Vitamins and Coenzymes
Vitamins are compounds that are required in the diet, either because the organism
cannot synthesize them, or because the rate of usage by the organism typically
exceeds the rate of synthesis of the compound. In nearly all cases, only very small
amounts of these compounds are required.
Vitamins are generally classed as either water-soluble or fat-soluble. The water-
soluble vitamins generally act as precursors to coenzymes; the functions of the fat-
soluble vitamins are more diverse and less easily categorized.
The water-soluble vitamins are readily excreted in the urine; toxicity as a result of
overdose is therefore rare. However, with few exceptions, the water-soluble
vitamins are not stored in large amounts, and therefore must be continually
supplied in the diet. In contrast, the fat-soluble vitamins are less readily excreted,
and are deleterious (and possibly lethal) in high doses. Many of the fat-soluble
vitamins are stored; for example, most well nourished individuals have a three-
month supply of vitamin D.
Water soluble vitamins
The water-soluble vitamins include the B complex vitamins (the actual B vitamins,
biotin, and folic acid) and vitamin C.
First we will look at three classes of vitamin-derived coenzymes used to carry
electrons: the nicotinamide coenzymes, the flavin coenzymes, and ascorbic acid.
Vitamin B3 (niacin)
Niacin is the name for both nicotinamide and nicotinic acid, either of which can act
as a precursor of nicotinamide coenzymes. Niacin is required for the synthesis of
two coenzyme molecules: NAD and NADP. Note the phosphate attached to the 2´-
position of the lower ribose ring in NADP, which is the only difference between the
molecules.
O O
NH2 NH2
N N
CH2 O CH2 O
O O
OH OH OH OH
OH NH2
NH2 NH2
O O
N N N N
O P O N O P O N
Niacin Niacin O O
N N N N
(nicotinic acid) (nicotinamide)
O P O CH2 O O P O CH2 O
Vitamin B3 Vitamin B3
O O
OH OH OH O
O P O
Nicotinamide adenine Nicotinamide adenine
O
dinucleotide dinucleotide 2´-phosphate
[NAD] [NADP]
Humans can synthesize nicotinamide cofactors from tryptophan. However, the
process is somewhat inefficient; synthesis of 1 mg of niacin requires about 60 mg of
Copyright © 2000-2016 Mark Brandt, Ph.D. 37
,tryptophan. Niacin deficiency therefore is usually the result of a diet deficient in
both niacin and tryptophan. However, some diets contain tryptophan or niacin in a
biologically unavailable form. In corn, the niacin is poorly absorbed unless the corn
is treated with alkali prior to ingestion. In the rural south of the early 20th century,
this preparation step was largely ignored; the symptoms of the
resulting pellegra (niacin-deficiency), such as sun-sensitivity H
and dementia, led to the pejorative term “red-neck” for O N
NH2
individuals from this region of the US. Pellegra is also observed
in high sorghum diets (sorghum contains niacin-synthesis
inhibitors) or in some individuals taking isoniazid (isoniazid is
an antibiotic used to treat tuberculosis, but also inhibits niacin Isoniazid
uptake and synthesis). N
Nicotinic acid (but not nicotinamide) reduces release of free fatty acids from adipose
tissue, probably via binding to a receptor that also binds hydroxycarboxylic acids,
and has been used to reduce plasma cholesterol. However, some individuals cannot
tolerate the high levels of nicotinic acid required.
The niacin derived coenzymes NAD and NADP act as soluble electron carriers
between proteins. NAD and NADP thus act as substrates for enzymes involved in
oxidation and reduction reactions. NAD is primarily involved in catabolic
reactions. NAD accepts electrons during the breakdown of molecules for energy. In
contrast, NADPH (the reduced form of NADP) is primarily involved in
biosynthetic reactions; it donates electrons required for synthesizing new
molecules. In most cells, NAD concentration is much higher than that of NADH,
while NADPH is actively maintained at levels much higher than those of NADP.
The two possible electronic states for the nicotinamide cofactors are shown below:
2 electrons
H O + H H O
1 proton
NH2 NH2
N N
R R
2 electrons
Oxidized + Reduced
NAD(P) 1 proton NAD(P)H
The oxidized forms of both nicotinamide coenzymes can only accept electrons in
pairs. The reduced forms of the coenzymes can only donate pairs of electrons.
