Metabolism of purines and pyrimidines
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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). PURINE BASES.

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Metabolism of purines and pyrimidines

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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)


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

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


Structure of purine and pyrimidine nucleotides

  • nucleotide= ester of phosphoric acid and a nucleoside

  • nucleoside= N-containing base + monosaccharide

  • -N-glycosidic bondbetween base and saccharide

  • nucleotide bases: aromatic heterocycles

    • purines: pyrimidine + imidazol ring

    • pyrimidines: pyrimidine ring


ribonucleosidedeoxyribonucleoside

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


ribonucleosidesdeoxyribonucleoside

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


ribonucleotidedeoxyribonucleotide

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


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 ofribonucleoside diphosphates (NADPH)


3´-phosphoadenosine-5´-phosphosulfate (PAPS)

used as the sulfate donor in metabolic reactions (sulfatation)

The figure was found at http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html (Jan 2007)


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


Synthetic analogs of purines and pyrimidines are usedin chemotherapy

The figure was adopted from Harper´s Illustrated Biochemistry 26th ed./ R.K.Murray; McGraw-Hill Companies, 2003, ISBN 0-07-138901-6.


  • 3) physiological mediators

    • cAMP, cGMP („second messengers“)

Cyclic adenosine monophosphate (cAMP)

The figure was found at http://www.benbest.com/health/cycAMP.gif (Jan 2008)


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 substrate for synthesis of bothpurines and pyrimidines

The figure was found at http://ead.univ-angers.fr/~jaspard/Page2/COURS/2N2NH3aaetUree/2Figures/9AAaromatiques/8PRPP.gif (Jan 2008)


PRPP = 5-phosphoribosyl-1-diphosphate

  • its synthesis is a key reaction of synthesis of the nucleotides

  • PRPP-synthetaseis 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

PRPP = PRDP

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 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


Synthesis of purine nucleotides

CYTOPLASM

The figure was found at http://web.indstate.edu/thcme/mwking/nucleotide-metabolism.html (Jan 2007)


IMP

AMP

GMP

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


Folate is a vitamin– it is not synthesized in human cells

Bacteria can synthesize the folate:sulfonamides are analogs of PABA→ bacteriostatic effect

The figure was found at http://www.dentistry.leeds.ac.uk/biochem/MBWeb/mb2/part1/aacarbon.htm (Jan 2008)


cytostatics

The figure was found at http://oregonstate.edu/instruct/bb450/lecturenoteskevin/enzymesoutline.html (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/fol-red.gif (Jan 2008)


Derivatives of tetrahydrofolate

The figure was found at http://www.dentistry.leeds.ac.uk/biochem/postgrad/thftypes.gif (Jan 2008)


Serin is the principal donor of methylene group

The figure was found at http://www.med.unibs.it/~marchesi/glycine_synth.gif (Jan 2008)


Folate in a metabolism

The figure was found at http://www.prema-eu.org/folatepathway/fig1.gif (Jan 2008)


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+


Synthesis of purine nucleotides de novo(II)

  • 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 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


Synthesis of pyrimidine nucleotides

CYTOPLASM

mitochondrion

The figure was found at http://web.indstate.edu/thcme/mwking/nucleotide-metabolism.html (Jan 2007)


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

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 pyrimidine nucleotidesde 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)


Synthesis of pyrimidine nucleotides de novo(II)

  • important intermediates:* orotic acid (pyrimidine derivative)* orotidine monophosphate (OMP) * uridine monophosphate (UMP)

  • products:* cytidine triphosphate (from UTP)* deoxythimidine monophosphate(from dUMP)


Synthesis of 2-deoxyribonucleotides

protein

NADP+

NADPH+H+

protein

The reaction is catalyzed byribonucleotide reductase

The figure was found at http://www.chm.bris.ac.uk/motm/vitaminb12/ribred.gif (Jan 2008)


Regulation of nucleotide synthesis

  • PRPP-synthetaseis inhibited by both purine and pyrimidine nucleoside di- and triphosphates

  • nucleotide synthesis: feed back inhibition

  • nucleoside diphosphate reductase:activated bynucleoside triphosphates, inhibited bydeoxyadenosine triphosphate (dATP)


Regulation of synthesisof purine nucleotides

The figure was found at http://www.med.unibs.it/~marchesi/purine_synth_reg.gif (Jan 2008)


Regulation of synthesisof pyrimidine nucleotides

The figure was found at http://www.med.unibs.it/~marchesi/pyrimidine_synth_reg.gif (Jan 2008)


Regulation of nucleotide synthesis


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)


Degradation of purines

The figure was found at http://www.med.unibs.it/~marchesi/purine_degradation.gif (Jan 2008)


URIC ACIDketo and enol form

  • 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


freeradicals

SUMMARY:

  • purines→ NH3, uric acid – it has antioxidative properties(partially excreted with urine; failure: hyperuricemia, gout)

    physiological range:

    serum220 – 420 µmol/l (men)140 – 340 µmol/l (women)

    urine0,48 – 5,95 mmol/l

  • pyrimidines: C, U →-alanine, CO2, NH3T → -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)


Principal differences between metabolism of purines and pyrimidines


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