25_Lecture - Ventura College

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Organic Chemistry
6th Edition
Paula Yurkanis Bruice
Chapter 25
The Organic
Chemistry of the
Coenzymes,
Compounds
Derived from
Vitamins
1
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• Many enzymes catalyze a reaction with the help of a
cofactor.
• Cofactors can be metal ions or organic molecules.
• An enzyme that has a tightly bound metal ion is called
a metalloenzyme.
• Cofactors that are organic molecules are coenzymes.
• Coenzymes are derived from vitamins.
2
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3
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The Pyridine Nucleotide Coenzyme Is Needed
for Many Redox Reactions
• NAD(P)+ are oxidizing agents.
• NAD(P)H are reducing agents.
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4
5
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NAD+ is composed of two nucleotides linked
together through their phosphate groups
The adenine nucleotide portion of NAD+ is
derived from ATP
6
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Many enzymes that catalyze oxidation reactions
are called dehydrogenase:
NAD+ and NADH are catabolic coenzymes, whereas
NADP+ and NADPH are anabolic coenzymes
7
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Mechanisms for the pyridine nucleotide coenzymes:
All the chemistry of the pyridine nucleotide coenzymes
takes place at the 4-position of the pyridine ring
8
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Glyceraldehyde-3-phosphate dehydrogenase uses NAD+
as an oxidizing coenzyme:
9
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10
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The mechanism for reduction by NAD or by NADPH:
NADH and NADPH are hydride donors
11
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• The structural complexity of a coenzyme is needed for
enzyme recognition.
• Molecular recognition allows the enzyme to bind the
substrate and the coenzyme in the proper orientation
for reaction.
• Biological redox reactions are equilibrium reactions
driven in the appropriate direction by the removal of
reaction products.
12
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A Biological Redox Reaction Is Highly Selective
13
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A reducing enzyme can distinguish between the two
hydrogens at the 4-position of the nicotinamide ring:
14
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FAD and FMN are coenzymes used to oxidize substrates
A flavoprotein is an enzyme that contains either FAD or
FMN
15
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The structure of the oxidized FMN cofactor:
16
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Biological Redox Reactions Involving FAD or FMN
17
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FAD and FMN are oxidizing agents, whereas FADH2
and FMNH2 are reducing agents:
18
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Mechanism for dihydrolipoyl dehydrogenase:
Thiolate addition to
4a position
Two-electron
transfer to the
flavin ring
19
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Mechanism for D- or L-amino acid oxidase:
20
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Unlike NAD+ and NADH, FAD and FADH2 do not
dissociate from the enzyme:
But NAD+ is required to reoxidize the
reduced cofactor
21
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Thiamine pyrophosphate (TPP) is the coenzyme
required by enzymes that catalyze the transfer of a twocarbon fragment:
22
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The enzyme pyruvate decarboxylase requires
thiamine pyrophosphate (TTP) as a coenzyme:
TTP affords a nucleophilic ylide carbanion that
facilitates decarboxylation:
23
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Mechanism for pyruvate decarboxylase:
Enamine
intermediate
24
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The conversion of pyruvate to acetyl-CoA requires
coenzymes TPP, lipoate, coenzyme A, FAD, and
NAD+
25
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Mechanism for acetyl-CoA formation:
26
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27
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Biotin is required by enzymes that catalyze the
carboxylation of a carbon adjacent to a carbonyl group:
28
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Enzymatic reactions utilizing the biotin coenzyme:
29
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In addition to requiring bicarbonate, biotin-requiring
enzymes require Mg2+ and ATP:
30
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Mechanism for carboxylation of acetyl-CoA by acetylCoA carboxylase:
31
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Pyridoxal phosphate (PLP) is required by enzymes
that
catalyze certain transformations of amino acids:
32
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Amino Acid Transformations
That Require PLP Coenzyme
33
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34
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35
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The first step of the reactions involves the breakage
of
the bond attached to Ca
36
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Mechanism for transimination:
37
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Mechanism for PLP-catalyzed decarboxylation of an
amino acid:
38
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Mechanism for PLP-catalyzed racemization of an Lamino acid:
39
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Mechanism for PLP-catalyzed transamination of an
amino acid:
40
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41
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Mechanism for PLP-catalyzed Ca—Cb bond cleavage:
42
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The bond cleaved in the first step depends on the
conformation of the enzyme-bound amino acid
43
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Enzymes that catalyze certain rearrangement reactions
require coenzyme B12
44
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Enzymatic Reactions Requiring B12
45
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In a coenzyme B12–requiring reaction, a group (Y)
bonded to one carbon changes places with a hydrogen
bonded to an adjacent carbon:
46
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Mechanism for a coenzyme B12–requiring
enzyme-catalyzed reaction:
47
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Tetrahydrofolate (THF) is the coenzyme required for
one-carbon transfer reactions:
48
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The Six Different THF-Coenzymes
49
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GAR transformylase is an example of an enzyme that
requires a THF-coenzyme:
50
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The Enzyme That Converts U into T
51
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Mechanism for the reaction catalyzed by thymidylate
synthase:
52
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Conversion of Dihydrofolate Back to
N5, N10-Methylene-THF
53
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5-Fluorouracil is a mechanism-based inhibitor or suicide
inhibitor of thymidylate synthase used in cancer
chemotherapy
54
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Aminopterin and methotrexate competitively
inhibit dihydrofolate reductase and are used as
anticancer drugs
55
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Vitamin K is required for proper clotting of blood
56
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Vitamin KH2 is required by the enzyme that
catalyzes the carboxylation of the -carbon of a
glutamate side chain
57
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Mechanism for the vitamin KH2–dependent
carboxylation of glutamate
Dioxetane formation:
58
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Carboxylation mediated by vitamin K base:
Dioxetane
intermediate
59
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Regeneration of Vitamin KH2
60
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