L11, Chapter 24

Chem 109 C
Fall 2014
Armen Zakarian
Office: Chemistry Bldn 2217
Chapter 24: Coenzymes
page 1133
2
FAD-FADH2, FMN-FMNH2
NH2
N
O
P
O - OO
OH
OH
OH
H
H
H
N
N
N
O
O
O
P
P
O -O -O
O
O
OH
HO
OH
OH
OH
H
H
H
CH2
NH2
N
O
NH
N
N
NH
N
O
O
FAD
O
N
N
CH2
N
FMN
N
-O
O
P
O-
O
O
P
O-
O
O
P
O-
N
N
O
O
HO
OH
adenosine triphosphate
PRACTICE PROBLEM
FAD is obtained by an enzyme-catalyzed reaction that uses FMN and
3
ATP as substrates. What is the other product of the reaction?
FAD-FADH2, FMN-FMNH2
Examples of reactions catalyzed by FAD or FMN:
HS
dihydrolipoyl
dehydrogenase
SH
O-
S S
+ FAD
O-
O
O
D- or L-amino acid
oxidase
O
R
+ FADH2
+ FAD
O-
O
R
NH2
+ FADH2
ONH
succinate
dehydrogenase
O
-O
O-
+ FAD
O
-O
O-
+ FADH2
O
O
NADH dehydrogenase
NADH +
H+
+ FMN
NAD+ +
FMNH2
4
FAD-FADH2, FMN-FMNH2
HS
dihydrolipoyl
dehydrogenase
SH
O-
S S
+ FAD
O-
O
O
D- or L-amino acid
oxidase
O
R
+ FAD
O-
O
R
NH2
succinate
dehydrogenase
O-
+ FAD
O
-O
O-
+ FADH2
O
O
NADH
+ FADH2
ONH
O
-O
+ FADH2
mechanism
is on page 1142
NADH dehydrogenase
+ H + FMN
NAD + FMNH
(and discussed in class)
+
+
2
5
FAD, FMN, FADH2, FMNH2
PRACTICE PROBLEM
Propose a mechanism for the reduction of lipoate by FADH2
HS
S S
O-
SH
O-
+ FADH2
O
O
H-B
:B
R
R
H
N
N
N
O
N
S
B
R
H
S
R
N
N
O
N
NH
N
H
O
O
O
FADH2
HS
-O
O
NH
N
H
NH
N
H
B:-
+ FAD
N
NH
N
O
O
O
S
O-
B
H
HS
SO-
O
O
6
FAD, FMN, FADH2, FMNH2
PRACTICE PROBLEM
Propose a mechanism for the reduction of lipoate by FADH2
HS
S S
O-
SH
O-
+ FADH2
O
O
H-B
:B
R
R
H
N
N
N
O
N
S
B
R
H
S
R
N
N
O
N
NH
N
H
O
O
O
FADH2
HS
-O
O
NH
N
H
NH
N
H
B:-
+ FAD
N
NH
N
O
O
O
S
O-
B
H
HS
SO-
O
O
7
FAD, FMN, FADH2, FMNH2
Oxidation of α-amino acids to α-imino acids
D- or L-amino acid
oxidase
O
R
O-
+ FAD
NH2
O
R
+ FADH2
ONH
H
R
N
N
B
O
NH
N
O
R
R C COOH+
NH
H
N
N
NH
N
H
O
H
H
O
B
R C COONH2
B:
8
FAD, FMN, FADH2, FMNH2
Covalent attachement of FAD to Cys
R
N
R
N
O
H
N
O
O
H+
NH
O
SCys
O
NH
N
N
N
R
N
N
Base
NH
N
FAD
O
R
CysS
N
H+
N
H
H
N
SCys
O
NH
oxidation
R
N
N
NH
N
O
O
O
E-FAD
9
Thiamine pyrophosphate, TPP
N+
N
N
vitamin B1:
H
NH2
S
O
O
P
P
O - O - OO
O
thiamine pyrophosphate, TPP
NH2
N+
N
S
OH
N
resonance structure
•  catalyze two-carbon transfer, many reactions in catabolism
•  source of thiamine: flax, oatmeal, potato, liver, eggs, etc.
