Transcript ppt

Metabolism of amino acids, purine and
pyrimidine bases
Pavla Balínová
Amino acids (AAs)
Sources of AAs:
• diet
• synthesis de novo
• protein degradation
dietary proteins
body proteins
proteosynthesis
AAs pool
de novo biosynthesis
(E,glc,fat)
N-compound synthes.
degradation
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.
Essential AA
Nonessential AA
Arg
Ala
His
Asn
Ile
Asp
Leu
Cys
Lys
Gln
Met
Glu
Phe
Gly
Thr
Pro
Trp
Ser
Val
Tyr
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)
l
Figure is found at http://web.indstate.edu/thcme/mwking/nitrogen-metabolism.html
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
F
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
TTP
● UTP inhibits regulatory enzyme, activator is PRPP
„Salvage pathway“:
● pyrimidine nucleosides are phosphorylated (ATP) to
nucleotides
Degradation of pyrimidine bases
→ β-amino acids are formed