METABOLISM OF AMINO ACIDS, PURINE AND PYRIMIDINE BASES
A. Metabolism of amino acids
Repeat structures and properties of amino acids.
Biosynthesis of amino acids
Humans can synthesize only 10 of the 20 amino acids (AA) needed for protein synthesis. Those amino acids that
cannot be synthesized de novo are called "essential", because they must be obtained from diet (see table).
Essential AA
Nonessential AA
Arg *
Ala
His
Asn
Ile
Asp
Leu
Cys
Lys
Gln
Met **
Glu
Phe ***
Gly
Thr
Pro
Trp
Ser
Val
Tyr
* Arg is synthesized by mammalian tissues, but the rate is not sufficient to meet the need during growth.
** Met is required in large amounts to produce cysteine if the latter is not supplied by the diet.
*** Phe is needed in large amounts to form tyrosine if the latter is not supplied by the diet.
Ala is synthesized from pyruvate.
Asn is synthesized from Asp and Gln (donor of NH3).
3-phosphoglycerate (from glycolysis) is a precursor of Ser.
Gly and Pro are synthesized from Glu.
Cys is synthesized from Met and Ser.
Tyr is formed by hydroxylation of Phe.
Amino acid degradation
At least 20 different multienzyme sequences exist for catabolism of amino acids. All 20 common amino acids are
converted to only 7 compounds: pyruvate, acetyl-CoA, acetoacetyl-CoA, α-ketoglutarate, succinyl-CoA,
fumarate, oxaloacetate.
We will look at some common degradation reactions including....
1. Transamination
2. Deamination
3. Decarboxylation
1. Transamination = an exchange of amino group (-NH2) between amino acids and α-ketoacids.
Transaminations occur in vivo for all 20 amino acids except Lys and Thr. These reactions are catalyzed by
enzymes transaminases (or aminotransferases). Most transaminases require α-ketoglutarate to accept the
amino group. Example is enzyme aspartate transaminase (AST) - see Fig. 1
Fig. 1: Transamination catalyzed by aspartate transaminase.
Figure is found on http://www.sbuniv.edu/~ggray/CHE3364/b1c25out.html
AST is abundant in heart muscle and a rapid rise in the concentration of AST in the blood is an indication of
myocardial infarction. AST is also present in the mitochondria of liver cells. High levels of AST in blood plasma
indicate harder damage of liver cells.
Another transaminase is alanine transaminase (ALT), which catalyzes transamination:
Ala + α-ketoglutarate  pyruvate + Glu
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ALT has a high activity in the cytosol of the liver, and an elevated serum level of this enzyme indicates the
liver damage.
The transaminase reactions are freely reversible. All transaminases have the same prosthetic group = pyridoxal
phosphate (PLP).
2. Deamination
a) simple deamination
Deamination of serine and threonine. Dehydration occurs before deamination. Enzymes dehydratases have
pyridoxal phosphate (= prosthetic group).
b) oxidative deamination
Glutamate is deaminated to α-ketoglutarate by oxidative deamination (see Fig. 2). The reaction is catalyzed
by enzyme glutamate dehydrogenase. NADH or NADPH may be produced. Ammonia produced is converted
to urea via the urea cycle and then excreted.
Fig. 2: Glutamate dehydrogenase reaction.
3. Decarboxylation
A few amino acids undergo decarboxylation to produce primary amines which serve specific biological functions.
a) decarboxylation of histidine (His) produces histamine (see Fig. 3). Histamine is a potent vasodilator released
as a result of allergic hypersensitivity or inflammation. It causes expansion of capillares.
.
Fig. 3: Decarboxylation of histine produces histamine.
Figure is found on http://www.sbuniv.edu/~ggray/CHE3364/b1c25out.html
b) decarboxylation of tryptophan (Trp) occurs in serotonin synthesis. Serotonin is a neurotransmitter and
vasoconstrictor.
c) decarboxylation of tyrosine (Tyr) occurs in synthesis of norepinephrine and epinephrine (see Fig. 4). This
occurs in the adrenal medulla which then secretes these hormones:
Fig. 4: Structures of epinephrine and norepinephrine.
