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Chapter 24
The Organic
Chemistry of the
Coenzymes,
Compounds
Derived from
Vitamins
Paula Yurkanis Bruice
University of California,
Santa Barbara
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Cofactors
Many enzymes need a cofactor in order to catalyze a reaction.
A cofactor can be a metal ion or an organic molecule.
A cofactor that is an organic molecule is called a coenzyme.
Coenzymes are derived from vitamins.
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The Substrate and the Coenzyme
are Bound to the Enzyme’s Active Site
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A Pyridine Nucleotide Coenzyme is Needed
for Many Redox Reactions
NAD+ and NADP+ are oxidizing agents.
NADH and NADPH are reducing agents.
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NAD+ is the Most Common Oxidizing Agent
NADPH is the Most Common Reducing Agent
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NAD+ is Composed of Two Nucleotides
Linked Together by Their Phosphate Groups
NAD+ = nicotinamide adenine dinucleotide
The nicotinamide nucleotide is derived from vitamin B3.
The adenine nucleotide is derived from ATP.
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ATP
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Metabolism
Metabolism = the reactions cells carry out to obtain the energy they need
and to synthesize the compounds they require.
Metabolism can be divided into two parts.
catabolism:
complex molecule
anabolism:
simple molecules + energy
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simple molecules + energy
complex molecule
NAD+ is an Oxidizing Agent
A dehydrogenase is an enzyme that catalyzes an oxidation reaction.
NAD+ and NADH are used in catabolic reactions.
Catabolic reactions are primarily oxidation reactions, so
NAD+ is the most common oxidizing agent.
NADP+ and NADPH are used in anabolic reactions.
Anabolic reactions are primarily reduction reactions, so
NADPH is the most common reducing agent.
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NADPH is a Reducing Agent
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The Mechanism for Oxidation
All the chemistry of the pyridine nucleotide coenzymes
takes place at the 4-position of the pyridine ring.
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Glyceraldehyde-3-Phosphate Dehydrogenase
Glyceraldehyde-3-phosphate dehydrogenase is an example of an
enzyme that uses NAD+ as an oxidizing agent.
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The Mechanism
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The Mechanism for Reduction
All the chemistry of the pyridine nucleotide coenzymes
takes place at the 4-position of the pyridine ring.
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Most Enzyme-Catalyzed Reactions are
Highly Selective
The oxidizing enzyme can distinguish between the two hydrogens of ethanol.
Only Ha is removed.
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Most Enzyme-Catalyzed Reactions are
Highly Selective
The reducing enzyme can distinguish between the two hydrogens of NADH.
Only Ha is transferred.
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FAD is an Oxidizing Agent
FAD = flavin adenine dinucleotide
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FAD-Catalyzed Reactions
Most oxidation reactions catalyzed by FAD do not involve a carbonyl group.
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FAD is Reduced to FADH2
FAD is an oxidizing agent.
FADH2 is a reducing agent.
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The Mechanism for
Dihydrolipoate Dehydrogenase
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The Mechanism for
Succinate Dehydrogenase
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The Mechanism for
D- or L-Amino Oxidase
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Unlike NAD+ and NADH,
FAD and FADH2 Do Not Dissociate From the Enzyme
NAD+ is required to reoxidize the reduced cofactor.
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Thiamine Pyrophosphate (TPP)
TPP is the coenzyme required by enzymes that catalyze the transfer of an acyl group.
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A Reaction That Requires TPP
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The Reactive Part of TPP
The TPP ylide is a good nucleophile.
All enzyme-catalyzed reactions that require TPP start by forming an enamine.
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The Mechanism for
Pyruvate Decarboxylase
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The Pyruvate Dehydrogenase Complex
The conversion of pyruvate to acetyl-CoA requires
five coenzymes: TPP, lipoate, coenzyme A, FAD, and NAD+.
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Part Two of the Mechanism
Part one of the mechanism is the reaction of the TPP ylide with
pyruvate to form the same enamine that is formed from the
reaction of the TPP ylide with pyruvate by pyruvate carboxylase.
Lipoate is attached to its enzyme by forming an amide with a lysine side chain.
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Part Three of the Mechanism
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Coenzyme A
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Biotin
Biotin is required by enzymes that catalyze the carboxylation
of a carbon adjacent to a carbonyl group.
Biotin is attached to its enzyme by forming an amide with a lysine side chain.
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Enzymes That Require Biotin
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Activating Bicarbonate
Biotin-requiring enzymes require Mg2+ and ATP.
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Mechanism for Carboxylation
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Pyridoxal Phosphate (PLP)
Pyridoxal phosphate is attached to its enzyme by forming
an imine with a lysine side chain.
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PLP Catalyzes
Reactions of Amino Acids
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PLP Catalyzes
Reactions of Amino Acids
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PLP Catalyzes
Reactions of Amino Acids
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The Amino Acid Becomes Attached to PLP
by Transimination
In the reactant, the imine is between PLP and a lysine side chain of the enzyme.
In the product, the imine is between PLP and the amino acid.
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The First Step in All
PLP-Catalyzed Reactions
The first step of the enzyme-catalyzed reactions is
breaking a bond attached to the alpha-carbon.
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The Mechanism for Decarboxylation
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The Mechanism for Racemization
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The Mechanism for Transamination
(Part 1)
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The Mechanism for Transamination
(Part 2)
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Coenzyme B12
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Enzyme-Catalyzed Reactions That Require B12
Enzymes that catalyze certain rearrangement reactions require
coenzyme B12.
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Y and H Change Places
In an enzyme-catalyzed reaction that requires coenzyme B12,
a group (Y) bonded to one carbon changes places with
a hydrogen bonded to an adjacent carbon.
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The Mechanism for a
Reaction that Requires B12
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Tetrahydrofolate (THF)
THF is the coenzyme required by enzymes that transfer a
group containing one carbon to their substrates.
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THF Coenzymes
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A Reaction That Requires THF
The C-8 of purine comes from a THF coenzyme.
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A Reaction That Requires THF
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Sulfa Drugs
(the first antibiotics)
Sulfanilamide and p-aminobenzoic acid have similar structures.
The sulfa drugs act by inhibiting the enzyme that incorporates
p-aminobenzoic acid into folic acid (the enzyme binds
sulfanilamide instead of p-aminobenzoic acid).
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The Enzyme That Converts U into T
The reaction reduces tetrahydrofolate (THF) to dihydrofolate (DHF).
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The Mechanism
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Conversion of Dihydrofolate
Back to Tetrahydrofolate
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Cancer Chemotherapy
5-fluorouracil is a suicide inhibitor of thymidylate synthase
If a cell cannot make Ts, it cannot make DNA.
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Competitive Inhibitors of
Dihydrofolate Reductase
Aminopterin and methotrexate are used as anticancer drugs.
Trimethoprim is used as an antibiotic.
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Vitamin K
Vitamin K is required for proper clotting of blood.
Vitamin K2 is the coenzyme.
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The Enzyme That Catalyzes Carboxylation of the
γ-Carbon of Glutamate Requires Vitamin KH2
The enzyme needs a strong base to remove the hydrogen from the γ-carbon.
Vitamin KH2 provides the strong base.
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making the
strong base
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Regenerating Vitamin KH2
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These Compounds Prevent
Blood Clotting
These compounds are competitive inhibitors of the enzyme that
converts vitamin K epoxide to vitamin KH2.
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