O
P
O
N
NH2
O
O
O
N
HO
OH
actual structure
N
OH
OH
N
N
HO
N
O
N
FAD - flavin dinucleotide
(a hydride acceptor)
NH
N
N
FAD
O
O
O
P
simplified structures
for FAD and FADH2
O
O
P
O
N
NH2
O
O
O
N
HO
OH
actual structure
OH
H
N
N
HO
N
OH
O
N
H
FADH2
flavin dinucleotide hydride
(a hydride donor)
N
NH
N
H
N
O
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H
FADH2
5
8. THF – tetrahdrofolate (transfer of one carbon units in various forms as CH3, CH2, CH) –recycles
cysteine to methionine and other 1C metabolic functions, many variations. Also works in
combination with vitamin B12 (cobalt vitamin).
R
Tetrahydrofolate (THF)
N
H2 N
R
V22-p762
N
H
N
N
H
N
=
5
actual
structure
5
O
N
H
N
One glutamate is
shown, but several
can be attached.
10
H
H
N
10
H
H
N
One carbon groups
can bond here in
various ways (see
below structures.
Ar
simplified
structure
CO2
CO2
O
different forms
R
R
R
R
N
N
N
N
NAD+
5
NADP+
5
NADH
N
N
CH3
HN
N5-methyl THF
H2C
Ar
N
N
resonance
5
N
10
N
10
Ar
Ar
5
N
HC
O
10
Ar
-H2O
+H2O
+NH3
R
-NH3
N
5
HN
HCO2
ATP
THF
5
N
THF
10
O
Ar
N
histidine
N
10
H
R
H
N
N10-formyl THF
10
N ,N -methenyl THF
glycine
or
serine
THF
N
H
-H2O
N
HC
N5,N10-methylene THF
+H2O
5
5
NADPH
10
R
HN
Ar
H
10
NH
9. Biotin –Involved in 1C transfers (CO2 as an activated carbonate derivative is added to activate
C=O for aldol type chemistry and then taken off when no longer needed). Helps at the end of odd
fatty acid chain metabolism (propanoyl CoA  succinate conversion).
simplified structure
O
O
H
N
N
H
H
N
N
H
H
N
S
R
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Ar
N5-formimino THF
N5-formyl THF
lysine amino acid on protein
S
O
6
10. SAM = S-adenosylmethionine (methyl transfer agent), The methyl group (CH3) attached to
the methionine sulfur atom in SAM is chemically reactive. This allows transfer of a methyl group
to an acceptor substrate in transmethylation reactions. More than 40 metabolic reactions involve
the transfer of a methyl group from SAM to various substrates, such as nucleic acids, proteins,
neurotransmitters, lipids and secondary metabolites. SAM can be made from methionine, which is
made from homocysteine (heart health moniter) and N5-methyl THF (just above).
SAM = S-adenosylmethionine
Rmet
leaving group was
triphosphate of an ATP
methionine NH2
Rad
N
NH2
O
O
S
N
S
=
CH3
OH
simplified structure
actual
structure
Rmet = methionine
Rad = adenonine
O
NH2
O
O
P
O
HO
OH
adenosine
SAM = S-adenosylmethionine
O
O
P
O
N
N
CH3
O
N
O
NH2
O
P
O
N
O
S
N
N
methionine
OH
CH3
SN 2
HO
OH
ATP
11. Lipoyl amide – important in fat metabolism
S
R
S
H
TPP enamine
chemistry
FAD
S
oxidized
N
S
R
reduced
simplified structures
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S
H
S
Enzyme
H
O
lipoamide
V2, p 543
7
12. Cytochrom P-450 enzymes are oxidizing agents in the body. They can convert nonpolar
alkane sp3 C-H bonds into polar C-OH bonds, and they can make epoxide groups at alkenes and
aromatic pi bonds. Iron loads up with oxygen by reacting with O2 and subsequent reactions (not
shown) to form the simplified structure that we use. The iron occurs in several oxidation states. In
the Bio-Organic Game we only use the simplified forms below.
Oxidations in the body often use cytochrom P-450 enzymes (free radical chemistry).
Oxygen can add at sixth ligand
location. Possible sequence shown
in separate sequence (just below).
N
N
+3
N
Fe
N
simplified
structure
N
N
simplified
structure
+3
Fe
N
N
+3
N
Fe
N
N
N
S
S
Enz
Enz
HO2C
CO2H
heme, protoporphyrin IX,
found in cytochrom P-450
oxidative enzymes, iron can
exist if various oxidation
states
O
O
The reactions used in the Bio-Organic Game.
O
O
Fe
+2
O
O
We only use this form.
3
sp C-H oxidation
O
iron binds
with O2
oxidation
oxidation
Both oxidized forms of
reaction
reaction
+3
Fe+2
iron will work in the
+3
Fe
Fe
Bio-Organic Game
reactions, but we will
only use the second form
O
O
to keep things simpler.
simplified structures, oxygen reacts like a diradical
+3
Fe
sp3 C-H oxidation
O
pi bond epoxidation
Fe +3
pi bond epoxidation
repeat
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Fe
+2
8
13. Halogenase Enzymes (related to cytochrom P-450 enzymes). The ‘full’ structure below only
shows a simplified form of iron complexed with imidazole ligands from a protein’s histadine
amino acids and a halogen as one of the ligands. The further simplified form used in the BioOrganic Game only shows the iron, halogen and oxygen (in the box).
Halogenations in an organism can occur using iron halogen bonds.
His
His
N
N
N
This is the structure
that we will use.
Cl
N
H
O
O
+4
Fe
+3
Fe
N
O
O
N
N
Fe+3
His
Cl
H
N
O
N
H
H
His
H
O
O
O
hydroxyl radical = danger!
Cl
H
14. Vitamin K (quinone and hydroquinone) – 1 electron transfers through membranes,
photosynthesis, etc.
Vit K (many versions) important in electron transport.
O
OH
gain
2 electrons
2 protons
lose
2 electrons
2 protons
O
OH
simplified structures
O
gain
1 electron
1 proton
R
O
N
Cl
simplified structure
B
Fe+4
His
N
N
OH
OH
gain
1 electron
1 proton
lose
1 electron
1 proton
R
O
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lose
1 electron
1 proton
R
OH
His
9
15. Vitamin B-12 organocobalt compound, free radical isomerizations in odd fatty acid chains,
synthesis of methionine, maintenance of folate levels, crucial to DNA synthesis and cells with a
high turnover (blood cells), mylene sheath of nerve cells
H2NOC
simplified
vitamin B12
CONH2
CH3
N
N
H2NOC
Co
N
N
CONH2
CH3
N
N
N
Co
Co = +3 oxidation state
N
Cobalt is a very uncommon metal in biochemistry.
H2NOC
Vitamin B12 is not made by animals, plants or fungi,
only by bacteria. It has nitrogen at 5 ligand sites and
either OH or CN at the sixth site. Once in a human
body that site is switched for a methyl group (N5-methyl THF).
The ring system is not common either and called a 'corrin' ring.
Without vitamin B12, fatal pernicious anemia occurs.
It is necessary for conversion of homocysteine to
methionine, which also requires N5 methyl tetrahydrofolate.
O
The recommended daily intake is about 2 g. Deficiency
can cause irreversible damage to the brain and nervous
system. Vitamin B12 is used to regenerate folate to produce
thiamine. When not present folate gets trapped as N5 methyl
and cannot make 5,10-methylene tetrahydrofolate used to make
thiamine so fast growing cells (blood cells) cannot make enough
DNA. It is also needed to make SAM used in the synthesis of
neurotransmitters, catecholamines and mylin sheath phospholipids.
It helps in the metabolism of odd carbon fatty acid chains, which
otherwise build up to toxic levels.
N
CONH2
N
C
N
NH
HO
vitamin B12
O
O
O
P
HO
O
OH
Antioxidant structures – vitamin E, vitamin C, glutathione, phenolics from plant diet, etc.
simplified structure
O
H
Vitamin E is located in cell membranes and can quench dangerous free radicals.
