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Clinical Presentation Curriculum A Guide to Intermediary Metabolism Jack Blazyk, Ph.D. 2003-2004. 2. 3. Thermodynamics. In an actively functioning pathway, the D G for ALL reactions is NEGATIVE. Enzyme Regulation. Covalent Modification (e.g., reversible phosphorylation). - PowerPoint PPT Presentation
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Clinical Presentation Curriculum
A Guide toIntermediary Metabolism
Jack Blazyk, Ph.D.2003-2004
Design of M et abolism
A ct ivat ed Pr ecur sor s M acr omolecules
Pr ecur sor s
GlycogenT r iglycer ides
Pr ot eins
U D P- GlucoseF at t y A cyl- CoA
A minoacyl t - RN A
GlucoseF at t y A c idsA mino A cids
CH E M I CA LPO W E R
O 2
E N E RGY
CO 2
H 2 ON H 3
H E A T
60%
40%
O x idat ion(Combust ion)
A nabolism(B iosynt hesis)
Cat abolism
2
In an actively functioning pathway,
the G for ALL reactions is NEGATIVE
Allosteric Regulation
Covalent Modification(e.g., reversible phosphorylation)
OR
Genetic Regulation
Thermodynamics
Enzyme Regulation
3
High-Energy Phosphates
Enol
Example
Phosphoenolpyruvate (PEP)
Acyl
Example
1,3-Bisphosphoglycerate
Amino
Example
Creatine phosphate
Pyro (Phosphoanhydride)
Example
Adenosine triphosphate (ATP)
Hydrolysis of Phosphates
Enol
-15
Acyl
-10
Amino
-10
Pyro
-7
Adenosine Pool
ATP
ADP
AMP
Hydrolysis of ATP
4
NAD+ + 2e- + H+ NADHOxidized Reduced
Nicotinamide Adenine Dinucleotide
Electron Transfer
NADP+ + 2e- + H+ NADPHOxidized Reduced
Nicotinamide Adenine Dinucleotide Phosphate
FAD + 2e- + 2H+ FADH2
Oxidized Reduced
Flavin Adenine Dinucleotide
Coenzyme A
ADP + Pantothenic Acid + SH
CoA - SH
CoA - S ~ C – CH3
O
Acetyl-CoA
Acyl Group Transfer
5
4. C4 C4 + 4e-
Citric Acid Cycleor
Tricarboxylic acid (TCA) Cycle
orKrebs Cycle
Located in mitochondrial matrix
Citrate
- COO-
Citric Acid
1. C2 + C4 C6
3. C5 C4 + CO2 + ~P + 2e-
2. C6 C5 + CO2 + 2e-
Oxidative Decarboxylations
Sneak Preview
6
Citrate Synthase Aconitase
Isocitrate Dehydrogenase
-KG Dehydrogenase
Oxidative Decarboxylations
Succinate ThiokinaseSuccinate
Dehydrogenase
FumaraseMalate
Dehydrogenase
CH3 - C - S - CoA
3 H2O
3 NAD+
1 FAD
GDP + Pi
O
In CoA - SH
2 CO2
3 NADH + 3 H+
1 FADH2
GTP + H2O
Out
7
Tap-Off Points
Malate
NADP+
PEP Carboxykinase
Malic Enzyme
Anaplerotic Pathway
Pyruvate Carboxylase
Pyruvate Oxaloacetate
ATP + CO2 ADP + Pi
Allosterically activated by Acetyl-CoA
Biotin (a water-soluble B vitamin) is a coenzyme
NADPH + H+ + CO2
Pyruvate
8
Oxidative Phosphorylation
Electron Transport Chain = Respiratory Chain
4 Membrane-Bound Complexes
• I – NADH-Q Reductase
• II – Succinate-Q Reductase
• III – Cytochrome Reductase
• IV – Cytochrome Oxidase
2 Mobile Electron Carriers
