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AMINO ACID METABOLISM

The Nitrogen Cycle and Nitrogen Fixation


Assimilation of Ammonia

A. Ammonia Is Incorporated into Glutamate and Glutamine


B. Transamination Reactions

Transfer of an amino group from an amino acid to an keto acid, catalyzed by a


transaminase. In biosynthetic reactions the initial amino acid is often In
transamination reactions involving glutamate as the amino group donor, the product is
ketoglutarate represents the precursor of a newly formed acid, (α-amino acid)2.
Assimilation of ammonia into amino acids:

(a) The glutamate dehydrogenase pathway.

(b) Combined action of glutamine synthetase and glutamate synthase


under conditions of low NH4 concentration.
Synthesis of Amino Acids
The origins of the carbon skeletons of amino acids.
A. Aspartate and Asparagine
B. Lysine, Methionine, and Threonine
C. Alanine, Valine, Leucine, and Isoleucine
D. Glutamate, Glutamine, Arginine, and Proline

Conversion of glutamate to proline and arginine.


E. Serine, Glycine, and Cysteine

Biosynthesis of serine

Biosynthesis of glycine
Biosynthesis of cysteine from serine in many bacteria and plants.

Biosynthesis of cysteine in mammals


F. Phenylalanine, Tyrosine, and Tryptophan

Synthesis of shikimate and chorismate


Biosynthesis of phenylalanine and tyrosine from chorismate in E. coli.
The biosynthesis of tryptophan from chorismate requires five enzymes. In the
first step, the amide nitrogen of glutamine is transferred to chorismate; elimination
of the hydroxyl group and the adjacent pyruvate moiety of chorismate produces
the aromatic compound anthranilate . Anthranilate accepts a phosphoribosyl
moiety from PRPP. Rearrangement of the ribose, decarboxylation, and ring closure
generate indole glycerol phosphate.

Anthranilate.

The final two reactions of tryptophan biosynthesis are catalyzed by tryptophan


synthase:
G. Histidine

Synthesis of histidine from phosphoribosyl pyrophosphate (PRPP) and ATP. Histidine is derived
from PRPP (5 C atoms), the purine ring of ATP (1 N and 1 C), glutamine (1 N), and
glutamate (1 N).
Amino Acids as Metabolic Precursors

A. Products Derived from Glutamate, Glutamine and Aspartate

• Glu and Gln, are important players in nitrogen assimilation

• Glu and Asp, are amino group donors in many transamination reactions and
required in the urea cycle.

• Gln and Asp are also required as precursors in both purine and pyrimidine
biosynthesis.

• Glu is required for synthesis of biologically active tetrahydrofolate.


B. Products Derived from Serine and Glycine
C. Synthesis of Nitric Oxide from Arginine

Conversion of arginine to nitric oxide and citrulline. NADPH is the source


of the five electrons.
Protein Turnover
• Proteins are continually synthesized and degraded in all cells, a process
called turnover.

• Their half-lives can vary from a few minutes to several weeks but the half-
life of a given protein in different organs and species is generally similar.

• Protein Degradation 2 ways:


1. Lysosomes
2. Ubiquitin Proteasome System (UPS), ATP dependent
Overview of catabolism of amino groups & Excretory forms of nitrogen
Degradation of Amino Acids

In animals, amino acids undergo oxidative degradation


in three different metabolic circumstances:

1. During the normal synthesis and degradation of cellular proteins (protein turnover),
some amino acids that are released from protein breakdown and are not needed for
new protein synthesis undergo oxidative degradation.

2. When a diet is rich in protein and the ingested amino acids exceed the body’s needs
for protein synthesis, the surplus is catabolized; amino acids cannot be stored.

3. During starvation or in uncontrolled diabetes mellitus,when carbohydrates are either


unavailable or not properly utilized, cellular proteins are used as fuel.
Six Amino Acids Are Degraded to Pyruvate

Amino acids catabolized to


pyruvate are both ketogenic and
glucogenic. The six are:
alanine,
tryptophan,
cysteine,
serine,
glycine, and
threonine
Seven Amino Acids Are Degraded to Acetyl-CoA:
Five Amino Acids Are Converted to -Ketoglutarate
Four Amino Acids Are Converted to Succinyl-CoA
Asparagine and Aspartate Are Degraded to Oxaloacetate
Isoelectric Points
• In acidic solution, the carboxylate and amine are in their
conjugate acid forms, an overall cation
• In basic solution, the groups are in their base forms, an
overall anion
• In neutral solution cation and anion forms are present
• This pH where the overall charge is 0 is the isoelectric point,
pI

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pI Depends on Side Chain
• The 15 amino acids thiol, hydroxyl groups or pure
hydrocarbon side chains have pI = 5.0 to 6.5 (average of
the pKa’s)
• D and E have acidic side chains and a lower pI
• H, R, K have basic side chains and higher pI

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Electrophoresis
• Proteins have an overall pI that depends on the net
acidity/basicity of the side chains
• The differences in pI can be used for separating proteins on
a solid phase permeated with liquid
• Different amino acids migrate at different rates, depending
on their isoelectric points and on the pH of the aqueous
buffer

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Amino Acid Catabolism
• Amino acids obtained from the degradation of endogenous proteins or from the
diet can be used for the biosynthesis of new proteins.