R
O
H
R
O
O
Vitamin C reduces vitamin E back to normal and ultimately washes out of the body because it is water soluble.
simplified structures
O
O
O
O
H
O
H
O
O
H
O
O
O
O
O
OH
H
H
O
R
O
reduced vitamin C
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R
O
O
R
oxidized vitamin C
Vitamin C
OH
10
Summary table of simplified biochemical structures
structure of NADH
structure of NAD+
Simplified Bio-Organic Game structures
O
O
H
O
O
P
O
ATP
O
P
O
O
ADP
O
P
O
adenosine triphosphate
NH2
H
AMP
O
aldehyde version
of Vit B-6
interconvert
via imine,
tautomers,
hydrolysis
O
N
N
R
R
adenosine monophosphate
adenosine diphosphate
1o amine version
of Vit B-6
H
ylid form
of TPP
structure of CoA
H
R
O
of lipoyl amide
CoA
S
S
N
R
of acetyl Co-A
reduced
S
O
S
CoA
N
N
H
H
S
S
H
oxidized
S
R
H
SAM =
S-adenosylmethionine
FADH2
FAD - flavin dinucleotide
(a hydride acceptor)
(a hydride donor)
H
Rmet
Halogenase
enzymes
cytochrome P-450
enzymes
Rad
S
N
O
N
CH3
N
+3
Fe
Fe
+2
Rmet = methionine
Rad = adenonine
N
FAD
+4
Fe
+3
Fe
OH
gain
2 electrons
2 protons
vitamin B12
N
O
vitamin K
O
FADH2
H
Cl
CH3
N
Co
N
N
R
N
lose
2 electrons
2 protons
R
O
Tetrahydrofolate (THF)
N5-methyl THF
R
R
N
N
5
5
N
H
N
10
H
5
resonance
NADPH
N
10
H
H2C
Ar
many different forms
(1C transfers)
N
10
5
5
N
N
N
HC
10
Ar
Ar
-H2O
-NH3
+NH3
R
Biotin - carboxyl transfer agent
O
N
NADP+
NADH
N
R
N
N
CH3
Ar
R
R
NAD+
N
OH
N5,N10-methenyl THF
N5,N10-methylene THF
SAM
+H2O
N
N
H
N
N
+H2O
N
N
Ar
5
R
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N
H
N
N
OH
S
histidine
5
H
R
-H2O
R
O
CO2
S
N
N
O
H
10
HC
R
5
H
H
O
HN
NH
HN
10
H
O
Ar
N5-formimino THF
10
O
N
10
Ar
Ar
H
N5-formyl THF
N10-formyl THF
11
Examples Reactions Used in the Bio-Organic Game
Organic reaction mechanisms are usually written to show each step along a path from starting
materials to products. Detailed organic mechanisms will show lone pairs, proper formal charge,
curved arrows to show how electrons move in each step, and possibly, resonance structures. This
is rarely done in biochemical mechanisms, in part, because biochemical molecules are so large and
so complicated. In the following pages, simplified examples of biochemical reactions are used to
introduce transformations similar in biochemistry and organic chemistry. Mechanism arrows used
in the “Bio-Org Game” are meant to suggest how the electrons move over a single transformation,
and are not necessarily meant to imply that all of the electrons and atoms transfer in one huge
“domino” cascade. While organic mechanisms are often multistep transformations, it’s harder to
pin down biochemical transformations. The symbolism used in these examples represents a
concise way to show electron movement involving making and breaking bonds. In this game, lone
pairs are rarely drawn. They are included on the generic base (B:) used to show proton transfers.
A generic acid (H-B+) is used to provide a proton. These are meant to represent a catalytic enzyme
site. Protons are removed or added, as needed, with B: or H-B+. Very occasionally a pair of
electrons is used when it provides some special effect (enamine reaction, resonance stabilization in
acetal formation or breakdown). Multiple resonance structures are not drawn. Only very
occasionally is an intermediate drawn, when confusion arises from too many arrows going in too
many different directions. Do not confuse these examples for real organic mechanisms! They are
designed to provide insight into how changes might occur in complex biochemical reactions.
Also, at physiological pH (7+) a few organic groups are ionized (RCO2H is anionic as RCO2--,
and RNH2 is cationic as RNH3+). They are drawn in their neutral forms in this game to simplify
the drawing of structures. The initial examples of biochemical transformations, just below, serve
as foundational reactions in endless biochemical sequences or cycles. Using these reactions we
can speculate on almost any biochemical transformation, providing insight about many aspects of
metabolism (anabolism = building up and catabolism = breaking down). These exercises can help
improve your organic “mechanistic” logic as well.
One organic example is provided to show the difference between these two ways of writing
mechanisms. The process shown is a simple tautomeric transfer of a proton and a pi bond. The
organic mechanism is longer because it shows each step and resonance intermediate structures. It
can be shown four ways: keto  enol and enol  keto in acid, and keto  enol and enol  keto
in base. The Bio-Organic Game mechanism (Example 1) combines both proton transfers in a
single step and does not show resonance structures. There are only two ways we show this:
keto  enol and enol  keto. Both the acid and base transfers are shown in a single reaction of
the Bio-Organic Game. In fact, this combination of steps may be possible in the active site of an
enzymatic reaction where key basic and acidic sites are held in correct proximity for simultaneous
proton transfers.
The organic way of showing tautomerization. A complete organic mechanism shows lone pairs, formal
charge, curved arrows for each individual step and resonance structures. This can be shown 4 ways:
keto to enol and enol to keto in acid and keto to enol and enol to keto in base. Compare these to the first
Bio-Organic Game reaction below.
keto
H
B
O
keto R
H
C
O
C
R
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R
C
H
resonance R
C
O
B
C
H
R
R
H
H
O
C
R
enol in acid
H
R
C
R
R
R
C
enol
R
12
keto
O
R
O
B
H
C
H
resonance
C
R
R
B
R
C
R
O
R
C
C
R
R
H
O
C
C
keto R
enol in base
R
enol
R
C
R
In the initial examples below, bare-bones biochemical reactions are provided to show the essence
of each type of reaction. A similar simple transformation follows without arrows so you can practice
how to use your own arrows. Following these reactions are several random, but “typical” types of
biochemical transformations in short made-up sequences providing further practice in how to use these
reactions. Finally, real biochemical cycles are shown to illustrate how you can explain the way Nature
works. With such practice, you can learn to recognize where, when and how similar transformations
might be occurring in real biochemical reactions that are presented without any mechanistic detail in a
book or article.
Nature uses a small number of simple strategies, applied to limited classes of molecules
(carbohydrates, lipids, fats, steroids, amino acids, nucleic acids, neurotransmitters, alkaloids,
terpenoids and more) having infinite variation of patterns. It’s amazing what you can speculate
upon using these few reactions. Remember, B: and B-H+ represent a catalytic enzyme site.
1. Tautomer reactions (keto  enol) and (enol  keto)
(two proton transfers and a shift of pi electrons).
H
B
B
H
B = general base,
possibly on an enzyme
O
O
B
C
C
H
R
R
C
R
R
keto
tautomer
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R
H
C
enol
R tautomer
B
H
B = general acid,
possibly on an enzyme
13
B
H
H
H
O
C
H
C
R
R
R
C
B
C
enol
tautomer
R
B
O
B
R
keto
tautomer
R
Supply correct curved arrows to show electron movement in tautomer transformations.
H
B
B
H
H
O
O
B
O
B
H
B
H
H
enol
tautomer
keto
tautomer
B
keto
tautomer
2. Hydration of carbonyl groups (C=O) / dehydration of hydrated carbonyl groups
Forward Direction = hydration = addition reaction
B
O
B
B
H
H
O
H
H
hydration
C
R
H
B
O
C
R
R
carbonyl hydrate
(addition
reaction)
R
O
H
aldehyde or ketone
Reverse Direction = dehydration = elimination reaction
B
B
H
H
O
H
H
B
H
B
O
O
H
B
H
dehydration
O
C
(elimination
reaction)
C
R
R
carbonyl hydrate
R
R
aldehyde or ketone
Supply correct curved arrows to show electron movement.
B
B
H
H
O
B
H
O
H
H
R
O
O
H
C
C
R
B
H
B
O
O
C
R
H
R
R
R
3. Hemiacetal (or hemiketal) formation is an addition reaction to a carbonyl by an alcohol. This
is similar to carbonyl hydration and dehydration using water (just above). The reverse reaction
reforms the carbonyl group and alcohol in an elimination reaction. A second alcohol can react
with the hemiacetal/ketal and undergo an SN1 reaction with the OH to form an acetal or ketal
(Example 4, just below). The example shown here represents a generic intramolecular reaction
and typically forms rings of 5 or 6 atoms. Similar reactions are possible without forming rings.
