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Coenzyme A
Pantothenate
2-mercaptoethylamine
ADP
Acyl carrier protein
ser - protein
Fritz Lipmann
Noble prize for Chemistry 1953 (shared with Sir Hans Krebs)
"for his discovery of co-enzyme A and its importance for
intermediary metabolism"
1899-1986
Pyruvate dehydrogenase
The core of the complex consists of 60 copies of E2.
At the periphery of the complex are:
 30 copies of E1 (itself a tetramer with subunits a2b2)
 12 copies of E3 (a homodimer), plus 12 copies of an
E3 binding protein that links E3 to E2.
Pyruvate dehydrogenase
OH
O
1.
H3C-C-COO-
+
H+
+
E1 TPP
TPP-CH
+
CO2
CH3
O
OH
2.
+
TPP-CH
S
S
E2
S – C –CH3
SH
E
2
CH3
O
3.
E
2
S – C –CH3
SH
+
CoA-SH
E2
+ H+
O
CoA-S - C –CH3
+
E2
Acetyl CoA
4.
5.
E2
SH
SH
FADH2
+
+
FAD
NAD
E2
S
S
FAD
+
+
FADH2
NADH + H+
SH
SH
Regulation of PDH:
1. Inhibited by AcCoA and NADH
 AcCoA (competes with CoA for E2),
NADH (competes with NAD for E3)
2. Regulated by phosphorylation
E2 is associated with PDH kinase and
PDH phosphatase which act on E1



phosphorylation of the E1 subunit inhibits
dephosphorylation activates.
Phosphorylation controled by NADH/NAD,
AcCoA/CoA and ATP/ADP.
Increasing these ratios promotes phosphorylation and
hence decreases activity.
THEREFORE: Phosphorylation of E1 increases and
activity
of PDH decreases when energy charge is high.
 Pyruvate inhibits PDH kinase in the presence of high
[ADP]
and therefore promotes dephosphorylation and
increase in activity.
 In muscle high [Ca2+] activates phosphatase. At onset
of exercise [Ca2+], pyruvate and ADP increase resulting
in increased PDH phosphatase (Ca) and decrease PDH
kinase due to increased pyruvate + ADP, and decreased
ATP/ADP ratio.
Sir Hans Krebs
Noble Prize for Chemistry
"for his discovery of the citric acid cycle"
1900 - 1981
or GTP
O
HO
COO-
SCoA
C
C
COO-
C
H
CH
COO-
O
Make a couple of copies of this for class
COO-
CH3
C H2
HO
HC H
C
COO-
C H2
COO-
COOCOO-
COOH
C H2
C
C
H
H
C
COO-
HO C
COO-
H
COO-
COOCOO-
C H2
COO-
C H2
C H2
COO-
H
C H2
H
C
H
C
O
C
COO-
H
C
O
O
COO-
COO-
COO-
C
CH
COO-
SCoA
HO
C
H
C H2
HO
HC H
C
COO-
C H2
COO-
COOCOO-
COO-
COOH
O
HO
C
COO-
C
H
CH
COO-
HO
HC H
COO-
H
COO-
C
C H2
COO-
C
C H2
C
H
H
C
COO-
C H2
COO-
COO-
C H2
COO-
C H2
C H2
C H2
H
COO-
C
H
C
H
C
O
COO-
HO C
COO-
H
COO-
COOCOO-
C H2
COO-
C H2
C H2
COO-
H
C H2
SCoA
H
H
C H2
H
C
H
C
O
SCoA
C
C
H
COO-
COO-
C
COO-
HO C
COOCOO-
C
H
O
COO-
C
C
H
O
COO-
Biotin
O
N
N
O
C
H2
S
C
H2
C C
H2 H2
C
N
H
Lys
ENZYME
+ CO2
O
O
C
O-
N
N
O
S
C
H2
C
H2
C C
H2 H2
C
N
H
Lys
ENZYME