12.09.08: Amino Acid Metabolism (Nitrogen Metabolism)
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M1 Renal: Nitrogen Metabolism (and Related Topics)
Fall 2008
• Amino Acid Metabolism (Nitrogen metabolism) • Folate Metabolism (“One-Carbon pathways”) • Nucleotide Metabolism
Dr. Robert Lyons Assistant Professor, Biological Chemistry
Director, DNA Sequencing Core Web: http://seqcore.brcf.med.umich.edu/mcb500
Supplementary study material on the Web: http://seqcore.brcf.med.umich.edu/mcb500
R. Lyons
Glu, Gln,Asp, NH3
Amino Acid metabolism Folate metabolism
Nucleic Acid metabolism
MethyleneTHF
MetCycle
Pu rin e s Py rim id in e s
Uric Acid
Urea
Amino acids
DNARNA
(energy)
TCA Cyclefumarate
oxaloacetate
R. Lyons
Protein Degradation: • Endogenous proteins degrade continuously
- Damaged - Mis-folded - Un-needed
• Dietary protein intake - mostly degraded Nitrogen Balance - expresses the patient’s current status - are they gaining or losing net Nitrogen?
Transaminases Collect Amines
General reaction overview:
C
H
R COO
NH2
aminoacid
C
H
R COO
NH2
aminoacid
(typically glutamate)
1 2CR COOO
!-ketoacid
(typicallyalpha-ketoglutarate)
(-)+ +2
CR COOO
!-ketoacid
(-)
1(-) (-)
Details of reaction mechanism:
C
H
R COO
NHC
H
R COO
N
N
CHO
CH
CH
OHOP
pyridoxalphosphate
aminoacid
+
H O2
3
2
CH
CH
CHOHOP
3
2
2
C
H
R COO
N
CHCH
CH
OHOP
3
2
+
H+
+
C
H
R COO
N
CH
CH
CHOHOP
3
2
+
CR COO
NH
CH
O
CH
CH
OHOP
pyridoxaminephosphate
+
3
2
2
+
H
!-ketoacid
(-)(-) (-) (-)
(-)
NH
NH
NH N
H
R. Lyons
NH
N
CH
CH
CH
OHOP
pyridoxaminephosphate
3
2
2
H
+
H
+ CR COOO
!-ketoacid
N
CHO
CH
CH
OHOP
pyridoxalphosphate
3
2
H
++ C
H
R COO
NH2
aminoacid
(-)
Transfer the amine back to an acceptor α-keto acid
R. Lyons
Some amino acid + α-ketoglutarate à some alpha keto acid + Glutamate
In other words, alpha-ketoglutarate is the preferred acceptor, and Glutamate is the resulting amino acid:
In peripheral tissues, transaminases tend to form Glutamate when they catabolize amino acids
Glutamate can donate its amines to form other amino acids as needed
Glutamate + oxaloacetate à α-ketoglutarate + aspartate
A specific example - production of Aspartate in liver (described a few slides from now):
Gett in g Amin es In to the L iv er
O C CH CH C
H
NH
CO
2
2 2 2 2
glutamate
NAD(P)
NAD(P)H
O C CH CH C CO2 2 2 2
!-ketoglutarate
+ NH3
ammonia
(-) (-) (-) (-)
O(mito)
C
H
OOC CH2
NH3(+)
(-)CH2COO(-)
glutamate glutamine
C
H
OOC CH2
NH3(+)
(-)CH
2C
O
NH2
NH3
ATP ADP Pi+ +
GlutamateDehydrogenase:
GlutamineSynthetase:
R. Lyons
In th e L iv er: Precursers for Urea Cycle
Glutamine is hydrolyzed to glutamate and ammonia:
C
H
OOC CH2
NH3(+)
(-) CH2C
glutamate
O
OH
glutamine
C
H
OOC CH2
NH3(+)
(-)CH2C
O
NH2
H O2 NH3
Glutamate donates its amino group to form aspartate:
Glutamate aspartateoxaloacetate
+ +
!-ketoglutarate
O C CH CH C
H
N H
CO
2
2 2 2 2(- ) (-) O CC H C
H
CO2 2 2
( -) ( -) O C CH CH C
O
C O2 2 2 2
(- ) (-) O C CH C
H
NH
CO
2
2 2 2(- ) (-)
O
Glutamate-aspartate aminotransferase:
.