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14
Forward Direction
H
B
H
H
O
O
C
C
B
B
O
H
R
R
addition
reaction
R
B
O
R
R
R
alcohol
cyclic hemiacetal / hemiketal,
typically 5-6 atoms large
aldehyde or ketone
Reverse Direction
B
H
B
B
H
H
R
B
H
O
O
elimination
reaction
R
R
O
O
C
C
R
R
R
alcohol
cyclic hemiacetal / hemiketal
aldehyde or ketone
B
B
H
H
O
B
B
O
R
O
C
R
H
O
O
C
C
forward
hemiacetal
R
H
O
R
C
O
C
C
B
C
R
H
O
B
C
O
O
C
C
R
H
H
R
O
R
R
forward
hemiacetal
reverse
hemiacetal
R
C
C
pyranose = 6 atom ring
4. Acetal (or ketal) formation from a hemiacetal (or hemiketal). The “OH” becomes a water
molecule leaving group that is replaced by an “OR” in an SN1 reaction, producing an ether
linkage. In the reverse reaction (acetal or ketal forming a hemiacetal or hemiketal) an alcohol
leaving group is replaced by a water molecule in an SN1 reaction. These are reversible
reactions that require acid catalysis. Because arrows are used in both directions on the same
bonds, we show the intermediate in this example. These reactions often occur when one sugar
molecule “OH” connects to another sugar molecule at its hemiacetal site (such as galactose +
glucose  lactose or glucose + fructose  sucrose). Such linkages can go on for hundreds of
y:\files\classes\201\topic 10 Bio-Org Game reactions.doc
B
R
O
O
C
H
H
reverse R
hemiacetal
B
H
R
R
C
furanose = 5 atom ring
B
R
H
R
R
O
R
R
B
O
O
C
R
R
H
B
H
B
R
R
B
reverse
hemiacetal
B
H
O
R
forward
hemiacetal
R
B
C
R
C
R
B
H
O
C
H
B
H
H
B
15
sugar molecules (glycogen in animals and cellulose in plants). Rings of 5 or 6 atoms are most
commonly encountered. (5 atom rings = furanoses, 6 atom rings = pyranoses)
Forward Direction
B
B
H
H
H
O
R
B
H
O
H
R
R
R
R
hemiacetal (R' = H)
hemiketal (R' = C)
O
R'
O
R'
eliminate
H2O
R
O
O
O
R'
H
R
R
add
ROH
acetal (R' = H)
ketal (R' = C)
intermediate
Reverse Direction
B
R
H
H
H
B
B
O
R
O
O
R
R
O
R
R
R
eliminate
ROH
acetal / ketal
O
R
R
R
H
O
O
R
H
H
add
H2O
hemiacetal / hemiketal
intermediate
Supply correct curved arrows to show electron movement.
B
B
H
H
H
H
O
H
O
R
B
R
O
R
O
R
R
R
H
H
R
H
O
R
B
O
H
O
R
H
O
R
O
R
O
R
R
R
B
H
O
R
O
R
R
R
H
O
O
R
B
R
R
R
These reactions may also occur by making the 'OH' into a better phosphate leaving group, followed by an
SN2 reaction by an alcohol.
O
B
H
H
O
R
O
P
O
O
O
B
ATP
PO3
R
O
R
R
O
O
R
R
R
B
O
R
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B
PO3
O
R
R
-2
H
-2
H
O
R
16
5. SN2 reactions at methyl – a strong electron pair donor attacks the backside of a methyl carbon
with a good leaving group in a concerted reaction leading to inversion of configuration. Used
in about 40 known reactions, including epigenetics.
S-adenosyl methionine (SAM-e) to methylate biomolecules.
B
NH2
6
H
Rmet
S
H3C
N 1
5
NH2
H
NH2
B
H 3C
N
H
N
2
CH3
4
Rad
N
N
O
3
N
H
H
H
cytosine
S-adenosyl methionine
O
O
5-methylcytosine
Supply correct curved arrows to show electron movement.
NH2
S
NH2
H3C
H
N
H
H3C
B
H
Rmet
B
NH2
N
N
CH3
N
Rad
O
N
H
N
O
O
H
H
Demethylation - reverse reaction
Rmet
B
H
NH2
Rmet
S
NH2
Rad
H3C
H 3C
N
N
S
6
H
Rad
H
NH2
CH3
N 1
5
N
2
4
O
N
N
O
H
H
5-methylcytosine
cytosine
H
O
3
Supply correct curved arrows to show electron movement.
Rmet
B
H
NH2
Rmet
S
Rad
H3C
N
NH2
S
H3C
H
Rad
N
NH2
CH3
6
H
N 1
5
2
N
O
H
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N
H
O
4
N
H
3
O
17
OH
H
OH
H
Rmet
N
N
H3 C
H
Rmet
S
S
Rad
B
HO
HO
OH
Rad
OH
norepinephrine
epinephrine = adrenoline
Supply correct curved arrows to show electron movement.
OH
H
OH
H
Rmet
N
N
H3C
H
Rmet
S
S
Rad
B
HO
HO
OH
Rad
OH
6. a. Formation of an imine, C=N-R, and water from a C=O (usually an aldehyde or ketone) and a
primary amine (RNH2). We don’t show it but a protonated iminium ion =NHR+, is used in
some tautomer changes instead of the C=O. When protonated, the positive iminium ion is a
better electron pair acceptor than a neutral C=O.
Formation of an imine
B
B
H
H
R
N
B
O
R
H
R
R
aldehyde or ketone
H
N
O
H
H
R
B
B
B
R
H
N
C
addition
reaction
C
H
elimination
reaction
R
O
C
R
aminal
H
R
imine
Supply correct curved arrows to show electron movement.
B
B
H
H
R
N
H
B
O
R
H
N
H
H
H
B
B
B
R
O
C
C
R
H
N
O
R
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R
R
R
R
H
18
b. Hydrolysis of an imine, C=N-R, with water to form a C=O (usually an aldehyde or ketone)
and a primary amine (RNH2)
Hydrolysis of an imine
B
B
H
H
B
H
H
R
O
N
N
R
addition
reaction
R
imine
R
H
N
O
B
O
H
C
C
R
R
H
B
H
B
H
C
R
R
aldehyde or ketone
elimination
reaction
R
aminal
Supply correct curved arrows to show electron movement.
B
H
B
B
H
H
H
R
O
N
R
H
R
N
O
H
N
R
R
B
O
H
C
C
R
B
H
B
H
C
R
R
R
7. a. Formation of an enamine, C=C-NR2, and water from a C=O (usually an aldehyde or ketone)
and a secondary amine (R2NH). The mechanism begins the same as imine formation, but the
second proton is lost from the C position of the carbonyl group since there is no second proton
on a secondary amine. That same C position becomes a good nucleophile with an added push
from the nitrogen lone pair (resonance) in subsequent reactions. We can see that push in
reactions of NADH, TPP enamine and more.
Formation of an imine
B
B
H
H
R
N
R
B
O
R
R
secondary
amine
C
H
C
R2
R
H
R
aldehyde or ketone
B
R
R
N
O
N
C
addition
reaction
H
O
H
H
B
H
H
C
R2
B
elimination
R
reaction
aminal
C
CR2
enamine
Supply correct curved arrows to show electron movement.
B
B
H
H
R
N
O
R
R
C
R
R
B
C
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R
H
B
R
O
H
H
B
H
C
H
C
R2
R
N
O
N
H
C
R2
H
R
B
CR2
19
b. Hydrolysis of an enamine, C=C-NR2, with water to form a C=O (usually an aldehyde or
ketone) and a secondary amine (R2NH).
Hydrolysis of an enamine
B
H
H
H
B
H
R
O
R
R
N
H
B
B
H
R
R
H
R
O
N
C
B
addition
reaction
C
CR2
R
H
C
R2
R
R
N
H
B
H
R
R
H
H
B
H
C
C
R
O
B
R
N
B
O
R
C
H
R
C
R2
CR2
H
C
R2
B
H
N
C
aldehyde or ketone
R
O
O
secondary
amine
R
elimination
reaction
Supply correct curved arrows to show electron movement.
B
B
R
aminal
enamine
H
N
H
C
R2
8. a. Reduction of a carbonyl bond, C=O, to an alcohol, CH(OH), with an NADH equivalent.
The carbonyl bond could be an aldehyde, ketone, ester or thioester. NADH is a hydride donor
that becomes aromatic (forms NAD+) with the transfer of the nucleophilic hydride to the
electrophilic C=O. A nearby acid protonates the oxygen, completing the addition reaction.
Reduction of a carbonyl group (C=O) with NADH
B
H
H
H
H
B
H
O
reduction of
a carbonyl
C
R
N
R
O
H
C
addition
reaction
R
R
aldehyde or ketone
NADH
equivalent
N
R
1o or 2o alcohol
R
NAD+
equivalent
Supply correct curved arrows to show electron movement.
B
H
H
H
H
B
H
O
C
C
R
H
O
R
N
R
R
R
N
R
b. Reduction of an imine, C=N-R, to an amine, CH(NHR), with an NADH equivalent. NADH
is a hydride donor that becomes aromatic (forms NAD+) with the transfer of the nucleophilic
hydride to the electrophilic C=O. A nearby acid protonates the nitrogen, completing the
addition reaction.
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20
Reduction of an imine
B
H
H
H
B
R
N
C
R
R
N
addition
reaction
N
R
H
H
reduction of
an imine
H
C
R
R
N
R
NADH
equivalent
imine
amine
Supply correct curved arrows to show electron movement.
B
H
H
H
R
B
NAD+
equivalent
H
H
R
R
N
N
H
C
C
R
R
N
R
R
N
R
R
9. a. Oxidation of an alcohol, CH(OH), to a carbonyl group, C=O, (1o ROH  aldehyde, 2o ROH
 ketone, hydrated aldehyde  carboxylic acid, thioacetal  thioester) with an equivalent of
NAD+. NAD+ accepts a hydride via conjugate addition, quenching the positive charge on the
nitrogen and forms NADH. A base removes a proton from the adjacent oxygen atom allowing
an elimination reaction to produce the C=O.
Oxidation of an alcohol with NAD+ (1o ROH
thioacetal
thioester).