• Amino acids not needed for the synthesis of proteins are catabolized in order to
make use of their nitrogen and their carbon skeletons.

• The first step in amino acid degradation is often removal of the group. Next, the
carbon chains are altered in specific ways for entry into the central pathways of
carbon metabolism.

• Removal of the group of an amino acid occurs in several ways. The amino acid
usually undergoes transamination with α--ketoglutarateto form an acid and
glutamate.

• The glutamate is oxidized to and ammonia by the action of mitochondrial


glutamate dehydrogenase.

• The net effect of these two reactions is the release of groups as ammonia and
the formation of NADH and α-keto acids:
Overview of amino acid catabolism in mammals. The amino groups and
the carbon skeleton take separate but interconnected pathways.
Conversion of the carbon skeletons of amino acids to pyruvate, acetoacetate, acetyl
B. Arginine, Histidine, and Proline
C. Glycine and Serine
D. Threonine
E. The Branched-Chain Amino Acids
F. Methionine
G. Cysteine

The major route of cysteine catabolism is a three-step pathway leading to pyruvate.


Therefore, cysteine is glucogenic. Cysteine is first oxidized to cysteinesulfinate, which
loses its amino group by transamination to form β-sulfinylpyruvat.
Nonenzymatic desulfurylation produces pyruvate
H. Phenylalanine, Tryptophan, and Tyrosine
I. Lysine
I. Lysine
The Urea Cycle Converts Ammonia into Urea
• Discovered by Hans Krebs and Kurt Henseleit in 1932, (almost exclusively in liver).

• In the first reaction, carbamoyl phosphate reacts in the mitochondrion with


ornithine to form citrulline in a reaction catalyzed by ornithine transcarbamoylase.

• Citrulline is then transported out, in exchange for cytosolic ornithine.

• The second nitrogen atom destined for urea comes from aspartate and is
incorporated when citrulline condenses with aspartate to form argininosuccinate.

• Argininosuccinate is cleaved nonhydrolytically to form arginine plus fumarate


in an elimination reaction catalyzed by argininosuccinate lyase.

• Final reaction of the urea cycle, the guanidinium group of arginine is hydrolytically
cleaved to form ornithine and urea in a reaction catalyzed by arginase.
The urea cycle.
• The exchange of glucose and alanine between muscle and liver, called the
glucose–alanine cycle , provides an indirect means for muscle to eliminate nitrogen
and replenish its energy supply.

Glucose–alanine cycle
Renal Glutamine Metabolism Produces Bicarbonate

• The body often produces acids as metabolic end products; the resulting anions are
eliminated in the urine and the protons remain in the body.

• Examples are: β-hydroxybutyric axid, sulfuric acid.


These acid metabolites dissociate to give protons and the corresponding anion.

• The blood has an effective buffer system for the protons, they react with bicarbonate.

to produce which is eliminated by the lungs (Fig). While this system effectively
neutralizes the excess hydrogen ions, it does so at the cost of depleting blood
bicarbonate. Bicarbonate is replenished by glutamine catabolism in the kidneys.

Glutamine → → α-Ketoglutarate 2- + 2 NH4+

The overall process is:

2 Glutamin + 3 O2 + 6 H2O → Glukosa + 4 HCO3- + 4 NH4+


• Nitrogen is fixed in only a few species of bacteria and blue-green algae by the
nitrogenase-catalyzed reduction of atmospheric to ammonia. Plants and
microorganisms can reduce nitrate and nitrite to ammonia.

• Ammonia is assimilated into metabolites by the reductive amination of to glutamate,


catalyzed by glutamate dehydrogenase. Glutamine, a nitrogen donor in
many biosynthetic reactions, is formed from glutamate and ammonia by the action of
glutamine synthetase.

• The amino group of glutamate can be transferred to an acid in a reversible


transamination reaction to form and the corresponding acid.

• Pathways for the biosynthesis of the carbon skeletons of amino acids begin with simple
metabolic precursors such as pyruvate and citric acid cycle intermediates.

• Nonessential amino acids are those that animals can produce in quantities that are
sufficient for growth. These amino acids are generally formed by short, energetically
inexpensive pathways. Essential amino acids must be supplied
in the diets of animals; these amino acids are synthesized by bacteria and plants.

• In addition to their role in protein synthesis, amino acids serve as precursors in a


number of other metabolic pathways.
• Protein molecules in all living cells are continually synthesized and degraded.

• Amino acids obtained from protein degradation or directly from food can be
catabolized. Catabolism begins with deamination, followed by modification of the
remaining carbon chains for entry into the central pathways of carbon metabolism.

• The pathways for the degradation of amino acids lead to pyruvate, acetyl CoA, or
intermediates of the citric acid cycle. Amino acids that are degraded to citric acid
cycle intermediates are glucogenic. Those that form acetyl CoA are ketogenic.

• In mammals, most nitrogen is excreted as urea, which is formed by the urea cycle in
the liver. The carbon atom of urea is derived from bicarbonate. One amino group is
derived from ammonia, and the other from aspartate.

• The metabolism of glutamine in the kidneys produces the bicarbonate needed to


neutralize acids produced in the body.

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