.
Ammonia can also be formed by the glutamate dehydrogenase reaction and several other reactions as well.
R. Lyons
Liver mitochondrion
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH3
(+)
Ornithine
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH3
(+)
Ornithine
C
H
OOC CH2
NH3(+)
(-) CH2CH
2NH C
(+)
Arginine
C
H
OOC CH2
NH3(+)
(-) CH2CH
2NH C
O
Citrulline
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH C
O
Citrulline
2ATP + HCO +3
NH2 C
O
3OPO(-)
Carbamoylphosphate
Pi
2ADP + Pi
O CCH C
H
2 2 2
aspartate
(-) (-)CO
i
ATP
AMP + PP
C
H
OOC CH2
NH3
(+)
(-)CH
2CH
2NH C
O CCH C
H
2 2 2(-) (-)CO
(+)
Argininosuccinate
Liver cytoplasm
O C C CH
2 2(-) (-)CO
H
Fumarate
H O2
CO
Urea
NH2
NH2
NH2
NH3
NH2
NH2
NH2
NH2
NH2NH2
1
5
4
3
2
R. Lyons
C a rbam oy l p h o s ph a te sy n th e ta s e I
H O C
O
O
A T P
A D P
P
N H
P
(- ) H O C
O
O
b ic ar b on at ec ar bo ny l
ph os p ha te i
3
H O C
O
N H2
ca rb a ma te
A T P
A D P
O C
O
N H2
P
ca rb a mo yl
ph os p ha te
R. Lyons
O rn ith in e T ra n s ca rb am oy las e
C
H
OO C C H2
N H3
(+ )
( -)C H
2C H
2N H3
(+ )
O rn ith in e
C
H
O O C C H2
N H3(+ )
(- )C H
2C H
2N H
2N HC
O
C it ru llin e
N H2
C
O
3O P O( -)
C arb am o y l p ho s p hateP i
C H2N H3
(+ )
R. Lyons
A rg in ino su c c in a te s yn the tas e
O CCH
C
H
NH2
2 2 2
aspartate
(-) (-)CO
C
H
OOC CH2
NH3(+)
(-)CH
2CH2NH
2NHC
O
Citrulline
iATP AMP + PP
C
H
OOC CH2
NH3
(+)
(-)CH
2CH2NH C NH
O CCH C
H
NH2
2 2 2(-) (-)CO
2(+)
Argininosuccinate
R. Lyons
A rg in in o s u cc ina te ly a se
C
H
OOC CH2
NH3(+)
(-)CH
2CH2NH NH
2CNH
2(+)
Arginine
C
H
OOC CH2
NH3
(+)
(-)CH
2CH2NH C NH
O CCH C
H
NH2
2 2 2(-) (-)CO
2(+)
ArgininosuccinateO C C C
H2 2
(-) (-)COH
Fumarate
R. Lyons
A rg in as e
C
H
OOC CH2
NH3(+)
(-)CH
2CH2NH3
(+)
Ornithine
C
H
OOC CH2
NH3(+)
(-)CH2CH
2NH NH2C
NH2(+)
ArginineNH2 C
ONH
2
Urea
H2O
R. Lyons
Liver mitochondrion
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH3
(+)
Ornithine
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH3
(+)
Ornithine
C
H
OOC CH2
NH3(+)
(-) CH2CH
2NH C
(+)
Arginine
C
H
OOC CH2
NH3(+)
(-) CH2CH
2NH C
O
Citrulline
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH C
O
Citrulline
2ATP + HCO +3
NH2 C
O
3OPO(-)
Carbamoylphosphate
Pi
2ADP + Pi
O CCH C
H
2 2 2
aspartate
(-) (-)CO
i
ATP
AMP + PP
C
H
OOC CH2
NH3
(+)
(-)CH
2CH
2NH C
O CCH C
H
2 2 2(-) (-)CO
(+)