Note the two changes in the ring during the reduction. The addition of the electron
pair is accomplished by the addition of a hydride ion to the carbon para to the
pyridine nitrogen, and results in the loss of the positive charge on the ring.
Copyright © 2000-2016 Mark Brandt, Ph.D. 38
, Nicotinic acid was first synthesized chemically in 1867 from nicotine:
O
HNO3
N OH
CH3
Nicotine N N Nicotinic acid
The name “niacin” was introduced to remove the association with nicotine and
tobacco.
Alcohol Dehydrogenase
An example of the role of NAD in redox chemistry is provided by the oxidoreductase
enzyme liver alcohol dehydrogenase. The name of the enzyme includes the
tissue of origin and the substrate. The word “dehydrogenase” is an indication of the
fact that the enzyme catalyzes an oxidation-reduction reaction. (“Dehydrogenase”
means “catalyzes hydrogen removal”.)
Alcohol dehydrogenase can catalyze the oxidation of several different alcohols. In
each case it uses NAD as the electron acceptor. The active site is thus moderately
non-specific for the alcohol, although it is quite specific for NAD compared to NADP.
In the absence of substrate, the alcohol dehydrogenase active site is occupied by
water molecules. Note the zinc ion, a metal ion cofactor that is required for catalytic
activity (alcohol dehydrogenase actually binds two zinc ions, but the other is
thought to have an exclusively structural role). The zinc is bound to three enzyme
side-chains (two cysteine residues and a histidine residue).
His67
His51
HN Ser48
Cys174
Cys46
N
OH NH
S
S N
Zn
H
O
H
Binding of substrate causes a conformational change that excludes water from the
active site, and that positions the substrates in preparation for catalysis. When the
substrate binds, the zinc ion coordinates (i.e. binds) to the alcohol oxygen. This bond
between the zinc ion and the substrate assists in stabilizing the negative charge
that will develop on the substrate oxygen (to put this in familiar terms, in the
Copyright © 2000-2016 Mark Brandt, Ph.D. 39
Vitamins are compounds that are required in the diet, either because the organism
cannot synthesize them, or because the rate of usage by the organism typically
exceeds the rate of synthesis of the compound. In nearly all cases, only very small
amounts of these compounds are required.
Vitamins are generally classed as either water-soluble or fat-soluble. The water-
soluble vitamins generally act as precursors to coenzymes; the functions of the fat-
soluble vitamins are more diverse and less easily categorized.
The water-soluble vitamins are readily excreted in the urine; toxicity as a result of
overdose is therefore rare. However, with few exceptions, the water-soluble
vitamins are not stored in large amounts, and therefore must be continually
supplied in the diet. In contrast, the fat-soluble vitamins are less readily excreted,
and are deleterious (and possibly lethal) in high doses. Many of the fat-soluble
vitamins are stored; for example, most well nourished individuals have a three-
month supply of vitamin D.
Water soluble vitamins
The water-soluble vitamins include the B complex vitamins (the actual B vitamins,
biotin, and folic acid) and vitamin C.
First we will look at three classes of vitamin-derived coenzymes used to carry
electrons: the nicotinamide coenzymes, the flavin coenzymes, and ascorbic acid.
Vitamin B3 (niacin)
Niacin is the name for both nicotinamide and nicotinic acid, either of which can act
as a precursor of nicotinamide coenzymes. Niacin is required for the synthesis of
two coenzyme molecules: NAD and NADP. Note the phosphate attached to the 2´-
position of the lower ribose ring in NADP, which is the only difference between the
molecules.
