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Reading: Stryer Edition 6: Chapters 23 and 24. Figures in this document are from
Stryer unless otherwise noted.
OBJECTIVES:
1. Understand the fates and sources of the amino acids in general terms.
4. Understand the common pathways for the removal of the -amino group from an -
amino acid during amino acid catabolism.
5. Understand how the fate of the ammonium ions generated during amino acid
degradation differs in the liver versus the peripheral tissues.
6. Understand the fundamentals of the urea cycle and how it is regulated. Understand
how defective urea cycle enzymes can lead to disease, and how those diseases are
treated.
7. Understand which -amino acid carbon skeletons feed into which major metabolic
intermediates during amino acid catabolism.
8. Know which amino acids are solely ketogenic, solely glucogenic, and both ketogenic
and glucogenic.
9. Know which steps in amino acid degradation lead to the following diseases: methyl-
malonic acedemia, homocystinuria, maple syrup disease, phenylketonuria, tyrosinemia
I, II and III, and alkaptonuria. For each disease, you should know the name of the
defective enzyme, the reaction catalyzed by the enzyme, and the pathway in which the
enzyme functions.
10. Know which amino acids are essential and which are non-essential in humans.
11. Know in humans, which major metabolic intermediates are able to serve as carbon
skeletons for the biosynthesis of which amino acids.
13. Know which amino acids can be used for the synthesis of which neurotransmitters.
14. Understand in general terms the biosynthesis of spermine, spermidine, creatine and
phosphocreatine.
B. PROTEIN CATABOLISM
E1=Ubiquitin-Activating
Enzyme
E2=Ubiquitin-
Conjugating Enzyme
E3=Ubiquitin-Protein
Ligase
6.
Ubiquitin is attached to
the -amino group of
lysine residues on
target proteins.
7. Clinical correlation:Human
papilloma virus (HPV) encodes a protein that activates
a specific E3 enzyme. The enzyme ubiquitinates the
tumor suppressor p53 and other proteins that control
DNA repair, which are then destroyed. The activation
of this E3 enzyme is observed in more than 90% of all
cervical carcinomas.
20S proteasome
(catalytic activity)
a. 700kD,
28 homologous
subunits: 14 of
type and 14 of
type .
b. Sub-
units are
arranged in 4
rings of 7 subunits each to form a sealed barrel.
1. Any amino acids generated by protein catabolism that are not needed
as building blocks for new biomolecular synthetic reactions are degraded to
carbon skeletons in the liver.
to -ketoglutarate to form
glutamate, which is
oxidatively deaminated to
yield ammonium ion.
The enzymes are named after their amino acid substrates, i.e. aspartate transaminase
catalyzes the transfer of the -amino group of aspartate to -ketoglutarate, yielding
oxaloacetate plus glutamate.
Dehydrogenation Hydrolysis
excreted
ALPHA KETOACID 1 AMINO ACID 2
d. All aminotransferases
contain the prosthetic
group pyridoxal
phosphate (PLP).
PLP is derived from
Pyridoxine (Vitamin B6).
e. PLP Tautomers:
The phenolic hydroxyl group is slightly
acidic, favoring deprotonation.
The pyridine ring is slightly basic, which favors protonation of the pyrimidine N.
(schiff-base linkage with the enzyme) (schiff-base linkage with the substrate)
1 2 3
3 2 1
g
.
4
AMINO ACID 2
(GLUTAMATE)
excreted
ALPHA KETOACID 1 AMINO ACID 2
h. Aspartate Aminotransferase
If amino acids are produced in tissues that lack the urea cycle, they
need a mechanism to release nitrogen in a form that can be
absorbed by the liver and converted into urea.
Glutamine Synthetase:
NH4+ + glutamate + ATP
glutamine
+ ADP + Pi
a. Once glutamine is in the liver, it can be
metabolized like any other amino acid and the nitrogen can end up in the urea cycle.
e. Ornithine acts as a
carrier of various atoms
in the process of
synthesizing urea.
c. Brings one C atom and one N atom into the urea cycle as a
carbamoyl group.
a. PPi 2 Pi quickly in a
reaction catalyzed by
pyrophosphotase.
b. Overall, four high energy
phosphate bonds are
broken to synthesize
each molecule of urea.
a. Fumarate production connects the urea cycle and the citric acid
cycle (fumarate malate oxaloacetate).
a. The
urea cycle removes
excess NH4+ which
comes from the
breakdown of amino
acids.
b.
Overall control of the
urea cycle is by
enzyme levels, which
change by as much
as ten-fold depending
on the diet.
d. Sometimes a low protein diet can help. The diet decreases the
amount of NH4+ that needs to be eliminated through the urea cycle.
c. High glutamine and glutamate may lead to brain damage, possibly by producing
osmotic effects that cause brain swelling
VII. FATES OF THE CARBON SKELETONS OF THE AMINO ACIDS
All 20 amino acids funnel into only 7 major metabolic intermediates.
1. The strategy of
3carbonaminoacids
ala,ser,cysentervia
pyruvate.
1. The skeletons of 4-
carbon amino acids enter at oxaloacetate.
c. -Ketoglutarate as an entry
point into metabolism
e. Clinical
Correlations:
1. Homocystinuria:
Scoliosis, muscle
weakness, mental
retardation, thin
blond hair
Cystathione -
synthase is defective.
2. Methyl-malonic
academia:
Methylmalonyl- CoA
mutase is defective.
(Figure from
Principles of
Biochemistry by
Lehninger and Fox,
Freeman Publishing)
branched-chain aminotransferase
c. Clinical Correlation:
In addition to PKU, a number of other
diseases are caused by defects in aromatic
amino acid metabolism. (Figure from
Principles of Biochemistry by Lehninger and
Fox, Freeman Publishing)
Phenylketonuria-phenylalanine
accumulates in body fluids, if untreated,
severe mental retardation. Treatment-
Alkaptonuria-homogentisate
accumulates in the urine, and is
excreted, which turns dark on
standing due to the oxidation of
homogentisate.
Harmless
d. Tryptophan
Degradation
1. Nearly all
cleavages of aromatic rings in biological systems are catalyzed by dioxygenases.
Tyrosine
*
Tyrosine
Tyrosine
Glutamate
Tryptophan
GABA
Histidine
1. Catecholamine Biosynthesis 3. Histamine Biosynthesis
4. Serotonin Biosynthesis
2. GABA Biosynthesis