OBJECTIVES

1
OBJECTIVES
Provide and overview of amino acid metabolism in
humans
Amino acids that can be synthesized
Catabolism of amino acids
Details of what happens when correct catabolism
does not occur.
2
AMINO ACID METABOLISM
20 amino acids used for synthesis of new protein,
an alternate source of energy, or building
material for other nutrients, like fats and
carbohydrates
valine(V), isoleucine (I), leucine(L), lysine(K),
threonine(T), tryptophan(W),methionine(M),
histidine(H), phenylalanine(F), arginine(R)
3
TRANSAMINATION
Pyridoxal phosphate(B6)
4
Synthesis of Non-essential Amino Acids
CYSTEINE
Triglycerides
CH2O6
Cystathionine
Pyruvate
TCA
ALANINE
SERINE
ASPARAGINE
B6
Oxalacetate
ATP
GLYCINE
Homocysteine
THF
ASPARTATE
PROLINE
C1pool
B6
TCA
SAM
GLUTAMATE
a-ketoglutarate
ATP
ATP
ORNITHINE
METHIONINE
GLUTAMINE
UREA cycle
DNA methylation
AGRININE
POLYAMINES
5
Nonketotic Hyperglycinemia
Oxalate
Formate
Creatine
Glutathione
Glyoxylate
pyruvate
Conjugates
GLYCINE NH2-CH2-COOH
SERINE
Purines
ethanolamine
GCS
Protein
Porphyrins
NH3CO2C1
THF
Also functions as a neurotransmitter Inhibitory
in brain and spinal cord
6
PKU
Melanine
albinism
Phenylalanine
7
Problems remaining for PKU
Maturnal PKU
Long term effects of single gene traits (aging)
Food supplements with Aspartane
Specific effects associated with specific
mutations
8
MAPLE SYRUP URINE DISEASE

• Autosomal recessive inheritance
• 1/150,000 GENERAL POPULATION
• 1/176 MENNONITE POPULATION
• NEWBORN SCREENING
• Protein Modified Diet

9
Atlanta Journal Constitution, 1983
Special Olympics
10
Thiamin -responsive MSUD
11
BCAA metabolism and block in MSUD
Amino acids
Proteins
(BCAAs)
Plasma Membrane
System L Transporter
VALINE
ISOLEUCINE
LEUCINE

Proteins
TRANSAMINASE
a-keto-b-methylvalerate




CYTOSOL
BCKD
complex


-methylbutyrylCoA
a
IsobutyrylCoA
IsovalerylCoA

HMGCoA
-methylacetoacetylCoA
a
b-OHisobutyrate


PropionylCoA
Acetoacetate
Methylmalonate semialdehyde

AcetylCoA
SuccinylCoA

MITOCHONDRION
12
P
CO2
?
a b
2
E1
kinase
TPP
(12)
2
a b
TPP
E1
2
2
ADP
ATP
(24)
NAD
E3FADH2
(6)
E3FAD
NADHH
CoASH
R-CH2-S-CoA
Reactions of the BCKD complex
13
BCKD activity in MSUD patient fibroblast lines
with unknown subunit deficiencies.
T
o
t
a
l

B
C
K
D

A
c
t
i
v
i
t
y

1
4
-
1
-
1
p
m
o
l

C
O

r
e
l
e
a
s
e
d

m
g

p
r
o
t
e
i
n

3

h
o
u
r
C
E
L
L
2
N
o
t
L
I
N
E
a
b
E
1
E
1
E
2
t
r
a
n
s
f
e
c
t
e
d

E
M
1
5
4
9
6
1
1


4

E
M
5
6
2
1
1


9

E
M
0
4
5
6
6
2
2


3
E
M
1
1
1
8

3
2
8
1


1
1
3
(
c
o
n
t
r
o
l
)
all cells were treated with ?-chloroisocaproate,
a specific inhibitor of BCKD kinase
14
BCKD activity in MSUD patient fibroblast lines
with unknown subunit deficiencies.
T
o
t
a
l

B
C
K
D

A
c
t
i
v
i
t
y

1
4
-
1
-
1
p
m
o
l

C
O

r
e
l
e
a
s
e
d

m
g

p
r
o
t
e
i
n

3

h
o
u
r
C
E
L
L
2
N
o
t
L
I
N
E
a
b
E
1
E
1
E
2
t
r
a
n
s
f
e
c
t
e
d




E
M
1
5
4
9
6
1
1


4
2
4
3
7


1
3
8

0
1
0


2




E
M
5
6
2
1
1


9
5


0
2
1
2
8


5
8
1
7


1




E
M
0
4
5
6
6
2
2


3
2
9


1
2
2
6


4
2
1
1
2


4
5
3
E
M
1
1
1
8

3
2
8
1


1
1
3
(
c
o
n
t
r
o
l
)
all cells were treated with ?-chloroisocaproate,
a specific inhibitor of BCKD kinase
15
Distribution of Mutant Subunits in MSUD population
?
10
10
E2
b
19
38
a
33
Current Study n63
16
A254D
Y166N
T211M
R297H
Q190K
C258Y
R314X
Y413C
R265W
A285P
A428del
I326T
G249S
Y438N
R159W
I213T
G290R
Q328K
T310R
A253T
M109T
N267S
R363W
R287X
R167Q
F409C
E1a
1
3
4
5
6
7
9
2
8
gt27kb
538delC
IVS5del-1 GgtC
147insC
R183P
887del8
S339L
G278S
N176Y
H206R
W277C
V251A
A137V
R324X
Y383X
E340K
E422X
E1b
2
4
5
6
7
8
9
10
3
11
106kb
92del11
52insG
954delT
326delG
IVS51GgtT
I138T
I98M
R291G
P134R
P134L
D137Y
F276C
X483L
R462P
H342N
G384S
R300G
K313N
K339K
G353R
E224X
H342Y
E68del
E2
1
2
3
4
5
6
7
9
10
11
8
60kb
IVS9-7AgtG
IVS8del1G
IVS4del-15 -4
IVS5del-1 1
IVS10del-91
20kb del
IVS4del-3.2KB-14
90delAT
354del7
501delAC
IVS8-700agtG
17
Problems remaining for MSUD

• Complications in adulthood ?
• Behavioral single gene, special diet, special
  treatment?
• Maternal MSUD is with us

18
Lessons to be learned
Essential vs Nonessential amino acids
Transamination
Inborn errors associated with AA metabolism
Important products obtained from amino acids