•  deficiency disease: peripheral NS, beriberi
thiamine
10
Lipoate-Dihydrolipoate
vitamin:
S S
H
N
Lys
S S
OH
O
lipoate
O
lipoic acid
redox
•  redox/part of pyruvate dehydrogenase system, aerobic catabolism
•  source of lipoate: almost all foods
11
•  deficiency disease: none
Coenzyme A (CoASH)
O
O
-O
O
P
OH
N
H
SH
O
-O
P
O
-O
O
P
OH
N
O
N
OH
O
P O
-O
CoASH
O
-O
N
H
P
O
-O
N
O
N
H
S
O
O
HO
N
N
vitamin B5:
O
NH2
O
N
N
O
N
H
O
NH2
O
-O
O
N
OH
O
N
H
OH
pantothenic acid
OH
O
P O
-O
acetyl-CoA
•  acyl transfer, part of PDH system, pyruvate metabolism
•  source of pantothenic acid: almost all foods, but more in meats
•  deficiency disease: extremely rare, similar to starvation
12
TPP
O
O-
+
H+
pyruvate decarboxylase
TPP
O
H
+
CO2
O
!  thiazole is relatively acidic
!  ylide carbanion is a good nucleophile
!  and, as a fairly week base, a good leaving group
13
TPP
O
O-
+
H+
pyruvate decarboxylase
TPP
O
H
+
CO2
O
OH
B
H
O-
CH3
O
R N+
O-
O
C
O
C
O
+
S
B
O
R N+
H
OH
CH3
C
S
R N+
C
OH
CH3
C
S
R N
C
C
S
:B
O
CH3
O
+
H
R N+
H
CH
C
S
14
Pyruvate dehydrogenase system
O
O-
+
pyruvate dehydrogenase
system
CoASH
O
SCoA
+
CO2
O
TPP, lipoate, CoASH, FAD, and NAD+
H
B
CONHEnzyme2
:B-
S
S
OH
CH3
R N+
OH
C
CH3
C
R N
S
C
CH3
C
R N+
S
O
H
C
S
SH
NHEnzyme2
C
S
O
O
CH3 C
R N+
C
S
CoASH
SH
SH
NHEnzyme2 +
NHEnzyme2
+
S
SH
O
CH3 C SCoA
O
O
FAD-Enzyme3
NAD+
FAD-Enzyme3
(-NADH, -H+)
FADH2-Enzyme3 +
S
S
NHEnzyme2
O
15
Pyruvate dehydrogenase system
O
O-
+
pyruvate dehydrogenase
system
CoASH
O
SCoA
+
CO2
O
TPP, lipoate, CoASH, FAD, and NAD+
H
B
CONHEnzyme2
:B-
S
S
OH
CH3
R N+
OH
C
CH3
C
R N
S
C
CH3
C
R N+
S
O
H
C
S
SH
NHEnzyme2
C
S
O
O
CH3 C
R N+
C
S
CoASH
SH
SH
NHEnzyme2 +
NHEnzyme2
+
S
SH
O
CH3 C SCoA
O
O
FAD-Enzyme3
NAD+
FAD-Enzyme3
(-NADH, -H+)
FADH2-Enzyme3 +
S
S
NHEnzyme2
O
16
practice problem
PRACTICE PROBLEM
Acetolactate synthase can also transfer the two-carbon fragment
from pyruvate to α-ketobutyrate, forming α-aceto-α-hydroxybutyrate.
This is the first step in the formation of isoleucine. Propose a
mechanism for this reaction.
acetolactase
synthase
TPP
O
O
OO
+
O-
O OH
COO-
+
CO2
O
17
Biotin
vitamin H or B7:
O
HN
NH
OH
S
biotin
(itself)
O
biotin
•  carboxylation (aldol with CO2)
•  source of biotin: liver, soybeans, tomato, carrots
•  deficiency: rare and mild, skin conditions, perosis, FLKS
18

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