Download Amino Acid Metabolism

Amino Acid Metabolism
Role of Amino Acids
• Protein monomeric units
• Energy source
• Precursors of other
biological molecules
Protein Monomeric Units
R1
+
R2
–
H3 N C COO
H
H2O
+
+
–
H3 N C COO
H
R1 O
R2
+
–
H3 N C C NH C COO
H
H
Energy Source
ADP + Pi
Amino Acids
ATP
Waste Products
Precursors
(Nitrogen-containing Compounds)
•
•
•
•
Heme
Nucleotides
Amines
Nucleotide
Coenzymes
• Glutathione
Precursors
(a-ketoacids)
Pyruvate
Amino Acids
Oxaloacetate
-Ketoglutarate
Glucose
Fatty Acids
Ketone Bodies
Classification
(Mammals)
• Essential amino acids
• Non-essential amino
acids
Amino Acid Deamination
(First Reaction in Amino Acid Breakdown)
O
R
H 3N
C
H
COO–
Nitrogen-containing compounds
-keto acid
R
+
C
COO–
Glutamate
KG
Aminotransferases
(Transaminases)
Fumarate
OAA
aKG
Aspartate
Urea
Cycle
H2 N
O
C
NH2
Urea
Aminotransferases
(Transaminases)
Amino Acid + -Ketoglutarate
Glutamate + Oxaloacetate
-Keto Acid + Glutamate
-Ketoglutarate + Aspartate
Oxidative Deamination
Glutamate + NAD(P)+ + H2 O
-Ketoglutarate + NH 4+ + NAD(P)H + H+
Glutamate
Dehydrogenase
Amino Acid Oxidase
Amino Acid + FAD + H2 O
FADH2 + O2
-Keto Acid + NH 3 + FADH2
FAD + H2 O2
Transamination
(Reactions)
Amino Acid + Enzyme
Enzyme–NH 2 + -Ketoglutarate
-Keto Acid + Enzyme–NH
Enzyme + Glutamate
2
Summary
Amino Acid + -Ketoglutarate
-Keto Acid + Glutamate
Degradative Fates of Glutamate
Regeneration of -Ketoglutarate
Carbon and Energy
Nitrogen-containing compounds
-ketoacid
Amino Acid
NH4+
Glutamate
-KG
CO2
Fumarate
OAA
KG
Aspartate
Urea
Cycle
H2 N
O
C
NH2
Urea
Glutamate-Aspartate Aminotransferase
Glutamate + Oxaloacetate
-Ketoglutarate + Aspartate
Glutamate Dehydrogenase
(Oxidative Deamination)
H2C
COO
–
NAD(P) +
NAD(P)H + H
+
H2C
CH 2
+
H3N
C
COO –
CH 2
COO
–
H2N
C
COO
NH 4+
H2C
-Iminoglutarate
COO –
CH 2
–
H
Glutamate
H2O
O
C
COO –
-Ketoglutarate
Formation of Urea
Aspartate + HCO3 - + NH4+
Urea Cycle
Urea
Degradative Fates of Glutamate
Regeneration of -Ketoglutarate
Carbon and Energy
Nitrogen-containing compounds
-ketoacid
Amino Acid
NH4+
Glutamate
-KG
CO2
Fumarate
OAA
KG
Aspartate
Urea
Cycle
H2 N
O
C
NH2
Urea
Urea Cycle
Urea Cycle
(Introduction)
Proteins
Fats
Carbohy drates
(Nutrients)
ADP
Catabolism
ATP
NADP+
(Oxidation)
(Biosy nthesis)
NADPH
Intermediates
Waste
(CO2/Urea/etc.)