H
B
aldehyde, 2o ROH
ketone, hydrated aldehyde
B
R
O
H
H
H
H
R
oxidation of
an alcohol
C
R
carboxylic acid,
H
N
1o or 2o alcohol or
a hydrated aldehyde
or thioacetal
C
elimination
reaction
R
O
N
R
R
+
aldehyde, ketone,
acid or thioester
NAD
equivalent
NADH
equivalent
Supply correct curved arrows to show electron movement.
H
B
H
B
R
O
H
H
H
R
C
R
H
C
N
O
N
R
R
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R
21
b. Oxidation of an amine, CH(NH), to an imine, C=N-R, (amines  imines) with an equivalent
of NAD+. NAD+ accepts a hydride via conjugate addition, quenching the positive charge on
the nitrogen and forms NADH. A base removes a proton from the adjacent nitrogen atom
allowing an elimination reaction to produce the C=N-R. Imines are often then hydrolyzed to
C=O and an amine by addition of water.
Oxidation of an amine to an imine (which can hydrolyze to a carbonyl).
R
N
H
B
R
H
H
H
elimination
reaction
C
R
H
N
R
C
N
N
R
R
NAD+
equivalent
amine
B
R
R
oxidation of
an amine
NADH
equivalent
imine
Supply correct curved arrows to show electron movement.
R
N
H
H
B
R
H
H
B
H
R
R
C
R
H
C
H
N
N
N
R
R
R
10. Reactions of ATP (many variations).
a. Phosphorylation of an OH (alcohol or phenol) with an ATP equivalent makes an inorganic
phosphate ester (can turn on or turn off an enzyme).
O
O
O
O
O
R
R
P
O
O
O
P
O
P
O
P
O
O
C
O
O
O
acyl-like
substitution
reaction
+2
Mg
H
R
O
B
Complexing with Mg+2 can make one phosphorous atom
more electrophilic and another one a better leaving group.
The Mg+2 is not required to show this reaction. Mg+2
is not used in the other reactions below, but it could be.
O
R
R
C
R
P
O
O
O
P
O
P
R
C
O
R
O
ATP
H
B
P
O
ADP
O
O
R
C
R
O
O
P
O
O
O
P
B
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O
inorganic phosphate ester
R
H
P
O
O
O
O
ADP = leaving group
O
O
ADP
O
Supply correct curved arrows to show electron movement.
O
O
Mg+2
R
O
P
ATP
O
O
H
B
22
b. Dephosphorylation of an inorganic phosphate ester to an alcohol or phenol and phosphate
(can turn on or turn off an enzyme). Mg+2 (or other cation, Zn+2, Ca+2, etc.) can make the
phosphate a better leaving group.
B
H
O
R
R
C
O
O
P
R
H
B
inorganic
ester
hydrolysis
O
R
O
B
acyl-like
substitution
reaction
H
H
R
O
C
O
O
P
H
R
H
O
O
B
Supply correct curved arrows to show electron movement.
B
R
C
O
R
B
H
O
R
O
P
B
H
H
R
O
R
O
O
C
O
P
H
R
H
O
H
O
O
B
c. Formation of high energy mixed phosphate anhydrides is possible with carboxylic acids
using ATP.
O
O
O
P
O
O
ATP
O
C
acyl-like
substitution
reaction
O
O
H
R
O
P
ADP
O
ADP = leaving group
O
H
mixed anhydride
carboxylic acid
O
O
C
R
B
P
O
O
B
Supply correct curved arrows to show electron movement.
O
O
O
O
P
O
ATP
O
O
C
R
P
O
O
C
O
O
R
H
B
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O
P
O
O
H
B
O
ADP
23
d. Making an ATP from a high energy enol phosphate (or other similar high energy compound,
like 1,3-diphosphoglycerate).
O
O
O
P
O
O
O
O
P
O
P
O
O
ADP
O
P
O
P
O
O
P
O
ATP
O
ATP
O
O
O
O
acyl-like
substitution
reaction
R
H
enol
phosphate
B
O
O
O
O
O
R
Supply correct curved arrows to show electron movement.
O
O
O
O
P
O
O
O
P
O
P
O
O
ADP
O
O
O
O
P
P
O
O
P
O
O
O
R
H
B
R
O
O
ADP-O
P
O
-2
H
B
O
O
P
O
P
B
O
-2
PO3
O
ADP
ATP-O
O
O
PO3
O
O
O
O
ATP
acyl-like
substitution
P
O
O
H
O
O
O
1,3-bisphosphoglycerate
3-phosphoglycerate
H
O
H
Supply correct curved arrows to show electron movement.
O
O
ADP-O
P
O
-2
H
B
PO3
O
O
O
P
O
P
B
O
-2
O
PO3
O
O
P
O
ATP-O
O
O
O
H
O
O
O
O
O
H
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H
24
e. An elimination reaction of a phosphate leaving group to make an alkene (pi bond). Could
actually be E1 or E2. Converting a poor OH leaving group into a phosphate makes it a much
better leaving group.
O
R
R
O
P
R
E1 or E2 (anti)
mechanisms
are possible
O
C
C
R
R
O
P
O
O
C
C
R
R
R
H
B
H
O
H
O
B
H
Supply correct curved arrows to show electron movement.
O
R
R
O
P
R
R
O
C
C
O
H
B
H
O
P
O
C
C
R
R
B
H
O
H
O
R
R
11. Formation of esters and high energy thioesters using high energy anhydrides.
B
B
organic-inorganic O
anhydride
H3C
acyl-like
substitution
reaction
O
O
P
S
O
H
O
O
B
O
H
O
P
Supply correct curved arrows to show electron movement.
B
B
H
S
C
H3C
A-oC
Co-A
H3C
O
H
S
O
H
O
P
B
O
H
O
O
O
phosphate
leaving group
O
B
O
very reactive thiol ester
(acetyl Co-A and other
acyl CoA's)
Co-A
S
C
H3C
O
H
CoA
H
B
P
O
O
12. Aldol reactions make a new carbon-carbon bond, forming a -hydroxycarbonyl compound. A
carbonyl C position becomes the nucleophile (as enol or enolate) and reacts with a separate
electrophilic carbonyl carbon. Reverse aldol reactions cleave the C-C bond, leaving the
electrons on a carbonyl C position and forming a C=O at the C-OH position. The aldol
y:\files\classes\201\topic 10 Bio-Org Game reactions.doc
25
product can proceed on an additional step as shown in Example 13 (reverse Michael 
,-unsaturated carbonyl compounds).
Forward Aldol
B
B
B
H
H
C
C
C
R
R
carbonyl electrophile
O
aldol
(addition
reaction)
O
O
H
C
R
R
H
O
C
C
R
This product also looks
like a Michael reaction.
See Example 13.
R
R R
R
R
carbonyl nucleophile
at C carbonyl position
B
-hydroxycarbonyl
Supply correct curved arrows to show electron movement.
B
B
H
B
H
O
O
C
H
C
C
R
R
O
R
C
R
H
O
B
C
R
C
R
R
R
R R
Imine groups can also be proposed to react this way (probably protonated). The nucleophilic
carbon could also be in its enamine form, so there are many variations of this reaction.
Forward Aldol
B
B
B
H
O
R
N
C
H
C
C
R
R
carbonyl electrophile
H
R
R
R
carbonyl nucleophile
at C carbonyl position
R
N
aldol
(addition
reaction)
C
R
H
O
B
C
C
R
This product also looks
like a Michael reaction.
See Example 13.
R
R R
-hydroxycarbonyl
Supply correct curved arrows to show electron movement.
B
B
H
B
O
R
N
C
R
R
R
R
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R
C
R
H
O
N
C
H
C
R
H
C
C
R
R R
R
B
26
Reverse Aldol
B
H
H
R
reverse
aldol
(elimination
reaction)
O
N
C
R
B
C
C
B
B
H
R
O
N
H
C
R
R
R
C
C
R
R
R R
-hydroxycarbonyl
R
R
Supply correct curved arrows to show electron movement.
B
H
H
R
N
B
R
O
N
C
C
B
H
O
C
R
B
H
C
R
R
R
C
C
R
R
R R
R
R
Reverse Aldol of imine
B
H
B
R
H
O
N
C
R
reverse
aldol
(elimination
reaction)
C
C
B
H
R
N
O
R
R
C
H
C
R
B
C
R
R
R R
-hydroxyimine (or iminium ion)
R
R
Supply correct curved arrows to show electron movement.
B
H
H
R
O
N
C
C
R
C
R
R
R R
B
reverse
aldol
(elimination
reaction)
B
H
R
N
O
H
C
R
C
C
R
R
R
R
13. Claisen reactions make a new carbon-carbon bond, forming -ketocarbonyl compounds. A
carbonyl C position becomes the nucleophile (as enol or enolate) and reacts with a separate
electrophilic carbonyl carbon (similar to Example 12, except carbonyl substitution occurs
instead of carbonyl addition). Ester groups are common in organic chemistry and both ester
and thiol ester groups (acetyl CoA) are common in biochemistry. Reverse Claisen reactions
cleave the C-C bond leaving the electrons on the carbonyl C position and forming a
carboxyl at the C=O position. The tetrahedral intermediate is omitted in the Bio-Organic
Game. Both of these reactions occur in fat metabolism (anabolism = bond formation and
catabolism = bond breakage).
