Metabolic pathway

1
Chemistry B11
Chapter 27 28 Metabolic pathway Energy
production
2
Metabolism
Chemical reactions in cells that break down or
build molecules. It produces energy and provide
substances to cell growth.
Catabolic reactions
Complex molecules ? Simple molecules Energy
Anabolic reactions
Simple molecules Energy (in cell) ? Complex
molecules
3
Metabolism in cell
Mitochondria
Urea NH4
Proteins
Amino acids
e
Citric Acid cycle
Glucose Fructose Galactose
Carbohydrates Polysaccharides
e
Glucose
Pyruvate
Acetyl CoA
CO2 H2O
Glycerol
Lipids
Fatty acids
Step 3 Oxidation to CO2, H2O and energy
Step 1 Digestion and hydrolysis
Step 2 Degradation and some oxidation
4
Cell Structure
Nucleus
Membrane
Mitochondria
Cytoplasm
(Cytosol)
5
Cell Structure
Nucleus consists the genes that control DNA
replication and protein synthesis of the
cell. Cytoplasm consists all the materials
between nucleus and cell membrane. Cytosol
fluid part of the cytoplasm (electrolytes and
enzymes). Mitochondria energy producing
factories.
Enzymes in matrix catalyze the oxidation of
carbohydrates, fats , and amino acids.
Produce CO2, H2O, and energy.
6
ATP and Energy

• Adenosine triphosphate (ATP) is produced from
  the oxidation of food.
• Has a high energy.
• Can be hydrolyzed and produce energy.

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ATP and Energy
- We use this energy for muscle contraction,
synthesis an enzyme, send nerve signal, and
transport of substances across the cell
membrane. - 1-2 million ATP molecules may be
hydrolysis in one second (1 gram in our
cells). - When we eat food, catabolic reactions
provide energy to recreate ATP.
ADP Pi 7.3 kcal/mol ? ATP
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Step 1 Digestion
Convert large molecules to smaller ones that can
be absorbed by the body.
Carbohydrates
Lipids (fat)
Proteins
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Digestion Carbohydrates
Salivary amylase
Dextrins

Mouth
Polysaccharides

Maltose
Glucose
Stomach
pH 2 (acidic)
Small intestine pH 8
Dextrins
a-amylase (pancreas)
Glucose
Glucose
Maltase

Maltose
Galactose
Glucose
Lactase

Lactose
Fructose
Glucose
Sucrase

Sucrose
Bloodstream
Liver (convert all to glucose)
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Digestion Lipids (fat)
Fatty acid
H2C
OH
H2C
lipase (pancreas)
HC
Fatty acid
2H2O
HC
Fatty acid
2 Fatty acids
Small intestine
H2C
Fatty acid
H2C
OH
Triacylglycerol
Monoacylglycerol
Intestinal wall
Monoacylglycerols 2 Fatty acids ?
Triacylglycerols
Protein
Lipoproteins
Chylomicrons
Lymphatic system
Bloodstream
Glycerol 3 Fatty acids
Enzymes hydrolyzes
Cells
liver
Glucose
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Digestion Proteins
HCl
Pepsinogen
Pepsin
Stomach
Proteins
Polypeptides
denaturation hydrolysis
Small intestine
Trypsin Chymotrypsin
Polypeptides
Amino acids
hydrolysis
Intestinal wall
Bloodstream
Cells
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Some important coenzymes
oxidation
Coenzyme Substrate
Coenzyme(2H) Substrate(-2H)
Reduced
Oxidized
2 H atoms
2H 2e-
NAD
Coenzymes
FAD
Coenzyme A
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NAD
Nicotinamide adenine dinucleotide
(vitamin)
Ribose
14
NAD

• Is a oxidizing agent.
• Participates in reactions that produce (CO)
  such as
• oxidation of alcohols to aldehydes and ketones.

O
CH3-CH2-OH NAD
CH3-C-H NADH H
NAD 2H 2e- ? NADH H
15
FAD
Flavin adenine dinucleotide
(Vitamin B2)
(sugar alcohol)
ADP
16
FAD

• Is a oxidizing agent.
• Participates in reaction that produce (CC) such
  as
• dehydrogenation of alkanes.

