Amino acid = NH3+- + C skeleton

• Oxidized to CO2 and H2O

Acetone
• Glucose (glucogenic a.a.) Acetoacetate
• Ketone bodies (ketogenic a.a.) D-b-hydroxybutyrate

BREAKDOWN OF C-SKELETON
 C-skeleton entering citric acid cycle
• 20 a.a. enter TCA cycle:
– Acetyl-CoA (7)
– a-ketoglutarate (5)
– Succinyl-CoA (4)
– Fumarate (2)
– Oxaloacetate (2)
– Pyruvate (6)
• Some a.a. yields more than one end products
(Different C fates)
– Ketogenic a.a.
– Glucogenic a.a.
Entering as Pyruvate (3C)
Threonine
N5,N10-
• 3C: Ala, (Trp), Cys, Ser, methylene
H4 folate H4 folate
• 2C: Gly Glycine
NAD+ NADH

Serine

Tryptophan

Cysteine
Alanine
 One-carbon transfer
• Transfer C1 groups in different oxidation states.
• Requires enzyme cofactors :
– Serve as donor/acceptor of C1 unit Biotin is a water-soluble B vitamin,
• Biotin also called vitamin B7 (from wiki)
– Transfer CO2 (e.g. pyruvate carboxylase)
• Tetrahydrofolate (THF, H4 folate)
– Transfer –HC=O, -HCOH, -CH2- or –CH3
» Gly  Ser
» His breakdown
» Met synthesis
» dU  dT
• S-adenosylmethionine (SAM, adoMet)
– Transfer –CH3 S-adenosylmethionine
(adoMet)
 1C transfer and folate
 Tetrahydrafolate (H4 folate) - 1C unit carrier  Derived from folic acid (Vit B9)
– Structure – Mammals cannot synthesis
• Pteridine • Diet
• p-aminobenzoate • Biosynthesized by microorganism in GI tract
• Poly-Glu

10
5
H4 folate

http://watcut.uwaterloo.ca/webnotes/Metabolism/C1ThfMediatedTransfer.html
 Tetrahydrofolate (THF, H4 folate)
• C1 carrier
– H4 folate inter-conversion
– C1 attached at N5, N10 or N5 and N10
• Transfer –CH3, –CH2–, –HC=O, -HC=NH, or -HC=
– Gly  Ser (N5, N10-methylene)
– His breakdown (N5-forminino)
– Met synthesis (N5-methyl)
– dU  dT (N5, N10-methylene)

DHF
reductase

Not synthesized
in mammals
 Tryptophan
• Trp = Ala + aromatic ring
– Degradation
– Precursor for other biological molecules

Nicotinate (niacin)

Auxin or IAA
(indoeacetate)

Acetoacetyl-CoA Serotonin
Phenylalanine and Tyrosine
• Phe + -OH  Tyr
– Phenylalanine hydroxylase
– Phenylketonuria (PKU)
• Phe, Tyr as precursor Phenylalanine
PKU
hydroxylase
– L-DOPA, Dopamine
– Norepinephrine
– Epinephrine
• Tyr as precursor in melanocyte
– L-DOPA  Melanin

Acetoacetyl-CoA
 PKU
• Alternative catabolism of Phe in PKU individuals

ABCDEF

A  B  C X D  EF

 C1  C12
 C13
 PKU
• Alternative catabolism of Phe in PKU individuals
– Phenylpyruvate
– Phenylacetate (odor)
– Phenyllactate
• Intermediates accumulation
– Impair brain development
– Mental retardation
• Treatment
– Rigid diet control
• The artificial sweetener aspartame
 NutraSweet (aspartame)
• Aspartame = Aspartate + Pheylalanine
 Phenylalanine hydroxylation
• Phenylalanine hydroxylase
– Mixed-function oxidase
– Requires the cofactor biopterin (pterin derivative)
• BH4  BH2
BH2
• BH2 reductase regenerate BH4 reductase

• BH2 reductase defect also cause PKU symptom Phenylalanine

hydroxylase
– Supplement of BH4 + L-DOPA, 5-OH Trp
• Required for formation of L-DOPA, and 5-OH Trp (BH2)

H2O
Branched-chain amino acids
• BCAA: Val, Ile, Leu
• Not degraded in the liver
• Oxidized as fuels in extrahepatic tissues
– Muscle, adipose, kidney and brain
– BCAA as fuel during fasting
• The 3 a.a. share the first 2 enzymes for catabolism
– Branched-chain aminotransferase  a-keto acids
– Branched-chain a-keto acid dehydrogenase complex  acyl-CoA derivatives
BCAA
a-keto acids Acyl-CoA derivatives

Valine a-keto-
isovalerate Isobutyryl
CoA

a-keto
Isoleucine b-methyl
Branched-chain a-methyl-
Branched-chain a-keto acids
aminotransferase valerate butyryl CoA
dehydrogenase
complex

a-keto-
Leucine isocaproate Isovaleryl
CoA
 Maple syrup urine disease
• MSUD
– Defective branched-chain a-keto acid dehydrogenase complex
– a-keto acids (odor) derived (Val, Ile and Leu) accumulate in blood and urine
• Abnormal brain development
• Mental retardation
• Death in infancy
– Treatment
• Rigid diet control
• Limit the intake of Val, Ile, Leu to min. requirement for normal growth.

罕見疾病基金會 15
Entering as a-Ketoglutarate (5C)
• 6C: Arg H2O ½ O2
• 5C: Gln, Glu, Pro
arginase Ornithine
d-aminotransferase H
Glutamate Δ-Pyrroline- Proline
Ornithine γ-semialdehyde 5-Carboxylate
Arginine
NHD(P)+

NHD(P)H + H+

N5-Formimino
H2O NH4+ H4 folate H4 folate H2O H2O NH4+

glutaminase

Glutamate Histidine
Glutamine Glutamate
dehydrogenase

α-Ketoglutarate
Entering as oxaloacetate (4C)
• 4C: Asn and Asp Asparagine

asparaginase

Aspartate

aspartate
aminotransferase

Oxaloacetate
 Summary
• Metabolic fates of C-skeleton
– Entering citric acid cycle as metabolic intermediates
– Glucogenic vs ketogenic a.a.
– One-carbon transfer and cofactors involved
– Genetic defects in a.a. degradation
 Catabolism of a.a. in mammals
• The NH3+ and the C skeleton take separate but interconnected pathways

Amino acids

Biosynthesis NH3+ C-skeleton

Shunt

Urea Fumarate Citric

cycle Malate acid
Asp OAA cycle

Excretion Energy