Download Lehninger Principles of Biochemistry 5/e

David L. Nelson and Michael M. Cox
LEHNINGER
PRINCIPLES OF BIOCHEMISTRY
Fifth Edition
CHAPTER 18
Amino Acid Oxidation and the
Production of Urea
© 2008 W. H. Freeman and Company
Introduction
1. In animal, AA undergo oxidative degradation in three different
metabolic circumstance
- The normal degradation of cellular protein
- A diet is rich in protein
- When carbohydrates are either unavailable, cellular proteins are
used as fuel
2.AA lose their amino groups to form a-keto acid
3.a-keto acid undergo oxidation to CO2 and H2O
4.a-kteo acid can converted by gluconeogenesis into glucose, the
fuel for brain, skeletal muscle, and other tissue
5.AA acid contains an amino group and thus aa degradation include
a key step in which the a-amono group is shunted into the
pathways of amino group metabolism
Overview of aa catabolism in mammal
Amino group catabolism
1.
2.
3.
4.
5.
6.
7.
Most aa are metabolized in the liver
The ammonia generated in this
process is recycled and used in a
variety of biosynthetic pathway
The excess is either excreted directly
or converted to urea or uric acid for
excretion
Excess ammonia generated in other
tissues travels to the liver for
conversion to the excretory form
In cytosol of hepatocytes, amino
groups are transferred to a-KG to
form Glu, which enter to Mito. To
form the ammonia
Excess ammonia from most other
tissue is converted to the amide
nitrogen of Gln which pass to liver
In skeletal muscle, excess amino
groups are tranffered to pyruvate to
form alanine
Gastrin : hormone which
stimulate the secretion of HCl
and pepsinogen
Secretin: hormone which
stimulate secretion of
bicarbonate by pancreas
Cholecystokinin: hormone
which stimulate trypsinogen,
chymotrypsinogen,
procarbosypeptidases
Why zymogens (inactive
precursors)?
1.First step is removal of the a-amino
groups by aminotranferase
2. In this transamination reaction, the aamino group is transferred to the a-carbon
atom of a-ketoglutarate
3. The glutamate then functions as the
amino group donor for biosynthetic
pathways or for excretion pathway
4. Amino transferase contain the prosthetic
group, pyridoxal phosphate (PLP)
5. PLP is covalently bound to lysine
through aldimine (Schiff base)
6. Aminotransferases are classic example of
ping-pong reaction.
1.In hepatocyte, glutamate is transported
from the cytosol into mitochondria, where
it undergoes oxidative deamination
catalyzed by glutamate dehydrogenase.
2. Combined action of an aminotransferase
and glutamate dehydregenase is referred to
as transdeamination.
3. a-kg can be used in citric acid cycle.
1.Ammonia is quite toxic to animal tissue
and thus much of free ammonia is
converted to a nontoxic compound before
export from the extrahepatic tissues into the
blood.
2. The free ammonia in tissues is combined
with glutamate to yield glutamine by
glutamine synthetase.
3. Glutaminase
1.Alanine also plays a special role in
transporting amino group to the liver in a
nontoxid from via a pathway called the
glucose-alanine cycle.
2. Alanine aminotransferase
3. Example of the intrinsic economy of
living organism.
1.The ammonia deposited in the
mitochondria of hepatocytes is
converted to urea in the urea cycle
2. Urea production occurs almost
exclusively in the liver .
3. The urea passes into the blood
stream and thus to the kidneys and is
excreted into the urine
4. Five enzymatic steps: two steps in
mito. And three steps in cyto.
5. Carbamoyl phosphate synthetase I
6. Orninthin transcarbamoylase
7. Arginosuccinate synthetase
8. Argrinosuccinase
9. Arginase
Nitrogen-acquiring reactions in the
synthesis of urea.
1.
2.
3.
4.
The citric acid cycle and urea cycle are interconnected through common
intermediate, fumarate.
Communication depends on the transport of key intermediates between Mito.
and Cyto.
Fumarate from the urea cycle is transported to Mito. and can be enter the citric
acid cycle.
Aspartate from the citric acid cycle is transported to cytosol and can transfer
amino group to citrulline
Regulation of the urea cycle
1.
2.
3.
4.
5.
When the dietary intake is
primarily protein, the carbon
skeletons of amino acid are used
for fuel, producing much urea
from the excess amino group
During prolong starvation, when
breakdown of muscle protein
begins to supply much of the
organism’s metabolic energy, urea
production increases
The activity of the urea cycle is
regulated at two level: long term
and short term regulation
Long term by regulation of the
rates of synthesis of urea cycle
enzyme
Short term by allosteric activation
of carbamoyl phosphate synthetase
I by N-acetylglutamate
Pathway interconnections reduce the energetic cost of urea
synthesis
1. The synthesis of urea requires four high-energy phosphate
groups.
- Two ATP molecules are required to make carbamoyl
phosphate
- Two for making arginosuccinate
2. The urea cycle also causes a net conversion of oxaloacetate
to fumarate (via aspartate), and the regeration of
axaloacetate produces NADH .
3. Each NADH can generate up to 2.5 ATP , greatly reducing
the overall energetic cost of urea synthesis.
1.
People with genetic defects in any
enzyme involved in urea formation
cannot tolerate protein-rich diets
2.
A protein-free diet is not treatment
option because humans are
incapable of synthesizing all a.a.
and these essential a.a must be
provided in the diet.
1.
2.
3.
4.
Careful administration of the
aromatic acids benzoate or
phenylbutyrate in the diet can help
lower the level of ammonia in the
blood
Benzate is converted to benzyolCoA, which combines with
glycine to form benzoylglycine
Phenylacetyl-CoA combines with
glutamin to form
phenyacetylglutamine.
Both products are nontoxic
compounds that are excreted in the
urine.
1. 20 catabolic pathways converge to form only six major products
2. The carbon skeletons are diverted to gluconeogenesis, ketogenesis or oxidation
3. Trp, Phe, Tyr, Thr, Ile are both ketogenic and transgenic.
1.
2.
3.
Two reactions are important for a.a catabolism
Transamination: PLP
One carbone transfer: Biotin (CO2), THF (intermediate
oxidation state), SAM (most reduced state, methyl group)
Six a.a are degraded to pyruvate
Seven a.a are degraded to acetyl-CoA
Phenylalanin Catabolism is genetically defected in some people
1.
2.
Phenylalanine hydroxylase: mixed function oxidase catalyze
simultaneous hydroxylation of a substrate by an oxygen atom of
O2 and reduction of other oxygen atom to H2O
Tetrahydrobiopterin : electron from NADPH to O2
Five a.a are degraded to a-ketoglutarate
Four a.a are degraded to succinyl-CoA
Two a.a are degraded to succinyl-CoA