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B
27
Forward Claisen
B
H
B
B
O
O
O
C
R
C
H
R
R
C
S
Claisen
(acyl substitution)
S
R
S
B
R
S
R R
-ketocarbonyl
ester or
thiol ester
alcohol
or thiol
B
B
B
C
C
H
R
carbonyl electrophile with
carbonyl
a leaving group, (often and
nucleophile
ester or thiol ester or a
mixed anhydride)
Supply correct curved arrows to show electron movement.
H
C
R
R
H
O
O
H
O
B
O
O
C
C
R
R
C
H
C
S
R
C
S
S
R
R
C
R
R
R R
S
R
H
Reverse Claisen
O
-ketocarbonyl
H
O
C
R
B
reverse Claisen
(acyl substitution)
O
C
R
C
S
R R
R
C
R
H
C
carbonyl electrophile
with a leaving group,
(often and ester or
thiol ester)
B
H
alcohol
or thiol
Supply correct curved arrows to show electron movement.
R
H
S
H
B
B
C
R
C
R
C
R
C
O
B
O
R
ester or
thiol ester
R
O
O
R
C
S
R
S
B
O
C
H
S
C
R
S
R
R
S
R
R R
S
H
B
H
B
14. Michael reactions (conjugate addition) and reverse Michael reactions (eliminations). Reactions
13 and 14 are common reactions in fat metabolism. Water is shown here as the nucleophile, but
alcohols (and other nucleophiles) also work. If you can think it, Nature has probably done it.
a. Michael Reaction = conjugate addition
H
B
H
R
O
C
C
B
O
R
C
(addition)
-unsaturated carbonyl
(Michael acceptor)
O
Michael
reaction
R
R
H
H
O
C
C
R
C
R
R
H
y:\files\classes\201\topic 10 Bio-Org Game reactions.doc
B
This product looks like
an aldol product. See
Example 12. It is now
able to do a reverse aldol,
or be oxidized to a
1,3-dicarbonyl, maybe
R followed by decarboxylation,
or retro Claisen, etc.
H
-hydroxycarbonyl B
28
Supply correct curved arrows to show electron movement.
H
B
H
O
R
O
C
C
B
H
H
O
R
C
O
C
R
C
R
H
R
C
B
R
R
R
B
H
b. Reverse Michael Reaction = elimination reaction
B
B
H
H
O
O
C
C
R
H
reverse
Michael
reaction
C
R
H
-hydroxycarbonyl
O
C
C
R
C
(elimination)
R
R
R
R
R
O
-unsaturated carbonyl
(Michael acceptor)
H
B
H
B
H
B
Supply correct curved arrows to show electron movement.
B
B
H
H
H
H
O
O
C
C
R
R
O
C
C
R
C
R
H
C
R
R
R
R
O
B
15. Decarboxylation (-CO2) of a -ketocarboxylic acid, forming an enol, which tautomerizes to a
keto group. You can show the product as the enol tautomer or the keto tautomer.
H
O
B
B
O
O
R
O
decarboxylation
to enol tautomer
C
C
C
B
H
H
B
carbon
dioxide
C
tautomers
B
H
C
R
B
C
R
R
enol tautomer
R
R
-ketocarboxylic acid
H
O
O
R
C
R
O
H
C
R
keto tautomer
Supply correct curved arrows to show electron movement.
H
O
B
H
O
O
C
C
R
C
R
B
B
H
O
H
C
B
H
O
O
H
C
O
R
y:\files\classes\201\topic 10 Bio-Org Game reactions.doc
C
R
R
R
C
C
R
R
B
R
B
29
H
B
B
O
O
C
C
B
O
H
C
R
C
C
R
R
R
-ketocarboxylic acid
B
H
B
C
H
R
decarboxylation
to keto tautomer
O
H
O
O
carbon
dioxide
R
keto tautomer
Supply correct curved arrows to show electron movement.
H
B
B
O
O
C
C
B
O
H
O
R
C
R
C
H
C
R
C
O
O
R
R
16. Decarboxylation of an -ketocarboxylic acid with TPP (thiamine diphosphate = newer name,
the old name was thiamine pyrophosphate). Also includes both “TPP ylid” and “TPP
enamine” chemistry. The enamine can be protonated to form an aldehyde (a smaller
carbohydrate) or it can react with another carbonyl compound to make a new carbon-carbon
bond (a larger carbohydrate in this game) or it can react with lipoly amide to make a C-S bond
(leading to a thioester). The TPP ylid is also regenerated, which can react again or protonate to
make TPP. See another reaction of -ketocarboxylic acids with Vit B-6 in Example 21.
TPP reaction with an -ketoacid, decarboxylation and formation of enamine.
R
OH
R
B
N
O
H
B
R O
N
C
H
S
TPP
pKa  18
S
TPP ylid
We use it
this way.
R
-ketoacid
B
H
C
O
O
C
N
C
TPP ylid
addition to
a carbonyl
S
OH
R
decarboxylation
(-CO2)
R
OH
N
C
S
TPP enamine
y:\files\classes\201\topic 10 Bio-Org Game reactions.doc
H
B
O
R
C
O
30
Supply correct curved arrows to show electron movement.
H
B
O
R
R
B
OH
O
N
N
H
S
S
R O
B
C
C
O
S
O
OH
N
C
R
C
R
O
N
C
B
H
H
OH
C
S
R
R
Reaction of TPP enamine nucleophile with a carbonyl electrophile followed by an E2-like reaction to from
a new (larger) carbohydrate.
R
B
R
R
N
B
OH
C
R
N
O
N
C
C
S
H
O
OH
H
C
R
R
S
R
TPP enamine
reaction with C=O
R
R
TPP enamine
addition to
a carbonyl
S
TPP ylid
elimination
reaction forms
a carbonyl group
H
O
C
R
B
OH
C
R
R
a new (larger) carbohydrate
R
Supply correct curved arrows to show electron movement.
R
H
O
OH
N
S
H
O
S
R
O
OH
C
R
B
N
R
N
C
H
C
B
H
B
C
S
R
C
R
R
H
R
OH
C
R
Reaction of enamine nucleophile with an acid to from a new (smaller) aldehyde carbohydrate.
B
R
R
N
OH
N
C
H
S
R
TPP enamine reaction
with a proton
y:\files\classes\201\topic 10 Bio-Org Game reactions.doc
B
C
S
acid/base
protonation of
TPP enamine
H
O
R
H
R
O
N
H
S
elimination
reaction forms TPP ylid
a carbonyl group,
similar to a
reverse aldol
B
C
R
H
a new (smaller)
carbohydrate
31
Supply correct curved arrows to show electron movement.
R
R
N
OH
N
H
C
S
B
H
O
S
H
B
O
N
C
R
R
B
H
C
S
R
H
R
17. Decarboxylation by E2 or E1 reactions with a good phosphate leaving group to make an alkene
(pi bond). This reaction occurs in the mevalonate pathway leading to steroids and terpenes.
H
O
a
R
R
O
C
R
O
P
O
C
B
O
decarboxylation
combined with
phosphate leaving
group
C
H
O
P
O
O
R
R
O
H
O
C
C
R
R
O
O
B
C
R
H
Supply correct curved arrows to show electron movement.
H
O
R
R
O
P
O
C
O
O
R
R
R
O
B
B
O
H
C
C
C
C
H
O
P
O
R
O
C
H
O
O
R
R
b. Hydrated carbonyl forming formate - part of cholesterol synthesis (D ring demethylation).
H
O
O
O
O
O
B
decarboxylation
combined with
phosphate leaving
group
CH
H
O
H
O
O
P
C
O
P
O
OH
H
B
H
O
H
Supply correct curved arrows to show electron movement.
H
O
O
P
O
O
O
C
O
B
H
H
CH
O
H
y:\files\classes\201\topic 10 Bio-Org Game reactions.doc
H
O
O
B
H
OH
O
P
O
32
18. FADH2 reduction (hydrogenation, also by NADPH) of C=C to CH-CH or the reverse reaction,
FAD oxidation of CH-CH to a C=C (dehydrogenation). Important reactions in fat metabolism.
FAD can also be recharged with NADH.
Simplified mechanism of action for reduction of C=C by FADH2
FAD (oxidation of FADH2 to FAD)
O
An ,-unsaturated
fatty acid chain.


CoA
R
A saturated fatty
acid chain.
S
H
S
H H
B
B
N
B
N
H
N
FADH2
B
CoA
R
H
N
O
H H
FAD
H
Supply correct curved arrows to show electron movement.
