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Amino Acid Oxidation and
the Production of Urea
Fate of Ammonium
Three major reactions in all cells
• Carbamoyl-phosphate synthetase I
– two ATP required - one to activate
bicarbonate, one to phosphorylate carbamate
• Glutamate dehydrogenase
– reductive amination of alpha-ketoglutarate to
form glutamate
• Glutamine synthetase
– ATP-dependent amidation of gamma-carboxyl
of glutamate to glutamine
The Urea Cycle
In ureotelic organisms the urea cycle disposes of approximately
90% of surplus nitrogen. Urea is formed from ammonia, CO2, and
aspartate in a cyclic pathway referred to as the urea cycle.
The urea cycle is a mechanism designed
to convert NH4+ to urea, a less toxic
molecule. Note that citrulline is transported
across the inner membrane by a carrier for
neutral amino acids. Ornithine is
transported in exchange for H+ or citrulline.
Fumarate is transported back into the
mitochondrial matrix.
Because the urea cycle was discovered
by Hans Krebs and Kurt Henseleit, it is
often referred to as the Krebs urea cycle or
the Krebs-Henseleit cycle.
Hans Krebs
Urea synthesis begins with the formation of carbamoyl
phosphate. The substrates for this reaction, which is
catalyzed by carbamoyl phosphate synthetase I, are NH4+
and HCO3- . Because two molecules of ATP are required
in the carbamoyl phosphate synthesis, this reaction is
essentially irreversible.
Carbamoyl phosphate subsequently reacts with ornithine to form
citrulline. This reaction, which catalyzed by ornithine
transcarbamoylase, is driven to completion because of the release of
phosphate from carbamoyl phosphate.
Citrulline is transported to the cytoplasm, where it reacts with
aspartate. The amino group of aspartate provides the second nitrogen
that is ultimately incorporated into urea. This reaction is catalyzed by
argininosuccinate synthase.
Argininosuccinate
lyase
subsequently
cleaves
arginosuccinate to form arginine (the immidiate precursor of
urea) and fumarate.
In the final reaction of the urea cycle, arginase catalyzes the
formation of urea. Ornithine, the other product of this reaction, is
transported into the mitochondrial matrix, thus enabling the urea
cycle to continue.
The Urea Cycle Is Energetically Expensive
The overall equation of the urea cycle is
2NH4+ + HCO3- + 3ATP4- + H2O
urea + 2ADP3- + 4Pi2- + AMP2- + 5H+
The synthesis of one molecule of urea requires four
high-energy phosphate groups.
Two ATPs are required to make
carbamoyl phosphate, and one ATP is
required to make argininosuccinate. In
the latter reaction, however, the ATP
undergoes a pyrophosphate cleavage to
AMP and pyrophosphate, which may be
hydrolyzed to yield two Pi.
After its transport back into the mitochondrial
matrix, fumarate is hydrated to form malate, a
component of the citric acid cycle. The oxaloacetate
product of the citric acid cycle can subsequently be
used in energy generation, or it can be converted to
glucose or aspartate. The relationship between the
urea cycle and citric acid cycle, often referred to as
Krebs bicycle.
Disorders of Amino acid Catabolism
Alcaptonuria caused by a deficiency of
homogentisate oxidase. Large quantities of
homogentisate, the substrate for defective enzyme, are
excreted with urine. Homogentisate turns black when it
is oxydized as the urine is exposed to air.
Alcaptonuria is not innocuous,
since alcaptonic patients develop
arthritis in later life. In addition, the
pigment accumulates gradually and
evenly darkens the skin.
Albinism
In this condition the enzyme tyrosinase
is deficient. Consequently, melanin, a black
pigment found in skin, hair, and eyes, is not
produced. It is formed from tyrosine in
several cell types (e.g. the melanocytes). In
such cells tyrosinase converts tyrosine to
DOPA and DOPA to dopaquinone.
The latter product condense to melanin.
Because of the lack of pigment, albinos are
extremly sensitive to sunlight. In addition
to their susceptibility to skin cancer and
sunburn, the eyesight of albino is often
adversely affected.
Phenylketonuria is caused by deficiency of phenylalanine
hydroxylase. If this condition is not treated immediately after birth,
mental retardation and other forms of irreversible brain damage
ensue.
This damage results from the accumulation of phenylalanine.
When it present in excess, phenylalanine undergoes transamination
to form phenylpyruvate, which is also subsequently converted to
phenyllactate and phenylacetate. Large amounts of these molecules
are excreted in the urine. Phenylacetate gives the urine its
characteristic musty odor. Phenylketonuria is treated with a low
phenylalanine diet.
In maple syrup urine disease, also called
branched chain ketoaciduria, the keto acids derived from
leucine, isoleucine, and valine accumulate in large
quantities in blood. Their presence in urine imparts a
characteristic odor that gives the malady its name. All tree
keto acids accumulate because of a deficient branched
chain keto acid dehydrogenese complex.
If left untreated affected individuals experience vomiting,
convulsions, severe brain damage, and mental retardation.
Death than occurs before one year of age. Treatment
consists of rigid dietary control.
TESTS FOR TOPIC CONTROL
1. A patient has an allergic reaction that is
accompanied by itches, edemata, and
rednesses. What biogenic amine
concentration increases in the tissues?
A
Tryptamine
B
Taurine
C
Serotonin
D
Putrescine
E
Histamine
2. Proteolytic enzymes of the GI tract
catalyze protein hydrolysis. Point the bond
that is broken up by these enzymes:
A
Ester
B
Peptide
C
Hydrogen
D
Phosphodiester
E
Glycosidic
3. Digestion of proteins in the stomach begins
under the action of pepsin that is secreted in a
form of pepsinogen – inactive precursor. The
conversion of pepsinogen to pepsin is fulfilled
by means of the N-end peptide removal under
the action of:
A
Acetic acid
B
Bile acid
C
Sulphuric acid
D
Hydrochloric acid
E
Amino acids
4. Gastric juice pH in milk-fed children varies
in the limits of 4.0 - 5.0. Name a gastric juice
enzyme that is active under these conditions.
A
Elastase
B
Pepsin
C
Chymotrypsin
D
Trypsin
E
Renin
5. Biogenic amines undergo deamination under the
action of a certain enzyme. Point it.
A
Decarboxylase
B
Monoamine oxidase
C
Amino acid dehydrogenase
D
Alanine transaminase
E
L-amino acid oxidase
6. Dysfunction of the liver is observed in a patient.
What biochemical index is to be determined in the
blood for estimation of the liver state?
A
LDH1
B
Aldolase
C
АLТ
D
Creatine phosphokinase
E
Lipase
7. Ammonia is generated in different tissues and
organs and neutralized in the liver by converting into
urea. What amino acid transports it from skeletal
muscles to the liver?
A
Glycine
B
Histidine
C
Alanine
D
Serine
E
Aspartic acid
8. The main way of ammonia detoxication is the urea
synthesis. This biochemical process begins from the
formation of:
A
Carbamoyl phosphate
B
Citrulline
C
Arginine
D
Ornithine
E
Pyrophosphate
9. Aminotransferases are the enzymes which transfer
amino groups from one compound to another. Point
the acceptor of amino groups.
A
Butyric acid
B
Lactic acid
C
Succinate
D
Acetone
E
α-Ketoglutaric acid
10. In a patient the amino acid transport in the
intestine cells is decreased. What substance
participates in the amino acid transport?
A
Glutathione
B
Antiserine
C
Amylase
D
Ornithine
E
Alanine