; AA_ Purine_ Pyrimidine Metabolism
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AA_ Purine_ Pyrimidine Metabolism

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									                 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




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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
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.




           .
                                                    2
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.

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).

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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.
   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.




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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:




   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:




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   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)             guanosine monophosphate (GMP)
Adenosine diphosphate (ADP)               guanosine diphosphate (GDP)
Adenosine triphophate (ATP)               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.
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.




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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 CO2 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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