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Coenzyme A (CoA)
HS-CoA
Coenzyme A
Aminoethanethiol
( vitamin B5)
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Coenzyme A (CoA)
- It activates acyl groups, particularly the
acetyl group.
O
O
CH3-C- HS-CoA
CH3-C-S-CoA
Acetyl group
Coenzyme A
Acetyl CoA
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Metabolism in cell
Mitochondria
Urea NH4
Proteins
Amino acids
e
Citric Acid cycle
Glucose Fructose Galactose
Carbohydrates Polysaccharides
e
Glucose
Pyruvate
Acetyl CoA
CO2 H2O
Glycerol
Lipids
Fatty acids
Step 3 Oxidation to CO2, H2O and energy
Step 1 Digestion and hydrolysis
Step 2 Degradation and some oxidation
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Step 2 Glycolysis

• We obtain most of our energy from glucose.
• Glucose is produced when we digest the
  carbohydrates in our food.
• We do not need oxygen in glycolysis (anaerobic
  process).

2 ATP
2 ADP 2Pi
O
C6H12O6 2 NAD
2CH3-C-COO- 2 NADH 4H
Pyruvate
Glucose
Inside of cell
21
Pathways for pyruvate
- Pyruvate can produce more energy.
Aerobic conditions if we have enough oxygen.
Anaerobic conditions if we do not have enough
oxygen.
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Aerobic conditions

• Pyruvate is oxidized and a C atom remove (CO2).
• Acetyl is attached to coenzyme A (CoA).
• Coenzyme NAD is required for oxidation.

O
O
O
CH3-C-C-O- HS-CoA NAD
CH3-C-S-CoA CO2 NADH
pyruvate
Coenzyme A
Acetyl CoA
Important intermediate product in metabolism.
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Anaerobic conditions

• When we exercise, the O2 stored in our muscle
  cells is used.
• Pyruvate is reduced to lactate.
• Accumulation of lactate causes the muscles to
  tire and sore.
• Then we breathe rapidly to repay the O2.
• Most lactate is transported to liver to convert
  back into pyruvate.

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Glycogen

• If we get excess glucose (from our diet),
  glucose convert to glycogen.
• It is stored in muscle and liver.
• We can use it later to convert into glucose and
  then energy.
• When glycogen stores are full, glucose is
  converted to triacylglycerols
• and stored as body fat.

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Metabolism in cell
Mitochondria
Urea NH4
Proteins
Amino acids
e
Citric Acid cycle
Glucose Fructose Galactose
Carbohydrates Polysaccharides
e
Glucose
Pyruvate
Acetyl CoA
CO2 H2O
Glycerol
Lipids
Fatty acids
Step 3 Oxidation to CO2, H2O and energy
Step 1 Digestion and hydrolysis
Step 2 Degradation and some oxidation
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Step 3 Citric Acid Cycle

• Is a central pathway in metabolism.
• Uses acetyl CoA from the degradation of
  carbohydrates, lipids,
• and proteins.
• Two CO2 are given off.
• There are four oxidation steps in the cycle
  provide H and
• electrons to reduce FAD and NAD (FADH2 and
  NADH).

8 reactions
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Reaction 1
Formation of Citrate
O
CH3-C-S-CoA
Acetyl CoA

COO-
CH2
COO-
H2O
HO
C
COO-
CoA-SH
CO
Oxaloacetate
CH2
CH2
COO-
COO-
Coenzyme A
Citrate
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Reaction 2
Isomerisation to Isocitrate

• Because the tertiary OH cannot be oxidized.
• (convert to secondary OH)

COO-
COO-
CH2
CH2
Isomerisation
HO
H
C
COO-
C
COO-
H
HO
CH2
C
COO-
COO-
Isocitrate
Citrate
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Reaction 3
First oxidative decarboxylation (CO2)

• Oxidation (-OH converts to CO).
• NAD is reduced to NADH.
• A carboxylate group (-COO-) is removed (CO2).

COO-
COO-
COO-
CH2
CH2
CH2
H
H
C
COO-
C
COO-
CH2
CO2
H
HO
O
O
C
C
C
COO-
COO-
COO-
Isocitrate
a-Ketoglutrate
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Reaction 4
Second oxidative decarboxylation (CO2)

• Coenzyme A convert to succinyl CoA.
• NAD is reduced to NADH.
• A second carboxylate group (-COO-) is removed
  (CO2).

COO-
COO-
CH2
CH2
CH2
CH2
CO2
O
O
C
C
COO-
S-CoA
a-Ketoglutrate
Succinyl CoA
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Reaction 5
Hydrolysis of Succinyl CoA

• Energy from hydrolysis of succinyl CoA is used
  to add a phosphate
• group (Pi) to GDP (guanosine diphosphate).
• Phosphate group (Pi) add to ADP to produce ATP.