Anabolism
Nitrogen Waste Products
O
N
N
O
O
NH 3
Ammonia
H2N
C
O
NH 2
Urea
(Vertebrates)
N
N
H
Uric Acid
(Birds and Reptiles)
Require less water for excretion
Classification of Organisms
(Nitrogen Excretion Patterns)
• Ammonotelic: ammonia excreting
• Ureotelic: urea excreting
• Uricotelic: uric acid excreting
Overall Urea Cycle
(Liver)
3ATP
NH 3 +
HCO 3–
+
H2C
COO –
C
–
+
H3N
COO
H
Aspartate
2ADP + 2P i + AMP + PP i
O
H2N
C
NH 2
Urea
+
HC
–OOC
COO –
CH
Fumarate
Glutamate Dehydrogenase
(Generation of NH3)
Glutamate + NAD(P)
+
+ H2O
-Ketoglutarate + NH 3 + NAD(P)H + H +
Carbamyl Phosphate Synthetase
(CPS)
(Mitochondrion)
2ATP
2ADP + Pi
O
NH3 + HCO3 –
H 2N
C
OP
Carbamyl Phosphate
Carbamyl Phosphate Synthetase
(CPS)
• CPSI (Mitochondria)
– Uses NH3
– Urea Cycle
• CPSII (Cytosol)
– Uses Glutamine
– Pyrimidine Biosynthesis
Ornithine Transcarbamylase
(OTC)
(Mitochondrion)
O
NH 2
C
NH 3+
O
H2N
C OP +
Carbamoyl P
(CH 2)3
+H N
3
C
COO –
NH
Pi
(CH 2)3
+H N
3
C
COO –
H
H
Ornithine
Citrulline
Non-standard amino acids
(not present in proteins)
Glutamate Dehydrogenase
Glutamate + NAD
+
+ H2O
-Ketoglutarate + NH 3 + NADH + H +
Regeneration of Aspartate
(Cytosol)
NAD+
Fumarate
NADH + H +
Malate
Fumarase
Oxaloacetate
Malate
Dehydrogenase
Aspartate
Glu-Asp
Aminotransferase
Oxidation of 2 NADH Yields 6 ATP
Activator
H2C
O
H3C
C
COO –
CH 2
N
H
C
H
COO –
N-Acetylglutamate
Products of Amino Acid Breakdown
• Glucogenic
–
–
–
–
–
Pyruvate
-Ketoglutarate
Succinyl-CoA
Fumarate
Oxaloacetate
• Ketogenic
– Acetyl-CoA
– Acetoacetate
Page 995
Degradation of
amino acids to
one of seven
common
metabolic
intermediates.
Animals cannot carryout net synthesis
of precursors of gluconeogenesis from
acetyl-CoA or acetoacetate
Conversion of Pyruvate and
Oxaloacetate to PEP
(Gluconeogenesis)
ATP
O
H 3C
C
COOH
+
Pyruvate
HCO 3–
(CO 2)
ADP + P i
Pyruvate
Carboxylase
COOH
CH2
O
C
COOH
Oxaloacetate
COOH
CH2
O
C
COOH
Oxaloacetate
GTP
GDP + CO2
PEP
Carboxykinase
OP
H 2C
C
COO –
Phosphoenolpyruvate
(PEP)
"Gluconeogenesis"
Glucose
Degradation to Pyruvate
Alanine, Cysteine, Glycine,
Serine and Threonine
Degradation of amino acids
• Amino acid breakdown can yield:
– Acetyl-CoA
--KG
– Succinyl-CoA
– OAA
– fumarate
-KG is generated from five
amino acids
•
•
•
•
•
Proline
Glutamate
Glutamine
Arginine
Histidine
Four amino acids are converted to
Succinyl-CoA
• Methionine
– Converted to homocysteine through methyl group transfer,
generates cysteine as converted to -ketobutyrate
• Isoleucine
– Transamination, oxidative decarboxylation to acetyl-CoA and
propionyl CoA
• Valine
– Transamination, decarboxylation to propionyl CoA
• Threonine
- -ketobutyrate generated and converted to propionyl CoA
Propionyl-CoA is
a common intermediate
for amino acids 
succinyl-CoA
Branched-chain -keto acid
dehydrogenase complex
• In certain body tissues, this enzyme catalyzes the
oxidative decarboxylation of valine, isoleucine,
and leucine yielding CO2, and acyl-CoA
derivatives.
• Shares ancestry with pyruvate dehydrogenase
complex, -KG dehydrogenase complex – another
example of gene duplication
Branched-chain …complex
Asparagine and aspartate are degraded to OAA
Fate of metabolites derived from
amino acids
• In addition to feeding the citric acid cycle, amino
acids can result in ketone bodies, while others are
gluconeogenic
Ketone bodies
• The six amino acids that are
degraded to acetoacetyl-CoA
and/or acetyl-CoA) can be
converted to acetoacetate and
b-hydroxybutyrate
Glucogenic amino acids
• Amino acids that are degraded to pyruvate, -KG,
succinyl-CoA fumarate, and/or OAA can be converted to
glucose