Metabolism of amino acids, purine and pyrimidine bases

Amino acids (AAs)

Sources of AAs:

• diet

• synthesis de novo

• protein degradation

dietary proteins proteosynthesis body proteins AAs pool N-compound synthes. de novo biosynthesis degradation (E,glc,fat)

Biosynthesis of amino acids (AA)

Humans can synthesize only 10 of the 20 AA.

Essential AA = AA that cannot be synthesized „de novo“. They must be obtained from diet.

Nonessential AA:

Ala is synthesized from pyruvate.

Cys is synthesized from Met and Ser.

Tyr is formed by hydroxylation from Phe.

Tyr Val

Ser Trp

Pro Thr

Gly Phe

Glu Met

Gln Lys

Cys Leu

Asp Ile

Asn His

Ala Arg

Nonessential AA Essential AA

Synthesis of AAs in a human body - 5 substrates -

1. oxaloacetate → Asp, Asn

2. -ketoglutarate → Glu, Gln, Pro, (Arg)

3. pyruvate → Ala

4. 3-phosphoglycerate → Ser, Cys, Gly

5. Phe → Tyr

Synthesis of thyrosine from phenylalanine

Figure is found at http://themedicalbiochemistrypage.org/amino-acid-metabolism.html#tyrosine

Formation of activated methionine = S-adenosylmethionine (SAM)

SAM is used as –CH3 group donor in metabolic methylations

Figure is found at http://themedicalbiochemistrypage.org/amino-acid-metabolism.html#cysteine

Synthesis of Cys from Met and Ser

Figure is found at http://themedicalbiochemistrypage.org/amino-acid-metabolism.html#cysteine

Degradation of AA

20 different multienzyme sequences exist for catabolism of AAs. All common 20 AAs are converted to only

7 compounds:

• pyruvate

• acetyl-CoA

• acetoacetyl-CoA

• α-ketoglutarate

• succinyl-CoA

• fumarate

• oxaloacetate

Three types of reactions are typical for degradation of AAs:

1. Transamination

2. Deamination

3. Decarboxylation

Transamination

= an exchange of –NH2 between amino acid and α-ketoacid

These reactions are catalyzed by transaminases (aminotransferases). Most of them require α-ketoglutarate as an acceptor of –NH2.

Coenzyme of transaminases: pyridoxal phosphate (vit. B6 derivative)

Figure is found at http://web.indstate.edu/thcme/mwking/nitrogen-metabolism.html

Aminotransferases (transaminases) important in medicine

Alanine aminotransferase (ALT)

Aspartate aminotransferase (AST)

Figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations,

4th ed. Wiley-Liss, Inc., New York, 1997. ISBN 0-471-15451-2

Deamination

e. g. oxidative deamination of Glu

Glu → α-ketoglutarate by glutamate dehydrogenase

Figure is found at http://www.sbuniv.edu/~ggray/CHE3364/b1c25out.html

Decarboxylation

→ primary amines

a) decarboxylation of His → histamine

b) decarboxylation of Trp → serotonin

c) decarboxylation of Tyr → epinephrine and norepinephrine

d) decarboxylation of Glu → GABA (γ-aminobutyrate)

Figure is found at http://www.sbuniv.edu/~ggray/CHE3364/b1c25out.html

Ammonia transport and detoxification

Glutamine (Gln) is the major transport form of ammonia.

Figure is found at http://www.sbuniv.edu/~ggray/CHE3364/b1c25out.html

Glucose-Alanine cycle

Figure is found at http://www.sbuniv.edu/~ggray/CHE3364/b1c25out.html

Urea cycle (ornithine cycle)

• substrates: NH4+, HCO3

-, Asp, ATP

• product: urea

• function: synthesis of non-toxic urea

• subcellular location: mitochondria and cytosol

• organ location: liver

• regulatory enzyme: carbamoyl phosphate synthetase I

Urea cycle (ornithine cycle)

Figure is found at http://web.indstate.edu/thcme/mwking/nitrogen-metabolism.html

l

The fate of carbon skeletons of AA during catabolism

• The strategy of the cell is to convert carbon skeletons to compounds useful in gluconeogenesis or CAC.

• Glucogenic AAs = AA that can form any of intermediates of carbohydrate metabolism

Gly, Ala, Ser, Cys, Thr → pyruvate

Glu, Pro, Arg, His → Glu → α-ketoglutarate

Met, Ile, Val → succinyl-CoA

• Ketogenic AAs are converted to acetyl-CoA and acetoacetyl-CoA. They yield ketone bodies.

Leu, Lys

● Glucogenic-ketogenic AAs = Thr, Phe, Tyr, Ile

Figure is found at http://www.biocarta.com/pathfiles/glucogenicPathway.asp Fig

De novo synthesis of purine nucleotides

Figure is found at http://web.indstate.edu/thcme/mwking/nucleotide-metabolism.html

Important notes about biosynthesis of purine nucleotides

• Subcellular location: cytoplasm

• PRPP = phosphoribosyl pyrophosphate is derived from ribose-5-P

• IMP = inosine monophosphate serves as the common precursor of AMP and GMP synthesis

• Gln, Gly, Asp are donors of C and N atoms

• CO2 is a source of C

• C1 units are transferred via tetrahydrofolate

„Salvage pathway“:

• purines from normal turnover of cellular NA can be converted to nucleoside triphosphates

• substrates: purine bases, PRPP, ATP

Degradation of purine nucleotides

→ uric acid is formed by enzyme xanthine oxidase

De novo synthesis of pyrimidine nucleotides

Figure is found at http://web.indstate.edu/thcme/mwking/nucleotide-metabolism.html

Important notes about synthesis of pyrimidine nucleotides

• Carbamoyl phosphate is formed from Gln and CO2

(2 ATP are consumed). This reaction is catalyzed by carbamoyl-P synthetase II (cytosolic enzyme) = regulatory step

• pathway occurs in cytoplasm but formation of orotate occurs in mitochondrion → orotate is linked by PRPP → OMP → UMP

• UMP → UTP → CTP

TTP

● UTP inhibits regulatory enzyme, activator is PRPP

„Salvage pathway“:

● pyrimidine nucleosides are phosphorylated (ATP) to nucleotides

TTP

Degradation of pyrimidine bases

→ β-amino acids are formed