Argininosuccinate
Liver cytoplasm
O C C CH
2 2(-) (-)CO
H
Fumarate
H O2
CO
Urea
NH2
NH2
NH2
NH3
NH2
NH2
NH2
NH2
NH2NH2
1
5
4
3
2
R. Lyons
Urea Cycle Connects to TCA Cycle
Arginine
CitrullineO CCH C
H
NH2
2 2 2
Aspartate
(-) (-)CO
Argininosuccinate
O C C CH
2 2(-) (-)CO
H
Fumarate
MalateOxaloacetate
TCA Cycle
!-Ketoglutarate
Citrate
Urea
Ornithine
Urea Cycle
R. Lyons
Gett in g Amin es In to the L iv er
O C CH CH C
H
NH
CO
2
2 2 2 2
glutamate
NAD(P)
NAD(P)H
O C CH CH C CO2 2 2 2
!-ketoglutarate
+ NH3
ammonia
(-) (-) (-) (-)
O(mito)
C
H
OOC CH2
NH3(+)
(-)CH2COO(-)
glutamate glutamine
C
H
OOC CH2
NH3(+)
(-)CH
2C
O
NH2
NH3
ATP ADP Pi+ +
GlutamateDehydrogenase:
GlutamineSynthetase:
R. Lyons
Liver mitochondrion
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH3
(+)
Ornithine
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH3
(+)
Ornithine
C
H
OOC CH2
NH3(+)
(-) CH2CH
2NH C
(+)
Arginine
C
H
OOC CH2
NH3(+)
(-) CH2CH
2NH C
O
Citrulline
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH C
O
Citrulline
2ATP + HCO +3
NH2 C
O
3OPO(-)
Carbamoylphosphate
Pi
2ADP + Pi
O CCH C
H
2 2 2
aspartate
(-) (-)CO
i
ATP
AMP + PP
C
H
OOC CH2
NH3
(+)
(-)CH
2CH
2NH C
O CCH C
H
2 2 2(-) (-)CO
(+)
Argininosuccinate
Liver cytoplasm
O C C CH
2 2(-) (-)CO
H
Fumarate
H O2
CO
Urea
NH2
NH2
NH2
NH3
NH2
NH2
NH2
NH2
NH2NH2
1
5
4
3
2
R. Lyons
C P S I is S t im u la ted by N A G
H O C
O
O
A T P
A D P
P
N H
P
( -) H O C
O
O
bi ca rb o na tec a rb on y l
p ho s ph at e i
3
H O C
O
N H2
c ar ba m at e
A T P
A D P
O C
O
N H2
P
c ar ba m oy l
p ho sp h at e
g lu t am ate
C
H
O O C C H2
N H3
( +)
( - )
C H2C
O
O H+ CoA -
C
H
O O C C H2
N H
( - )
C H2C
O
O H
C O
C H3
C O
C H3
a cety l Co A N -acety l g lu t am a te(N AG )
N -a ce ty lg lu ta m a tesy n th e tase
( re pe a t in g the f igu re from pa ge 3 o f y ou r h an do u t)
R. Lyons
Muscle
Liver
Glucose Pyruvate
Alanine
Amino acids
(Amines)
!-ketoglutarate
Glutamate
Alanine
PyruvateGlucose
bloodtransport
!-ketoglutarate
Glutamate NH3
Urea
--
R. Lyons
Arginine
Amino acids:
Alanine Glutamate
Glutamine
Transamination Deaminationpurine
deamination:
NH4(+)
Glutamine
Alanine NH4(+)
Citrulline
NH4(+) Urea
Muscle:
Liver:
Intestine:
Alanine
AspartateGlu
Glutamine
NH3
Kidney:
Arginine
Citrulline
Glutamine
NH4(+)
Complicating the picture: Other tissues may be involved
R. Lyons
Why is Ammonia Toxic?