Figure is found on http://www.sbuniv.edu/~ggray/CHE3364/b1c25out.html
d) decarboxylation of glutamate (Glu) produces GABA (= γ-aminobutyrate). GABA is found in very high
concentrations in the brain, it is neurotransmitter.
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4. Ammonia transport and detoxification
Ammonia produced in tissues outside the liver is converted to glutamine (Gln) in brain and muscles and then
transported to the liver for metabolism (via urea cycle) and excretion (see Fig. 5).
Glutamine is the major transport form of ammonia. It is normally at much higher blood concentrations than
other amino acids. Glutamine serves as a source of amine groups for biosynthesis (i. e. biosynthesis of purine
nucleotides).
Fig. 5: Glutamine synthesis and its transport in blood to the liver.
Figure is found on http://www.sbuniv.edu/~ggray/CHE3364/b1c25out.html
Alanine also serves to transport ammonia to the liver via the glucose-alanine cycle (see Fig. 6).
Fig. 6: Glucose-alanine cycle.
Figure is found on http://www.sbuniv.edu/~ggray/CHE3364/b1c25out.html
Urea cycle (ornithine cycle) (= ammonia detoxification)
The urea cycle was proposed by Hans Krebs and Kurt Henseleit in 1932. Krebs also discovered Citric acid cycle.
Urea is produced in five-step process by the liver. Localization in liver cell: mitochondrion and cytosol (see Fig.
7).
1. Ammonia enters to the cycle after condensation with bicarbonate to form carbamoyl phosphate. 2 ATP
are consumed. This reaction is catalyzed by enzyme carbamoyl phosphate synthetase I. This enzyme
occurs in mitochondrial matrix and requires the allosteric activator N-acetylglutamate  regulatory
enzyme.
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2. Carbamoyl phosphate reacts with ornithine to form citrulline. Formation of citrulline is catalyzed by
ornithine transcarbamoylase in the mitochondrial matrix. Citrulline is transported from the
mitochondria to the cytosol and other reactions of the urea cycle occur in the cytosol.
3. Aspartate and citrulline react to form argininosuccinate by enzyme argininosuccinate synthetase.
4. Cleavage of argininosuccinate by argininosuccinate lyase produces arginine and fumarate.
5. Arginine is cleaved by arginase to ornithine and urea. Urea is then transported to the kidney and excreted
in urine.
Fig. 7: Urea cycle.
Figure is found on http://web.indstate.edu/thcme/mwking/nitrogen-metabolism.html
5. The fate of carbon skeletons of the amino acids during catabolism
The strategy of the cell is to convert carbon skeletons to compounds useful in gluconeogenesis or citric acid cycle.
All 20 common amino acids are converted to only 7 compounds:
pyruvate
acetyl-CoA
acetoacetyl-CoA
α-ketoglutarate
succinyl-CoA
fumarate
oxaloacetate
We will not look at all reaction details. We will focus on an overwiew:
a)
Glycine (Gly) and all three-carbon amino acids (Ala, Ser, Cys, Thr) are converted to pyruvate:
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b) Four-carbon amino acids (Asn, Asp) are converted to oxaloacetate:
c) Five-carbon amino acids (Gln, Pro, Arg, His, Glu) are converted to α-ketoglutarate:
d) Nonpolar amino acids Met, Ile and Val are converted to succinyl-CoA.
Some amino acids (AA) are converted to acetyl-CoA and acetoacetyl-CoA. These AA are called "ketogenic",
because they yield ketone bodies. Leucine (Leu) is only one amino acid that is exclusively ketogenic.
"Glucogenic" amino acids = amino acids that can form any of intermediates of carbohydrate metabolism. Those
AA can be converted to Glc (via gluconeogenesis). Certain AA fall into both categories.
B. Metabolism of nucleotides
Nucleotides are building blocks for nucleic acid synthesis (DNA and RNA).