O
O
H H
CoA
R
CoA
S
R
H
H
N
H H
B
B
N
B
N
B
S
H
N
H
Reverse Michael reaction = reduction of FAD, oxidation of -CH2CH2- to -CH=CHH
H
N
N
FADH2 - flavin
dinucleotide
(a hydride donor)
FAD - flavin dinucleotide
(a hydride acceptor) used
to reoxidize fats for energy.
N
N
H
H
H
C
C
C
R
H
O
Enz
S
C
H
FADH2
O
H
R
B
B
B
A saturated fatty acid chain.
y:\files\classes\201\topic 10 Bio-Org Game reactions.doc
Enz
C
C
S
H
H
An ,-unsaturated fatty acid chain.
B
33
Supply correct curved arrows to show electron movement.
H
N
H
B
N
N
H
H
O
H
H
C
C
R
B
N
C
Enz
O
C
C
S
FADH2
R
Enz
C
S
H
H
H
B
B
H
NADH recharge of FAD (...or could be run the other way).
H
H
NADH
H
N
N
N
N
B
FAD
H
R
N
N
R
B
H
Supply correct curved arrows to show electron movement.
H
H
H
N
NAD+
FADH2
N
N
N
B
H
R
N
N
R
B
H
19. Lipoyl amide – important in fat metabolism, cycles between oxidized and reduced forms.
R
H
S
O
B
R
H
O
N
S
B
B
H
R
O
N
S
S
S
R
H
N
S
TPP enamine
R
oxidized
lipoyl amide
S
SH
S
R
H
TPP ylid
S
fat metabolism
H
glycolysis
gluconeogenesis
(Enz too)
H
TCA cycle
steroid
structures
S
S
reduced
lipoyl amide
CoA
citric acid
cycle
y:\files\classes\201\topic 10 Bio-Org Game reactions.doc
CoA
B
O
acetyl CoA
(a part of many cycles)
S
R
H
34
Supply correct curved arrows to show electron movement.
R
H
S
O
O
N
S
B
R
H
B
B
R
O
N
N
S
S
S
S
R
H
H
S
SH
SH
R
S
R
H
B
glycolysis
gluconeogenesis
fat metabolism
H
S
TCA cycle
steroid
structures
CoA
(Enz too)
S
S
CoA
citric acid
cycle
R
acetyl CoA
O
H
Oxidation back to lipoyl amide disulfide structure with FAD (hydride acceptor)
B
H
B
H
S
S
N
S
R
S
B
H
H
N
R
B
N
H
FAD
N
H
N
B
N
H
N
R
FAD
B
H
N
R
N
R
H
FADH2
NADH
NAD+
Supply correct curved arrows to show electron movement.
B
H
S
B
S
H
FAD
B
S
R
R
B
N
H
N
B
y:\files\classes\201\topic 10 Bio-Org Game reactions.doc
H
H
N
N
N
H
N
H
H
N
B
S
R
H
35
20. THF chemistry (tetrahydrofolate): 1C metabolism
R
R
R
N
N
N
N
S
CH3
5
(vitamin B12
participation)
5
R
H
N
CH2
10
H
R
5
N
H
Ar
N
10
N
10
H
CH2
Ar
H
H
B
N
Ar
O
B
H
N
R
NAD+
R
R
H
R
B
N
-2
PO3
N
N
5
O
O
N
5
5
N
H
H
N
H
N
C
10
H
C
Ar
O
N
O
10
H
Ar
B
B
H
B
H
N
N
Ar
B
N
NAD+
R
N
R
H
H
R
R
10
HN
5
N
resonance
5
5
N
N
N
HC
N
C
Ar
O
H
10
10
H
N
HC
Ar
Ar
B
H
R
B
R
H
N
N
possible addition
of methyl group
to vitamin B12
N
Co
N
N
N
N
5
N
vitamin B12
10
N
CH3
N
H
y:\files\classes\201\topic 10 Bio-Org Game reactions.doc
Ar
N
5
Co
N
N
N
vitamin B12
H
N
10
CH3
N
H
10
Ar
36
Supply curved arrows to show electron movement.
R
R
R
N
N
N
R
N
S
CH3
5
(vitamin B12
participation)
5
H
N
CH2
10
H
R
5
N
H
Ar
N
10
N
10
H
CH2
Ar
H
H
B
N
Ar
O
B
H
N
R
NAD+
R
R
H
R
B
N
-2
PO3
N
N
5
O
O
N
5
5
N
H
H
N
H
N
C
10
H
C
Ar
O
N
O
10
H
Ar
B
B
H
B
H
N
N
Ar
B
N
NAD+
R
N
R
H
H
R
R
10
HN
5
N
resonance
5
5
N
N
N
HC
N
C
Ar
O
H
10
10
H
N
HC
Ar
Ar
B
H
R
B
R
H
N
N
possible addition
of methyl group
to vitamin B12
N
Co
N
N
N
N
5
N
vitamin B12
10
N
N
H
y:\files\classes\201\topic 10 Bio-Org Game reactions.doc
10
Ar
N
5
Co
N
N
N
vitamin B12
H
N
CH3
CH3
N
H
10
Ar
37
21. Biotin – also involved in 1C transfers (activated CO2 added to activate C=O for aldol type
chemistry and then taken off when no longer needed, fatty acid metabolism).
H
activated carbonic acid - good phosphate leaving group
O
P
O
H
HO
B
O
O
B
O
O
P
O
ATP
HO
O
O
O
P
O
O
O
ADP
O
O
Biotin - carboxyl transfer agent
O
H
H
N
O
H
N
H
O
O
B
B
B
H
O
N
O
N
OH
P
HO
CoA
O
S
O
O
R
S
H
R
S
H
B
propionyl CoA
V2, p 674
O
O
H
repeat
N
O
H
N
CoA
HO
S
H
activated carbonyl
(CO2 lost after essential reaction)
R
S
H
Supply correct curved arrows to show electron movement.
O
O
P
O
H
HO
O
O
B
O
B
P
O
ATP
HO
O
O
O
P
O
O
O
ADP
O
O
Biotin - carboxyl transfer agent
O
H
H
N
N
O
H
B
B
H
O
N
O
N
OH
P
HO
CoA
O
S
O
O
S
H
O
O
B
R
S
R
H
B
O
repeat
H
N
N
O
H
O
CoA
HO
S
y:\files\classes\201\topic 10 Bio-Org Game reactions.doc
R
S
38
22. Vit B-6 reactions – There are many.
1. imine formation with -keto acid and the amino version of Vit B-6 (similar to Example 6a),
B
H
OH
B
H
H
O
B
OH
H
OH
O
N
N
H
N
O
R
-keto acid
becomes
-amino acid
B
R
imine
synthesis
N
O
R
H
H
N
O
B
dehydration
(-H2O)
N
O
H
vitamin B-6
(1o amine version)
H
H
vitamin B-6
(imine version)
H
Similar to aminal example.
H
Supply correct curved arrows to show electron movement.
B
H
H
B
OH
H
O
O
N
H
H
B
OH
OH
N
N
O
O
R
R
O
B
N
N
H
R
H
H
B
N
O
H
H
H
H
2. tautomerization (Example 1
B
OH
OH
B
H
H
B
H
N
O
H
R
keto / enol
tautomerization,
moves imine from
one side to the
other side
N
O
B
H
R
Similar to Example 1.
N
N
H
H
y:\files\classes\201\topic 10 Bio-Org Game reactions.doc
39
Supply correct curved arrows to show electron movement.
B
OH
B
OH
H
H
B
H
N
N
O
O
H
B
R
H
R
N
N
H
H
3. imine hydrolysis to  amino acid and the aldehyde version of Vit B-6 (similar to Example 6b).
B
H
OH
H
H
O
H
B
B
H
H
B
B
H
H2N
OH
O
O
N
O
hydrolysis
of imine
(elimination)
N
N
N
H
H
vitamin B-6
(imine version)
H
vitamin B-6
(aldehyde version)
Similar to aminal example.
Supply correct curved arrows to show electron movement.
B
H
OH
H
B
H
B
H
H
R
-amino acid,
came from
 keto acid
R
addition
of water
R
H
O
O
O
H
H
H
N
H
OH
B
B
B
B
OH
H
H
H 2N
OH
O
H
H
O
N
N
O
H
O
O
R
R
N
N
N
H
H
H
y:\files\classes\201\topic 10 Bio-Org Game reactions.doc
R
40
Three additional vit B6 reactions from aromatic imine using pyridinium ion as an electron sink.
1. Decarboxylation
H
O
B
C
H
O
B
H
O
O
H
N
N
H
B
H
B
H
B
N
H
H
O
R
H
R
R
decarboxylation
N
N
N
H
H
H
O
H
B
H
H
H
O
N
N
H
R
R
N
N
H
H
Supply correct curved arrows to show electron movement.