O O
NH2 NH2
N N
CH2 O CH2 O
O O
OH OH OH OH
OH NH2
NH2 NH2
O O
N N N N
O P O N O P O N
Niacin Niacin O O
N N N N
(nicotinic acid) (nicotinamide)
O P O CH2 O O P O CH2 O
Vitamin B3 Vitamin B3
O O
OH OH OH O
O P O
Nicotinamide adenine Nicotinamide adenine
O
dinucleotide dinucleotide 2´-phosphate
[NAD] [NADP]
Humans can synthesize nicotinamide cofactors from tryptophan. However, the
process is somewhat inefficient; synthesis of 1 mg of niacin requires about 60 mg of
Copyright © 2000-2016 Mark Brandt, Ph.D. 37
,tryptophan. Niacin deficiency therefore is usually the result of a diet deficient in
both niacin and tryptophan. However, some diets contain tryptophan or niacin in a
biologically unavailable form. In corn, the niacin is poorly absorbed unless the corn
is treated with alkali prior to ingestion. In the rural south of the early 20th century,
this preparation step was largely ignored; the symptoms of the
resulting pellegra (niacin-deficiency), such as sun-sensitivity H
and dementia, led to the pejorative term “red-neck” for O N
NH2
individuals from this region of the US. Pellegra is also observed
in high sorghum diets (sorghum contains niacin-synthesis
inhibitors) or in some individuals taking isoniazid (isoniazid is
an antibiotic used to treat tuberculosis, but also inhibits niacin Isoniazid
uptake and synthesis). N
Nicotinic acid (but not nicotinamide) reduces release of free fatty acids from adipose
tissue, probably via binding to a receptor that also binds hydroxycarboxylic acids,
and has been used to reduce plasma cholesterol. However, some individuals cannot
tolerate the high levels of nicotinic acid required.
The niacin derived coenzymes NAD and NADP act as soluble electron carriers
between proteins. NAD and NADP thus act as substrates for enzymes involved in
oxidation and reduction reactions. NAD is primarily involved in catabolic
reactions. NAD accepts electrons during the breakdown of molecules for energy. In
contrast, NADPH (the reduced form of NADP) is primarily involved in
biosynthetic reactions; it donates electrons required for synthesizing new
molecules. In most cells, NAD concentration is much higher than that of NADH,
while NADPH is actively maintained at levels much higher than those of NADP.
The two possible electronic states for the nicotinamide cofactors are shown below:
2 electrons
H O + H H O
1 proton
NH2 NH2
N N
R R
2 electrons
Oxidized + Reduced
NAD(P) 1 proton NAD(P)H
The oxidized forms of both nicotinamide coenzymes can only accept electrons in
pairs. The reduced forms of the coenzymes can only donate pairs of electrons.
Note the two changes in the ring during the reduction. The addition of the electron
pair is accomplished by the addition of a hydride ion to the carbon para to the
pyridine nitrogen, and results in the loss of the positive charge on the ring.
Copyright © 2000-2016 Mark Brandt, Ph.D. 38
, Nicotinic acid was first synthesized chemically in 1867 from nicotine:
O
HNO3
N OH
CH3
Nicotine N N Nicotinic acid
The name “niacin” was introduced to remove the association with nicotine and
tobacco.
Alcohol Dehydrogenase
An example of the role of NAD in redox chemistry is provided by the oxidoreductase
enzyme liver alcohol dehydrogenase. The name of the enzyme includes the
tissue of origin and the substrate. The word “dehydrogenase” is an indication of the
fact that the enzyme catalyzes an oxidation-reduction reaction. (“Dehydrogenase”
means “catalyzes hydrogen removal”.)
Alcohol dehydrogenase can catalyze the oxidation of several different alcohols. In
each case it uses NAD as the electron acceptor. The active site is thus moderately
non-specific for the alcohol, although it is quite specific for NAD compared to NADP.
In the absence of substrate, the alcohol dehydrogenase active site is occupied by
water molecules. Note the zinc ion, a metal ion cofactor that is required for catalytic
activity (alcohol dehydrogenase actually binds two zinc ions, but the other is
thought to have an exclusively structural role). The zinc is bound to three enzyme
side-chains (two cysteine residues and a histidine residue).
His67
His51
HN Ser48
Cys174
Cys46
N
OH NH
S
S N
Zn
H
O
H
Binding of substrate causes a conformational change that excludes water from the
active site, and that positions the substrates in preparation for catalysis. When the
substrate binds, the zinc ion coordinates (i.e. binds) to the alcohol oxygen. This bond
between the zinc ion and the substrate assists in stabilizing the negative charge
that will develop on the substrate oxygen (to put this in familiar terms, in the
Copyright © 2000-2016 Mark Brandt, Ph.D. 39