Why is Ammonia Toxic? • Possible neurotoxic effects on
glutamate levels (and also GABA)
(due to shifting equilibria of reactions involving these compounds)
Why is Ammonia Toxic? • Possible neurotoxic effects on
glutamate levels (and also GABA)
(due to shifting equilibria of reactions involving these compounds)
• Possible metabolic/energetics effects: - alpha-ketoglutarate levels - glutamate levels - glutamine
Liver mitochondrion
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH3
(+)
Ornithine
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH3
(+)
Ornithine
C
H
OOC CH2
NH3(+)
(-) CH2CH
2NH C
(+)
Arginine
C
H
OOC CH2
NH3(+)
(-) CH2CH
2NH C
O
Citrulline
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH C
O
Citrulline
2ATP + HCO +3
NH2 C
O
3OPO(-)
Carbamoylphosphate
Pi
2ADP + Pi
O CCH C
H
2 2 2
aspartate
(-) (-)CO
i
ATP
AMP + PP
C
H
OOC CH2
NH3
(+)
(-)CH
2CH
2NH C
O CCH C
H
2 2 2(-) (-)CO
(+)
Argininosuccinate
Liver cytoplasm
O C C CH
2 2(-) (-)CO
H
Fumarate
H O2
CO
Urea
NH2
NH2
NH2
NH3
NH2
NH2
NH2
NH2
NH2NH2
1
5
4
3
2
R. Lyons
Defects are diagnosed based on the metabolites seenin the blood and/or urine.
CPSD
OTCD
ASD
ALD
AD
No elevation except ammonia; diagnosed by elimination.Elevated CP causes synthesis of OrotateElevated citrullineElevated argininosuccinateElevated arginine
Inherited Defects of Urea Cycle Enzymes: Diagnosis
Liver mitochondrion
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH3
(+)
Ornithine
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH3
(+)
Ornithine
C
H
OOC CH2
NH3(+)
(-) CH2CH
2NH C
(+)
Arginine
C
H
OOC CH2
NH3(+)
(-) CH2CH
2NH C
O
Citrulline
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH C
O
Citrulline
2ATP + HCO +3
NH2 C
O
3OPO(-)
Carbamoylphosphate
Pi
2ADP + Pi
O CCH C
H
2 2 2
aspartate
(-) (-)CO
i
ATP
AMP + PP
C
H
OOC CH2
NH3
(+)
(-)CH
2CH
2NH C
O CCH C
H
2 2 2(-) (-)CO
(+)
Argininosuccinate
Liver cytoplasm
O C C CH
2 2(-) (-)CO
H
Fumarate
H O2
CO
Urea
NH2
NH2
NH2
NH3
NH2
NH2
NH2
NH2
NH2NH2
1
5
4
3
2
R. Lyons
C P S I is S t im u la ted by N A G
H O C
O
O
A T P
A D P
P
N H
P
( -) H O C
O
O
bi ca rb o na tec a rb on y l
p ho s ph at e i
3
H O C
O
N H2
c ar ba m at e
A T P
A D P
O C
O
N H2
P
c ar ba m oy l
p ho sp h at e
g lu t am ate
C
H
O O C C H2
N H3
( +)
( - )
C H2C
O
O H+ CoA -
C
H
O O C C H2
N H
( - )
C H2C
O
O H
C O
C H3
C O
C H3
a cety l Co A N -acety l g lu t am a te(N AG )
N -a ce ty lg lu ta m a tesy n th e tase
( re pe a t in g the f igu re from pa ge 3 o f y ou r h an do u t)
R. Lyons
Liver mitochondrion
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH3
(+)
Ornithine
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH3
(+)
Ornithine
C
H
OOC CH2
NH3(+)
(-) CH2CH
2NH C
(+)
Arginine
C
H
OOC CH2
NH3(+)
(-) CH2CH
2NH C
O
Citrulline
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH C
O
Citrulline
2ATP + HCO +3
NH2 C
O
3OPO(-)
Carbamoylphosphate
Pi
2ADP + Pi
O CCH C
H
2 2 2
aspartate