COO-
COO-
CH2
CH2
ADP Pi
ATP
H2O GDP Pi
GTP CoA-SH
CH2
CH2
O
C
COO-
S-CoA
Succinate
Succinyl CoA
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Reaction 6
Dehydrogenation of Succinate

• H is removed from two carbon atoms.
• Double bond is produced.
• FAD is reduced to FADH2.

COO-
COO-
CH2
CH
CH2
CH
COO-
COO-
Fumarate
Succinate
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Reaction 7
Hydration

• Water adds to double bond of fumarate to produce
  malate.

COO-
COO-
H2O
CH
HO
H
C
CH
CH2
COO-
COO-
Fumarate
Malate
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Reaction 8
Dehydrogenation forms oxaloacetate

• -OH group in malate is oxidized to oxaloacetate.
• Coenzyme NAD is reduced to NADH H.

COO-
COO-
H
HO
H
C
CO
CH2
CH2
COO-
COO-
Oxaloacetate
Malate
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Summary

• The catabolism of proteins, carbohydrates, and
  fatty acids
• all feed into the citric acid cycle at one or
  more points

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Summary
12 ATP produced from each acetyl-CoA
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Electron Transport
H and electrons from NADH and FADH2 are carried
by an electron carrier until they combine with
oxygen to form H2O.
FMN (Flavin Mononucleotide)
Fe-S clusters
Electron carriers
Coenzyme Q (CoQ)
Cytochrome (cyt)
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FMN (Flavin Mononucleotide)
H
2H 2e-
H
-
FMN 2H 2e- ? FMNH2
Reduced
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Fe-S Clusters
S
S
S
Cys
Cys
S
Cys
Cys
1 e-
Fe3
Fe2
S
S
S
S
Cys
Cys
Cys
Cys
Fe3 1e- Fe2
Reduced
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Coenzyme Q (CoQ)
OH
2H 2e-
OH
Reduced Coenzyme Q (QH2)
Coenzyme Q
Q 2H 2e- ? QH2
Reduced
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Cytochromes (cyt)

• They contain an iron ion (Fe3) in a heme group.
• They accept an electron and reduce to (Fe2).
• They pass the electron to the next cytochrome
  and
• they are oxidized back to Fe3.

Fe3 1e- Fe2
Reduced
Oxidized
cyt b, cyt c1, cyt c, cyt a, cyt a3
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Electron Transfer
Mitochondria
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Electron Transfer
Complex I
NADH H FMN ? NAD FMNH2
FMNH2 Q ? QH2 FMN
NADH H Q ? QH2 NAD
Complex II
FADH2 Q ? FAD QH2
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Electron Transfer
Complex III
QH2 2 cyt b (Fe3) ? Q 2 cyt b (Fe2) 2H
Complex IV
4H 4e- O2 ? 2H2O
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Oxidative Phosphorylation
Transport of electrons produce energy to convert
ADP to ATP.
ADP Pi energy ? ATP
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Chemiosmotic model

• H make inner mitochondria acidic.
• Produces different proton gradient.
• H pass through ATP synthase (a protein complex).

ATP synthase
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Total ATP
Glycolysis 6 ATP Pyruvate 6 ATP Citric
acid cycle 24 ATP
36 ATP
Oxidation of glucose
C6H12O6 6O2 36 ADP 36 Pi ? 6CO2 6H2O 36
ATP
48
Metabolism in cell
Mitochondria
Urea NH4
Proteins
Amino acids
e
Citric Acid cycle
Glucose Fructose Galactose
Carbohydrates Polysaccharides
e
Glucose
Pyruvate
Acetyl CoA
CO2 H2O
Glycerol
Lipids
Fatty acids
Step 3 Oxidation to CO2, H2O and energy
Step 1 Digestion and hydrolysis
Step 2 Degradation and some oxidation
49
Oxidation of fatty acids

• Oxidation happens in step 2 and 3.
• Each beta oxidation produces acetyl CoA and a
  shorter fatty acid.
• Oxidation continues until fatty acid is
  completely break down to acytel CoA.

