metabolism of purines and pyrimidines vladimíra kvasnicová the figure was found at (jan 2008)
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Metabolism of purines and pyrimidines
Vladimíra Kvasnicová
The figure was found at http://www.mahidol.ac.th/mahidol/ra/rapa/mong/26uric.jpg
(Jan 2008)
The 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
PURINE BASES
The 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
PYRIMIDINE BASES
Structure of purine and pyrimidine nucleotides
• nucleotide = ester of phosphoric acid and a nucleoside
• nucleoside = N-containing base + monosaccharide
-N-glycosidic bond between base and saccharide
• nucleotide bases: aromatic heterocycles purines: pyrimidine + imidazol ring
pyrimidines: pyrimidine ring
The 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
ribonucleoside deoxyribonucleoside
N-glycosidic bond
The 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
ribonucleosides deoxyribonucleoside
The 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
Ribonucleotides
* N-glycosidic bond* ester bond* anhydride bond
The 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
ribonucleotide deoxyribonucleotide
Classification of nucleotides• purine nucleotides: contain adenine, guanine,
hypoxanhine or xanthine
• pyrimidine nucleotides: contain cytosine, uracil or thymine
• ribonucleotides (saccharide = ribose)
• deoxyribonukleotidy (saccharide = deoxyribose)
formed by reduction of ribonucleoside diphosphates (NADPH)
The figure was found at http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html (Jan 2007)
3´-phosphoadenosine-5´-phosphosulfate (PAPS)
used as the sulfate donor in metabolic reactions (sulfatation)
Properties of nucleotides
• strong absorption of UV radiation (260 nm)
• purines are less stable under acidic conditions than pyrimidines
• polar terminal phosphate groups alternative names: adenylate or adenylic acid, ...
Purine and pyrimidine nucleotides
• essential for all cells
• mainly 5´-nucleosidedi and triphosphates
• ribonucleotides: concentration of a sum of them is constant (mM), only their ratio varies(main ribonucleotide of cells: ATP)
• deoxyribonucleotides: their concentration depends on a cell cycle (µM)
Nucleotides in a metabolism
1) energetic metabolism ATP = principal form of chemical energy
available to cells – „as money of the cell“
(30 kJ/mol / spliting off phosphate)
phosphotransferase reactions (kinases) muscle contraction, active transport
2) monomeric units of RNA and DNA substrates: nucleoside triphosphates
The figure was adopted from Harper´s Illustrated Biochemistry 26 th ed./ R.K.Murray; McGraw-Hill Companies, 2003, ISBN 0-07-138901-6.
Synthetic analogs of purines and pyrimidines are used
in chemotherapy
The figure was found at http://www.benbest.com/health/cycAMP.gif
(Jan 2008)
Cyclic adenosine monophosphate (cAMP)
3) physiological mediators cAMP, cGMP („second messengers“)
4) components of coenzymes NAD+, NADP+, FAD, CoA
The figures were found at http://lxyang.myweb.uga.edu/bcmb8010/pic/NAD+.gif a http://oregonstate.edu/instruct/bb450/stryer/ch14/Slide26.jpg (Jan 2008)
5) activated intermediates UDP-Glc, GDP-Man, CMP-NANA CDP-choline, ethanolamine, diacylglycerol SAM methylation PAPS sulfatation
6) allosteric efectors regulation of key enzymes of metabolic pathways
PRDP = 5-fosforibosyl-1-diphosphate
The figure was found at http://ead.univ-angers.fr/~jaspard/Page2/COURS/2N2NH3aaetUree/2Figures/9AAaromatiques/8PRPP.gif (Jan 2008)
= the substrate for synthesis of bothpurines and pyrimidines
PRPP = 5-phosphoribosyl-1-diphosphate
• its synthesis is a key reaction of synthesis of the nucleotides
• PRPP-synthetase is regulated by feed back inhibition by nucleoside di- and triphosphates
• precursors: * ribose-5-phosphate (from HMPP)* ribose-1-phosphate(phosphorolysis of nucleosides)
• function: regulation of
nucleotide synthesis
substrate of nucleotide synthesis
The 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
PRPP = PRDP
Synthesis of purine nucleotides• de novo = new building of a nucleotide rings
• salvage reactions = synthesis from bases or nucleosides less energy need than for de novo synthesis they inhibit de novo synthesis substrates: a) base (adenine, guanine,
hypoxanthine) PRPP
b) ribonucleosides ATP
The figure was found at http://web.indstate.edu/thcme/mwking/nucleotide-metabolism.html (Jan 2007)
Synthesis of purine nucleotides
CYTOPLASM
The 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
AMPGMP
IMP
The 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
The figure was found at http://www.dentistry.leeds.ac.uk/biochem/MBWeb/mb2/part1/aacarbon.htm (Jan 2008)
Bacteria can synthesize the folate:
sulfonamides are analogs of PABA→ bacteriostatic effect
Folate is a vitamin– it is not synthesized in human cells
The figure was found at http://oregonstate.edu/instruct/bb450/lecturenoteskevin/enzymesoutline.html (Jan 2008)
cytostatics