Composition of nucleosides:
base + ribose are linked through N-glycosidic bond
Composition of nucleotides:
base + ribose + phosphate group(s)
Bases: (repeat structures of purine and pyrimidine bases)
● purine: adenine, guanine
● pyrimidine: uracil, cytosine, thymine
Purine nucleotides:
Adenosine monophosphate (AMP)
Adenosine diphosphate (ADP)
Adenosine triphophate (ATP)
guanosine monophosphate (GMP)
guanosine diphosphate (GDP)
guanosine triphosphate (GTP)
Pyrimidine nucleotides:
Uridine mono(di, tri) phosphate
Cytidine mono(di, tri) phosphate
Thymidine mono (di, tri) phosphate
Biosynthesis of purine nucleotides
De novo synthesis of purine nucleotides lead to inosine monophosphate (IMP). IMP serves as the common
precursor for AMP and GMP synthesis. All enzymes involved in synthesis of purine nucleotides are found in the
cytosol of the cell.
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Pentose monophosphate pathway produces ribose-5-P  phosphoribosylpyrophosphate (PRPP) 
phosphoribosylamine contains -NH2 group (from Gln), which will be used for formation of N-glycosidic bond) 
formation of purine ring  inosine monophosphate (IMP). IMP is the common precursor for AMP and GMP.
Fig. 8: Structure of PRPP (phosphoribosylpyrophosphate).
Synthesis of purine nucleotides requires:
● amino acids as C and N donors (Gln, Gly, Asp)
● CO2 as a carbon source
● C1 units (formyl) transferred via tetrahydrofolate
Fig. 9: Schematic representation of purine biosynthesis. THF = tetrahydrofolate, IMP = inosine monophosphate
Figure is found on http://www-medlib.med.utah.edu/NetBiochem/purpyr/pp.html
Degradation of purine nucleotides (see Fig. 10)
Enzymes nucleotidases have relatively high specifity to various purine nucleotides.
Purines are metabolized by enzyme xanthine oxidase to form uric acid (= a unique end product of purine
nucleotide degradation in humans). Xanthine oxidase requires O2 as a substrate. Uric acid is not very soluble in
aqueous solutions. There are clinical conditions in which elevated levels of uric acid result in deposition of sodium
urate crystals primarily in joints  gout.
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Fig. 10: Degradation of purine bases.
Figure is found on http://www-medlib.med.utah.edu/NetBiochem/purpyr/pp.html
Biosynthesis of pyrimidine nucleotides
De novo synthesis of pyrimidine ring requires amino acids as C and N donors and CO 2 as a carbon donor.
De novo synthesis of pyrimidine ring leads to UMP (= uridine monophosphate). ATP hydrolysis is required to
drive several steps in the pathway.
Formation of carbamoyl-P is catalyzed by enzyme carbamoyl-P synthetase II (cytosolic) = regulatory enzyme
(see Fig. 11)  formation of orotate from dihydroorotate is catalyzed by mitochondrial enzyme. Orotate is linked
by PRPP to form orotidine monophosphate  reactions produce UMP. Other enzymes of the pathway are found in
the cytosol Other major pyrimidine nucleotides are synthetized from UTP  CTP and TTP.
UTP inhibits the regulatory enzyme = carbamoyl-P synthetase II. This enzyme is activated by PRPP.
Fig. 11: Formation of carbamoyl phosphate by enzyme carbamoyl phosphate synthetase II.
Figure is found on http://www-medlib.med.utah.edu/NetBiochem/purpyr/pp.html
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Degradation of pyrimidine nucleotides
Pyrimidine nucleotides are degraded to β-amino acids. Uracil is degraded to β-alanine, NH4+ and CO2.
Thymine is degraded to β-aminoisobutyric acid, NH4+ and CO2.
References:
http://www.sbuniv.edu/`ggray.wh.bol/CHE3364/b1c25out.html
Koolman, J., Roehm, K-H.: Color Atlas of Biochemistry, 2nd edition, Thieme, Stuttgart (2004)
Pavla Balínová
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