(-) (-)CO
i
ATP
AMP + PP
C
H
OOC CH2
NH3
(+)
(-)CH
2CH
2NH C
O CCH C
H
2 2 2(-) (-)CO
(+)
Argininosuccinate
Liver cytoplasm
O C C CH
2 2(-) (-)CO
H
Fumarate
H O2
CO
Urea
NH2
NH2
NH2
NH3
NH2
NH2
NH2
NH2
NH2NH2
1
5
4
3
2
R. Lyons
Clinical Management of Urea Cycle Defects
• Dialysis to remove ammonia • Provide the patient with alternative ways to excrete
nitrogenous compounds: • Levulose - acidifies the gut • Low protein diet
* Intravenous sodium benzoate or phenylacetate * Supplemental arginine
Ornithine
Arginine
Citrulline
i
ATP
AMP+PPArgininosuccinate
HO2
CO
UreaNH2NH2 Aspartate
Excreted by kidney
Excreted by kidney
XDietaryArginine
carbamoylphosphate
XASD
ALD
R. Lyons
Degrading the Amino Acid Carbon Backbone
Easily-degraded products after transamination:
O C CH C
H
NH3
2 2 2
aspartate
(-)COtransamination
O CCH CO
2 2 2(-)CO
oxaloacetate
(-) (-)
(+)
O C CH C
H
NH3
2 2 2
glutamate
(-)
transaminationCH C
O2 2
(-)
!-ketoglutarate
CH2
O C2
CH2
CO CO(-) (-)
(+)
CH C
H
NH3
3 2
alanine
(-)COtransamination
CH C
O3 2
(-)CO
pyruvate(+)
We also already know how to degrade Glutamine: Glutamine ----------------> glutamate + ammonia Asparagine ---------------> aspartate + ammonia
…and by analogy, how to degrade Asparagine:
glutaminase
asparaginase
glutaminase
R. Lyons
Many amino acids are purely glucogenic: Glutamate, aspartate, alanine, glutamine, asparagine,…
Some amino acids are both gluco- and ketogenic: Threonine, isoleucine, phenylalanine, tyrosine, tryptophan
Amino Acids are categorized as ‘Glucogenic’ or ‘ketogenic’ or both.
The only PURELY ketogenic Amino Acids: leucine, lysine
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH NH
2C
NH2(+)
Arginine
Urea (viathe urea cycle)
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH3
(+)
Ornithine!-ketoglutarate
glutamate
C
H
OOC CH2
NH3
(+)
(-)CH
2C
glutamate - 5 - semialdehyde
O
H
NAD(P)
NAD(P)H
(+)
C
H
OOC CH2
NH3(+)
(-)CH
2C
glutamate
O
OH
! - ketoglutarate
NH
(+)OOC(-)
Proline
glutamine
C
H
OOC CH2
NH3(+)
(-)CH
2C
O
NH2
H O2
NH3
Amino acids with 5-carbon backbones tend to form α-ketoglutarate
R. Lyons
C
H
OOC NH3(+)
(-)
H
Glycine
NAD NADH(+)
THF N -N - methylene THF5 10
+CO NH4
(+)
2
CH
OOC NH3(+)
(-)2
GlycineTHF N -N - methylene THF5 10Serine
CHOOC NH3(+)
(-)
CH OH2
GlycineSynthase:
SerineHydroxymethyl-transferase:
Serine
CHOOC NH3(+)
(-)
CH OH2
H O2
COOC NH3
(+)(-)
CH2
COOC NH2
(+)(-)
CH3
COOC(-)
CH3
H O2
NH4
(+)
OSerine
Dehydratase:
Degradation and Biosynthesis of Serine and Glycine
R. Lyons
C
H
COOCH2
NH3
(+)
(-)CH2
Methionine
Serine
C
H
COOCH2
NH3(+)
(-)HO
SCH3
C
H
COOCH2
NH3(+)
(-)CH2
S-Adenosyl Methionine
SCH3
ATP +H O2
PPi +Pi
(+)
CH2
O
HH H
HOH OH
Adenine
C
H
COOCH2
NH3
(+)
(-)CH2
Homocysteine
HS
C
H
COOCH2
NH3(+)
(-)CH2
S-Adenosyl Homocysteine
HS(+)
CH2
O
HH H
HOH OH
Adenine
BiosyntheticMethylation
reaction
Methyl acceptor
Methylated acceptor*see examples
C
H
COOCH2
NH3(+)
(-)
Cysteine
HS