The figure was found at http://www.dentistry.leeds.ac.uk/biochem/postgrad/fol-red.gif (Jan 2008)
Activation of folate(reduction)
Dihydrofolate reductase can be inhibited by Methotrexate
The figure was found at http://www.dentistry.leeds.ac.uk/biochem/postgrad/thftypes.gif (Jan 2008)
Derivatives of tetrahydrofolate
The figure was found at http://www.med.unibs.it/~marchesi/glycine_synth.gif (Jan 2008)
Serin is the principal donor of methylene group
The figure was found at http://www.prema-eu.org/folatepathway/fig1.gif (Jan 2008)
Folate in a metabolism
Synthesis of purine nucleotides de novo
(I)• high consumption of energy (ATP)
• cytoplasm of many cells, mainly in the liver
• substrates: * 5-phosphoribosyl-1-diphosphate(= PRDP = PRPP)* amino acids(Gln, Gly, Asp)* tetrahydrofolate derivatives, CO2
• coenzymes: * tetrahydrofolate (= THF)* NAD+
• important intermediates: 5´-phosphoribosylamine
inosine monophosphate (IMP)
• products: nucleoside monophosphates (AMP, GMP)
• interconversion of purine nucleotides:
via IMP = common precursor of AMP and GMP
(inosine monophosphate: base = hypoxanthine)
Synthesis of purine nucleotides de novo(II)
Synthesis of pyrimidine nucleotides
• de novo = new building of a nucleotide rings
• salvage reactions = synthesis from bases or nucleosides
substrates:
a) * base (not cytosine) * PRPP
b) * ribonucleosides * ATP
The figure was found at http://web.indstate.edu/thcme/mwking/nucleotide-metabolism.html (Jan 2007)
Synthesis of pyrimidine nucleotides
CYTOPLASM
mitochondrion
The 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
The 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
Synthesis of thymidine monophosphate
Synthesis of pyrimidine nucleotides de novo
(I)• cytoplasm of cells (exception: one enzyme is found at
mitochondria /dihydroorotate-DH)
• substrates: * carbamoyl phosphate (Gln,CO2,2ATP)
* aspartate* PRPP* methylene-THF (only for thimidine)
Karbamoyl phosphate is formed in urea synthesis as well
(only in mitochondria of hepatocytes)
• important intermediates:
* orotic acid (pyrimidine derivative)* orotidine monophosphate (OMP)
* uridine monophosphate (UMP)
• products: * cytidine triphosphate (from UTP)
* deoxythimidine monophosphate(from dUMP)
Synthesis of pyrimidine nucleotides de novo
(II)
The figure was found at http://www.chm.bris.ac.uk/motm/vitaminb12/ribred.gif (Jan 2008)
Synthesis of 2-deoxyribonucleotides
The reaction is catalyzed byribonucleotide reductase
NADP+
NADPH+H+
protein
protein
Regulation of nucleotide synthesis
• PRPP-synthetase is inhibited by both purine and pyrimidine nucleoside di- and triphosphates
• nucleotide synthesis: feed back inhibition
• nucleoside diphosphate reductase:activated by nucleoside triphosphates,
inhibited by deoxyadenosine triphosphate (dATP)
The figure was found at http://www.med.unibs.it/~marchesi/purine_synth_reg.gif (Jan 2008)
Regulation of
synthesisof purine
nucleotides
The figure was found at
http://www.med.unibs.it/~marchesi/pyrimidine_synth_reg.gif (Jan 2008)
Regulation of synthesis
of pyrimidine nucleotides
Regulation of nucleotide synthesis
regulatory enzyme activation
inhibition
glutamine-PRPP amidotransferase
(purines)
PRPP IMP, GMP, AMP (allosteric inhibition)
carbamoylphosphatesynthetase II = cytosolic
(pyrimidines)
PRPP ATP
UTP
Degradation of purines and pyrimidines
• exogenous: mostly not used for resynthesis
• endogenous:
enzymes * nucleases (split off nucleic acids)* nucleotidases (...nucleotides)* nucleoside phosphorylases (nucleosides)* deaminase (adenosine)* xanthinoxidase (substrates: hypoxanthine, xanthine)
inhibited by allopurinol (pharmacology)
The figure was found at
http://www.med.unibs.it/~marchesi/purine_degradation.gif (Jan 2008)
Degradation of purines
URIC ACIDketo and enol form
N
N N
N
O
O
O
H
HH
H N
N N
N
O
O
O
H
H
H
H
• salts of uric acid = urates• pH of blood: mononatrium urate
The figure was adopted from Color Atlas of Biochemistry / J. Koolman, K.H.Röhm. Thieme 1996. ISBN 0-86577-584-2
Degradation of pyrimidines
SUMMARY:
purines → NH3, uric acid – it has antioxidative properties(partially excreted with urine; failure: hyperuricemia, gout)
physiological range:
serum 220 – 420 µmol/l (men)140 – 340 µmol/l (women)
urine0,48 – 5,95 mmol/l
pyrimidines: C, U → -alanine, CO2, NH3
T → -aminoisobutyrate, CO2, NH3
The figures were adopted from http://www.uni-koeln.de/med-fak/biochemie/biomed/versuche/v07/abb05.gif and http://www.healerpatch.com/images/gout.jpg (Jan 2008)
freeradicals
Principal differences between metabolism of purines and
pyrimidinespurines pyrimidines
formation of N-glycosidic bond
in 1st step of their biosynthesis(PRDP is the 1st substrate)
a heterocyclic ring is formed first, then it reacts with PRDP
location of biosynthesis
cytoplasm cytoplasm + 1 enzymeis in a mitochondrion
products of degradation
uric acid (poor solubility in
H2O),NH3
CO2, NH3, -AMK (soluble in H2O)
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