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Oxidation of fatty acids
Fatty acid activation
- Before oxidation, they activate in cytosol.
O
O
ATP HS-CoA
R-CH2-C-OH
R-CH2-C-S-CoA
H2O AMP 2Pi
Fatty acyl CoA
Fatty acid
?-Oxidation 4 reactions
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Reaction 1 Oxidation (dehydrogenation)
O
H
H
O
H
R-CH2-C-C-C-S-CoA
FAD
R-CH2-CC-C-S-CoA FADH2
H
H
H
Fatty acyl CoA
Reaction 2 Hydration
O
O
HO
H
H
R-CH2-CC-C-S-CoA H2O
R-CH2-C-C-C-S-CoA
H
H
H
52
Reaction 3 Oxidation (dehydrogenation)
HO
O
H
O
O
R-CH2-C-C-C-S-CoA NAD
R-CH2-C-CH2-C-S-CoA NADH H
H
H
Reaction 4 Cleavage of Acetyl CoA
O
O
O
O
R-CH2-C-CH2-C-S-CoA CoA-SH
CH3-C-S-CoA
R-CH2-C-S-CoA

Acetyl CoA
Fatty acyl CoA
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Oxidation of fatty acids
One cycle of ?-oxidation
O
R-CH2-CH2-C-S-CoA NAD FAD H2O CoA-SH
O
O
R-C-S-CoA
CH3-C-S-CoA NADH H FADH2

Acetyl CoA
Fatty acyl CoA
of fatty acid carbon
of Acetyl CoA
1 ? oxidation cycles
2
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Ketone bodies

• If carbohydrates are not available to produce
  energy.
• Body breaks down body fat to fatty acids and
  then Acetyl CoA.
• Acetyl CoA combine together to produce ketone
  bodies.
• They are produced in liver.
• They are transported to cells (heart, brain, or
  muscle).

O
Acetone
O
CH3-C-S-CoA
O
O
CH3-C-CH3 CO2 energy
CH3-C-CH2-C-O-
O
OH
O
CH3-C-S-CoA
Acetoacetate
CH3-CH-CH2-C-O-
Acetyl CoA
?-Hydroxybutyrate
55
Ketosis (disease)

• When ketone bodies accumulate and they cannot be
  metabolized.
• Found in diabetes and in high diet in fat and
  low in carbohydrates.
• They can lower the blood pH (acidosis).
• Blood cannot carry oxygen and cause breathing
  difficulties.

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Fatty acid synthesis

• When glycogen store is full (no more energy
  need).
• Excess acetyl CoA convert to 16-C fatty acid
  (palmitic acid) in cytosol.
• New fatty acids are attached to glycerol to make
  triacylglycerols.
• (are stored as body
  fat)

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Metabolism in cell
Mitochondria
Urea NH4
Proteins
Amino acids
e
Citric Acid cycle
Glucose Fructose Galactose
Carbohydrates Polysaccharides
e
Glucose
Pyruvate
Acetyl CoA
CO2 H2O
Glycerol
Lipids
Fatty acids
Step 3 Oxidation to CO2, H2O and energy
Step 1 Digestion and hydrolysis
Step 2 Degradation and some oxidation
58
Degradation of amino acids

• They are degraded in liver.
• Transamination
• They react with a-keto acids and produce a new
• amino acid and a new a-keto acid.

O
NH3

-OOC-C-CH2-CH2-COO-
CH3-CH-COO-
alanine
a-ketoglutarate

CH3-C-COO-
-OOC-CH-CH2-CH2-COO-
pyruvate
glutamate
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Degradation of amino acids
Oxidative Deamination
glutamate dehydrogenase
H2O NAD
-OOC-CH-CH2-CH2-COO-
glutamate
-OOC-C-CH2-CH2-COO-
NH4 NADH H
a-ketoglutarate
60
Urea cycle

• Ammonium ion (NH4) is highly toxic.
• Combines with CO2 to produce urea (excreted in
  urine).
• If urea is not properly excreted, BUN (Blood
  Urea Nitrogen) level in blood
• becomes high and it build up a toxic level
  (renal disease).
• - Protein intake must be reduced and hemodialysis
  may be needed.

2NH4 CO2
H2N-C-NH2 2H H2O
urea
61
Energy from amino acids

• C from transamination are used as intermediates
  of the citric acid cycle.
• amino acid with 3C pyruvate
• amino acid with 4C oxaloacetate
• amino acid with 5C a-ketoglutarate
• 10 of our energy comes from amino acids.
• But, if carbohydrates and fat stores are
  finished, we take energy from them.