H
O
B
C
H
O
B
H
O
O
H
N
N
H
B
H
B
N
H
H
O
R
H
R
R
decarboxylation
N
N
N
H
H
H
O
B
H
H
H
H
H
O
N
B
N
H
R
R
y:\files\classes\201\topic 10 Bio-Org Game reactions.doc
N
N
H
H
41
2. Elimination of side R group, like serine or threonine.
serine aa
H2C
B
H
O
B
O
H
N
H
B
H
O
H
N
B
N
CO2H
CO2H
CO2H
decarboxylation
N
N
H
vitamin B-6
(imine version)
N
H
H
H
B
B
Propose a mechanism.
also threonine aa
H
O
O
O
N
H
H
H
H
H
N
O
N
B
H
H
H
CO2H
B
CO2H
N
CO2H
glycine aa
N
H
N
glycine aa
CO2H
H
H
vitamin B-6
(aldehyde version)
N
H
Supply correct curved arrows to show electron movement.
H2C
B
H
O
B
O
H
N
H
B
H
O
H
N
B
N
CO2H
CO2H
CO2H
N
N
H
H
N
B
B
H
H
H
also threonine aa
H
O
O
O
H
B
H
N
N
H
H
O
N
H
H
H
CO2H
B
CO2H
N
CO2H
N
H
H
N
glycine aa
CO2H
H
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N
H
42
3. Epimerize a proton at the C position of an amino acid.
S amino acid
H
proton adds on
the opposite face
B
N
R
H
N
CO2H
B
R amino acid
R
N
R
H
CO2H
CO2H
N
H
vitamin B-6
(imine version)
N
N
H
H
vitamin B-6
(imine version)
Supply correct curved arrows to show electron movement.
H
N
B
B
N
R
H
B
N
R
H
CO2H
CO2H
CO2H
B
R
N
N
N
H
H
H
23. Vitamin B12 – Not ready for prime time yet (load up methyl from N5-methyl THF).
24. Cytochrom P-450 oxidation of sp3 C-H bonds to make sp3 C-OH groups.
R
R
O
H
C
H
R
alcohols
R
sp3 C-H bonds
C
H
R
O
O
C
R
R
R
Fe +3
Fe +3
The free radical-like oxygen atom abstracts
a hydrogen atom from a sp3 C-H bond in the
enzyme cavity, forming an O-H bond and a
carbon free radical.
R
Fe +2
The carbon free radical abstracts hydroxyl (OH) from
iron, making an C-OH bond where a C-H bond had
been. The iron is reduced back to Fe+2 and begin the
process all over again. Different iron oxidation states
are possible.
Supply correct curved arrows to show electron movement.
R
H
O
O
H
Fe +3
C
R
R
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Fe +3
R
R
C
R
H
R
Fe +2
O
C
R
R
43
25. Cytochrom P-450 oxidation of C=C pi bonds (alkenes and aromatics) to make epoxides, which
can be opened to diols.
R
R
R
C
C
C
O
R
R
R
R
C
C
R
O
R
R
O
epoxides
Fe +2
Fe +3
Fe +3
R
R
C
The carbon free radical abstracts the oxygen atom from
the iron, making an epoxide ring. The iron is reduced
back at Fe+2 to begin the process all over again. Reactive
epoxides can be opened up to diols (more water soluble).
The free radical-like oxygen atom adds to a
C=C bond (alkene or aromatic) in the enzyme
cavity, forming a O-C bond and a carbon free
radical.
Supply correct curved arrows to show electron movement.
R
R
R
C
C
C
O
R
R
R
R
R
R
C
O
Fe +2
Fe +3
C
R
O
R
R
C
epoxides
Fe +3
The large strain energy allows realtively easy ring opening to a more water soluble diol using a nucleophilic
oxygen combined with an acidic proton.
R
R
C
O
R
R
C
R
B
H
H
R
H
H
R
epoxide
H
B
O
O
O
B
H
R
diol
B
Supply correct curved arrows to show electron movement.
R
R
C
O
R
R
C
R
B
H
H
R
H
H
O
O
H
O
R
B
B
R
B
H
26. Cytochrom P-450 oxidation of sulfur and nitrogen lone pairs.
S
O
S
R
R
sulfur
substrate
(1e-)
Fe +3
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O
Fe +3
O
R
R
sulfur
substrate
Fe +2
S
R
R
sulfoxides, further oxidation is
possible, all the way to sulfate, SO4-2
44
R/H
N
R/H
N
R
R
O
Fe +3
R
O
nitrogen
substrate
(1e-)
O
R
Fe +2
nitrogen
substrate
N
R
Fe +3
R/H
R
N-oxides, further oxidation is
possible, all the way to nitrate, NO3-1
Supply correct curved arrows to show electron movement.
O
O
O
S
S
R
R
R
Fe +2
R
Fe +3
Fe +3
S
R
R
Supply correct curved arrows to show electron movement.
R/H
O
N
N
R
R
Fe +3
O
R/H
O
R
Fe +2
N
R
Fe +3
R
R/H
R
27. Free radical halogenation of sp3 C-H bonds to make C-X groups (X = Cl, Br, I) using halogenase
enzymes and hypohalous acids from halide with hydrogen peroxide.
Halogenations in an organism can use iron halogen bonds.
H
H
B
B
H
O
H
O
O
O
Cl
Cl
H
H
hydrogen peroxide chloride
Fe +3
O
H
R
H
C
O
R
R
Fe +4
The free radical-like oxygen atom abstracts
a hydrogen atom from a C-H bond in the
enzyme cavity, forming an O-H bond and a
carbon free radical.
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+4
Fe
R
H
C
R
Cl
Cl
R
R
O
O
hydroxyl radical dangerous!
(possible protection from antioxidants)
hypochlorous acid
sp3 C-H bonds
O
Cl
Fe +4
R
C
R
H
Cl
O
Fe +3
The carbon free radical abstracts a halogen (Cl or Br)
forming an unusal halogenated bioorganic molecule
(reasonably common in ocean organisms).
45
Supply correct curved arrows to show electron movement.
H
B
H
B
H
O
H
Cl
Cl
O
O
O
H
H
O
Fe +3
O
H
+4
Fe
Cl
O
R
R
R
O
H
C
R
H
C
O
R
R
R
Cl
R
Cl
Fe +4
C
H
O
Cl
R
Fe +4
Fe +3
28. Halogenations of aromatic rings using X-OH to make sp2 C-X bonds (X = Cl, Br, I,
thyroxine = I).
Iodide is stored in the thyroid gland. Iodoperoxidase enzyme makes it electrophilic (instead of nucleophilic
iodide). It could react as hypoiodous acid, or the oxygen could be made into an even better leaving group if
was a phosphate (using ATP).
H
O
O
O
H
O
H
I
B
O
H
O
H
P
O
ATP
O
O
I
H
I
O
P
O
O
B
possibly an even
better leaving group
a good leaving group on iodine
Supply correct curved arrows to show electron movement.
O
O
H
H
O
O
H
O
O
H
I
B
P
O
ATP
O
O
H
I
B
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H
O
I
P
O
O
46
Speculative mechanism for iodinating tyrosine and formation of thyroxine from two tyrosines.
O
I
H
H
O
B
B
H
H
I
CO2H
H
NH2
CO2H
H
attached
to enzyme
H
O
NH2
O
tyrosine
I
CO2H
B
H
NH2
repeat at
other ortho
position
O
I
I
H
CO2H
H
NH2
O
diiodotyrosine - makes thryoxine (T4 and T3)
O
O
I
H
H
B
I
B
CO2H
H
H
CO2H
H
H
NH2
H
O
NH2
O
I
CO2H
H
NH2
O
I
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B
repeat at
other ortho
position
I
H
H
CO2H
NH2
O
47
29. Anti-oxidation reactions using vit E (fat soluble), vit C (water soluble), (also possible are
glutathione, resveratrol and other bio-antioxidants).
possible dangerous free
radical reduced by vit E
reduced radical neutralized
by body's buffer system
R
R
R
H
O
H
H
free radical protection by vitamin E
(possibly in cell membrane)
B
B
O
H
R
R
O
resonance and inductive
effects stabilize radical so
it does not do damage
vitamin E located
in cell membranes
quenches radicals
H
R
O
O
O
R
R
R
R
R
O
H
O
H
vitamin C reduces
vitamin E back to
normal and ultimately
washes out of the body
H
B
H
O
O
R
vitamin C
O
R
O
O
H
H
O
O
O
H
O
O
H
O
R
O
R
O
O
R
H
O
B
R
O
O
O
O
H
R
vitamin E is recharged
and still in cell membrane
O
H
O
R
O
O
O
O
resonance stabilized vitamin C radical is
less reactive so it does not do damage
protects a
second time
H
H
B
O
water soluble oxidized
vitamin C form washes
out of the body
O
B
R
O
R
resonance stabilized vitamin C radical is
less reactive so it does not do damage
other possible anti-oxidants
glutathione = tripeptide (3 amino acids)
electron supplied from sulfur
OH
SH
NH2
O
H
O
N
N
OH
HO
resveratrol
(similar to above)
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O
OH
glutaric acid
( linkage)
H
OH
O
cysteine
glycine
48
Supply correct curved arrows to show electron movement.