• Ubiquinone (Coenzyme Q)
• Cytochrome c
Complex INADH-Q Reductase
Transfers electrons from NADH to Q
NADH + H+ + Q NAD+ + QH2
• Flavin Mononucleotide (FMN)
• Iron-sulfur (Fe-S) proteins
Complex IISuccinate-Q Reductase
Transfers electrons from Succinate to Q
Succinate + Q Fumarate + QH2
• Flavin Adenine Dinucleotide (FAD)
• Iron-sulfur (Fe-S) proteins
Complex IIICytochrome Reductase
Transfers electrons from QH2 to Cyt c
QH2 + 2Cyt c(Fe+3) Q + 2H+ + 2Cyt c(Fe+2)
• Cytochrome b (2 types)
• Iron-sulfur (Fe-S) proteins
• Cytochrome c1
Complex IVCytochrome Oxidase
Transfers electrons from Cyt c to O2
2Cyt c(Fe+2) + ½O2 + 2H+ 2Cyt c(Fe+3) + H2O
• Cytochrome a
• Cytochrome a3
• Copper (Cu)
9
Chemiosmotic Mechanism
• Proposed by Peter Mitchell
• Proton Motive Force
• PMF = pH +
10
ATP Production via CAC and Ox Phos
3 NADH ~9 ATP
1 FADH2 ~2 ATP
1 GTP 1 ATP
~12 ATP per Acetyl-CoA
GTP + ADP GDP + ATP
Regulation of CAC and Ox Phos
• Availability of Acetyl-CoA
• Availability of O2
• Energy Charge =
• Respiratory Control
[ATP] + ½ [ADP]
[ATP] + [ADP] + [AMP]
X
X
Electron Transport
Inhibitors
CO
CN -
N3-
Rotenone
11
Oxidative Phosphorylation
Inhibitors
Oligomycin
Atractyloside
X
X
Uncouplers
2,4-
Dinitrophenol
+ H+
NO2NO2
O -
NO2NO2
OH
H+
H+
H+
X
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39R-COOH
40Fatty Acid Oxidation
41
42
43Fatty Acid Biosynthesis
44Regulatio
n
45
46Triglyceride Metabolism
47Lipogenesis
Lipolysis
48
49Amino Acid Metabolism
50
Amino Group Shuttles
Matrix Cytoplasm
Liver
Urea Cycle
From Harper’s Biochemistry, Murray et al., 25th ed., 2000, Fig. 31-14
51
Well-Fed Conditions
Gly
coly
sis
Glycogenesis
PentoseShunt
Fatty AcidSynthesis
CholesterolSynthesis
TriglycerideSynthesis
52
Gly
coly
sis
PentoseShunt
Fatty AcidSynthesis
CholesterolSynthesis
TriglycerideSynthesis
Well-Fed Conditions
53
Well-Fed Conditions
Glycogenesis
54
Insulin
RBC
Liver
Muscle
Adipose
Brain
Gut
Portal Vein
Lymphatics
Glucose
Glycogen
Glucose
CO2 + H2O
Protein
TG
Urea
Pancreas
Glucose
TGPyruvate
Lactate
Lactate
Chylomicrons
VLDL
Glycogen
CO2 + H2O
CO2 + H2O
Well-Fed State
55
Glu
con
eog
enes
is
Fatty AcidOxidation
Ketone Body Synthesis
GlycogenolysisFasting Conditions
56
Fatty AcidOxidation
TriglycerideBreakdown
No Uptake
Fasting Conditions
57
No Uptake
Fatty AcidOxidation
Ketone BodyUtilization
Fasting Conditions
58
Early Fasting State
Glucagon
RBC
Liver
Muscle
Adipose
Brain
Gut
Portal Vein
Lymphatics
Glycogen
GlucoseG
luco
se
CO2 + H2O
Pancreas
Pyruvate
CO2 + H2OCO2 + H2O
FA
FA
Lactate
Lactate
59
Extended Fasting State
Glucagon
RBC
Liver
Muscle
Adipose
Brain
Gut
Portal Vein
Lymphatics
CO2 + H2O
Pancreas
Pyruvate CO2 + H2O
KB
Lactate
FA
Glycerol
FA
CO2 + H2O
Protein
Cortisol
Glucose
Urea
60