(remainder ofhomocysteine
degradedfor energy)
tetrahydrofolate
N5 methyltetrahydrofolate
Methionine Cycle And Biological Methyl Groups
R. Lyons
Phenylalanine and Tyrosine
CH2 CH COO
NH3(+)
(-)
Phenylalanine
Tetrahydrobiopterin + O2Dihydrobiopterin + H2O
CH2 CH COO
NH3(+)
(-)
Tyrosine
HO
Homogentisate
Enzyme:Phenylalaninehydroxylase
Enzyme:homogentisatedioxygenaseCH2 C COO
(-)
Phenylpyruvate
O
Phenylketonuria(no phenylalanine
hydroxylase)
(Normal path shown in black, pathological reaction shown in red)
(you don’t need to know the rest)
Deficiency: Alkaptonuria “Ochronosis”
R. Lyons
Branched Chain Amino Acids
Isoleucine Leucine Valine
CH COO(-)
NH3(+)
CHCH2CH3
CH3
CH COO(-)
NH3(+)
CHCH 2CH3
CH3
CH COO(-)
NH3(+
)
CHCH3
CH3
C COO(-)
O
CHCH2CH3
CH3
C COO(-)
CHCH 2CH3
CH3
C COO(-)
CHCH3
CH3
O O
C
O
CHCH2CH3
CH3
CCHCH 2CH3
CH3
C S-CoACHCH3
CH3
O O
NAD, CoASH+
NADH +CO
2
NAD, CoASH+ NAD, CoASH+
NADH + CO2 NADH + CO2
S-CoAS-CoA
!"KG !"KG !"KG
Glu Glu Glu
---------------- Transamination ----------------
--- Branched-chain !-keto acid dehydrogenase ---
(continues on to degradation path similar to #-oxidation of fatty acids)R. Lyons
Synthesis of Bioactive Amines
CH2 CH COO
NH3
(+)
(-)
Tyrosine
HO CH2 CH COO
NH3
(+)
(-)HO
HO
DihydroxyphenylalanineTyrosine
hydroxylase(L-DOPA)
HO
HO
CH2CH NH3
(+)
2
Dopamine
CH CH NH3
(+)
2
Norepinephrine
OH
H
HO
HO
CHCH NH
2
Epinephrine
OH
H
HO
HO
CH3
R. Lyons
N
CH2 CH COO
NH3(+)
(-) HO
N
CH2 CH COO
NH3(+)
(-)
Tryptophan 5-hydroxytryptophan
Tryptophanhydroxylase
CO2
HO
N
CH2 CH NH3(+)
Serotonin
2
PLP-dependentdecvarboxylation
NAD+
Synthesis of Bioactive Amines
R. Lyons
CH2 CH COO
NH3(+)
(-)CH2COO
(-)
Glutamate
Glutamatedecarboxylase
(PLP-dependent )
CH2 CH NH3(+)CH2COO
(-)
!-aminobutyric acid(GABA)
2
N
NH
CH2 CH COO
NH3(+)
(-)
Histidine
Histidinedecarboxylase
(PLP-dependent )
N
NH
CH2 CH NH3(+)
Histamine
2
Synthesis of Bioactive Amines
R. Lyons
Glutamate, aspartate, alanine, glutamine, asparagine, (proline), glycine, serine (cysteine, tyrosine)
NON-Essential Amino Acids:
Essential Amino Acids:
Arginine (!), phenylalanine, methionine, histidine, Isoleucine, leucine, valine, threonine, tryptophan, lysine
Slide 4: Robert Lyons Slide 5: Robert Lyons Slide 7: Robert Lyons Slide 8: Robert Lyons Slide 11: Robert Lyons Slide 12: Robert Lyons Slide 13: Robert Lyons Slide 14: Robert Lyons Slide 15: Robert Lyons Slide 16: Robert Lyons Slide 17: Robert Lyons Slide 18: Robert Lyons Slide 19: Robert Lyons Slide 20: Robert Lyons Slide 21: Robert Lyons Slide 22: Robert Lyons Slide 23: Robert Lyons Slide 24: Robert Lyons Slide 25: Robert Lyons Slide 29: Robert Lyons Slide 31: Robert Lyons Slide 32: Robert Lyons Slide 33: Robert Lyons Slide 34: Robert Lyons Slide 36: Robert Lyons Slide 38: Robert Lyons Slide 39: Robert Lyons Slide 40: Robert Lyons Slide 41: Robert Lyons Slide 44: Robert Lyons Slide 45: Robert Lyons
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