R
R
R
H
B
B
O
H
R
O
H
H
R
R
O
H
R
R
R
O
O
O
O
O
H
R
R
H
H
B
H
B
O
R
O
O
H
O
H
O
O
O
H
O
O
H
O
O
R
R
O
R
O
B
O
R
H
O
R
H
O
R
B
O
O
H
O
O
O
O
O
O
H
H
O
R
B
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O
R
O
B
O
R
49
30. Possible Vitamin K synthesis and chemistry, important in electron transport through membranes.
H
H
B
vit K synthesis
O
O
O
HO
P
O
O
geranyl phosphate
H
O
H
B
O
O
-2
PO3
shown as SN2,
could be SN1
can lose 2e-/2H+
B
H
NAD+
H
B
N
simplified structures
O
R
R
O
H
H
OH
R
B
H
O
Vit K (many versions)
important in electron
transport.
N
NADH
R
OH
O
can gain 2e-/2H+
Supply correct curved arrows to show electron movement.
H
H
B
O
O
O
HO
P
O
O
B
H
-2
PO3
O
H
H
O
B
B
H
N
H
H
B
H
R
O
N
R
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O
O
50
Electron transport using vitamin K quinone / hydroquinone pi systems
adding 2 electrons and 2 protons to quinone
H
B
B
H
H
O
O
O
add 1e
+
proton
1e
1e
add 1e
+
proton
R
R
O
B
R
O
H
O
B
H
Supply correct curved arrows to show electron movement.
B
H
H
B
O
H
O
O
add 1e
+
proton
1e
1e
add 1e
+
proton
R
R
O
B
R
O
H
O
B
H
donating 2 electrons and 2 protons from hydroquinone
B
H
H
H
O
1e
R
1e
lose 1e
+
proton
R
R
lose 1e
+
proton
R
R
B
B
O
O
R
O
O
B
H
O
H
Supply correct curved arrows to show electron movement.
B
H
H
1e
lose 1e
+
proton
R
R
O
O
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R
lose 1e
+
proton
R
H
H
O
1e
R
B
B
O
O
B
H
R
O
51
1. 3 types of problems are possible
1. Fill in the missing mechanistic details.
2. State what transformation occurred (and provide the missing mechanistic details).
3. Given the term, draw the step (and provide the missing mechanistic details).
Summary of Biochemical Topics having examples provided above:
1. Keto/enol tautomerization (proton transfer, resonance, proton transfer).
2. Carbonyl hydration (addition reaction of H2O to a C=O) / carbonyl hydrate dehydration
(elimination reaction forms a C=O and H2O).
3. Hemiacetal (or hemiketal) formation (an addition reaction) of an alcohol to a C=O, forms an ether
and an alcohol group on the same carbon. The reverse reaction reforms the carbonyl and alcohol
from an elimination reaction. Typical ring sizes in the intramolecular reaction are 5-6 atoms.
These transformations are very similar to carbonyl hydration / dehydration, presented in example 2
above.
4. Acetal (or Ketal) formation from a hemiacetal (or hemiketal) makes a water molecule leaving
group that is replaced by an alcohol in an SN1 reaction, producing a second ether linkage. In the
reverse reaction (acetal or ketal forming a hemiacetal or hemiketal) an alcohol leaving group is
replaced by a water molecule in an SN1 reaction. Both are reversible reactions. Because arrows
are used in both directions on the same bonds, we show the intermediate in this reaction.
5. S-adenosyl methionine (SAM) to methylate biomolecules. SN2 reactions at methyl carbon of SAM.
6. a. Formation of an imine, C=N-R, and water from a C=O and a primary amine (RNH2).
b. Hydrolysis of an imine, C=N-R, with water to form a C=O and a secondary amine (R2NH)
7. a. Formation of an enamine, C=C-NR2, and water from a C=O and a secondary amine (R2NH). The
mechanism begins the same as imine formation, but the second proton is lost for the C position of
the carbonyl group since there is no second proton on a secondary amine.
b. Hydrolysis of an enamine, C=C-NR2, with water to form a C=O and a secondary amine (R2NH)
8. a. Reduction of a carbonyl bond, C=O, to an alcohol, CH(OH), with an NADH equivalent. The
carbonyl bond could be an aldehyde, ketone, ester or thiolester. NADH is a hydride donor that
becomes aromatic (forms NAD+) with the transfer of the nucleophilic hydride to the electrophilic
C=O. A nearby acid protonates the oxygen, completing the addition reaction.
b. Reduction of an imine, C=N-, to an amine, CH(NHR), with an NADH equivalent. NADH is a
hydride donor that becomes aromatic (forms NAD+) with the transfer of the nucleophilic hydride to
the electrophilic C=O. A nearby acid protonates the nitrogen, completing the addition reaction.
9. a. Oxidation of an alcohol, CH(OH), to a carbonyl group, C=O, (aldehyde, ketone, carboxylic acid)
with an equivalent of NAD+.
b. Oxidation of an amine, CH(NH), to an imine, C=N, (amines  imines) with an equivalent of
NAD+.
10. Reactions of ATP (many variations).
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52
a. a. Phosphorylation of an OH with an ATP equivalent (making a phosphate ester) – common in
enzyme signaling
b. Dephosphorylation of an inorganic phosphate ester to an alcohol or phenol and phosphate.
Common in enzyme signaling.
c. Formation of mixed phosphate anhydrides at carboxylic acids using ATP. Can be made into
thioesters.
d. Making an ATP from an enol phosphate.
e. An elimination reaction of a phosphate leaving group to make an alkene (pi bond). Could actually
be E1 or E2.
11. Formation of esters and thioesters using anhydrides.
12. Aldol (makes a -hydroxy carbonyl compound). Reverse aldol, (makes 2 C=O from a -hydroxy
carbonyl compound).
13. Claisen (makes a -keto ester). Reverse Claisen (makes two esters). Often occurs using thiol
esters in biochemistry (such as acetyl Co-A).
14. Michael reaction (addition / hydration) adds a nucleophile at the beta carbon of an ,-unsaturated
carbonyl compound (usually OH in this game) and adds a proton at the alpha carbon. Reverse
Michael reaction (elimination / dehydration) of -hydroxy carbonyl compounds, an elimination
reaction forms ,-unsaturated carbonyl compounds and carries an aldol reaction one step farther.
15. Decarboxylation (-CO2) of a -ketocarboxylic acid, forming an enol, which tautomerizes to a keto
group. You can show the product as the enol tautomer or the keto tautomer.
16. Decarboxylation of an -ketocarboxylic acid with TPP (thiamine diphosphate). Also includes
both “TPP ylid” and “TPP enamine” chemistry. The enamine can be protonated to form an
aldehyde (a smaller carbohydrate) or it can react with another carbonyl compound to make a new
carbon-carbon bond (a larger carbohydrate in this game) The TPP ylid is also regenerated, which
can react again or protonate to make TPP.
17. Decarboxylation by E2 or E1 reactions with a good phosphate leaving group to make an alkene (pi
bond). This reaction occurs in the mevalonate pathway leading to steroids and terpenes.
18. FADH2 reduction (hydrogenation) of C=C to CH-CH or the reverse reaction, FAD oxidation of
CH-CH to a C=C (dehydrogenation). Important reactions in fat metabolism. FAD can also be
recharged with NADH.
19. Lipoyl amide – important in fat metabolism, cycles between oxidized and reduced forms.
20. THF chemistry (tetrahydrofolate): 1C metabolism
21. Biotin – also involved in 1C transfers (activated CO2 added to activate C=O for aldol type
chemistry and then taken off when no longer needed).
22. Vit B-6 reactions – Many reactions are possible. 1. imine formation with an -keto acid and the
primary amine version of Vit B-6, 2. tautomerization to a different imine, and 3. imine hydrolysis
to an amino acid and the aldehyde version of Vit B-6. The imine complex also allows for the loss
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53
of various groups on amino acids (the acid part, CO2H, an alpha C-H proton, and certain amino
acid side groups, -CH2OH in serine, and -CHCH3OH in threonine). Imines are also seen in
Example 6 and -keto acids in Example 16.
23. Vitamin B12 – Many functions.
24. Cytochrom P-450 oxidation of sp3 C-H bonds to make sp3 C-OH groups.
25. Cytochrom P-450 oxidation of C=C pi bonds (alkenes and aromatics) to make epoxides, which can
be opened to diols.
26. Cytochrom P-450 oxidation of sulfur and nitrogen lone pairs.
27. Free radical halogenation of sp3 C-H bonds to make C-X groups (X = Cl, Br, I) using halogenase
enzymes and hypohalous acids from halide with hydrogen peroxide.
28. Halogenations of aromatic rings using X-OH to make sp2 C-X bonds (X = Cl, Br, I, thyroxine = I).
29. Anti-oxidation reactions using vit E (fat soluble), vit C (water soluble), (also possible are
glutathione, resveratrol and other bio-antioxidants).
30. Possible Vitamin K synthesis and chemistry, important in electron transport through membranes.
31.
32.
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