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

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)


Metabolism of purines and pyrimidines

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


Metabolism of purines and pyrimidines

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

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


Metabolism of purines and pyrimidines

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


Metabolism of purines and pyrimidines

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


Metabolism of purines and pyrimidines

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


Metabolism of purines and pyrimidines

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

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)


Metabolism of purines and pyrimidines

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

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

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

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


Metabolism of purines and pyrimidines

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.


Metabolism of purines and pyrimidines

  • 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)


Metabolism of purines and pyrimidines

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)


Metabolism of purines and pyrimidines

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

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

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)


Metabolism of purines and pyrimidines

  • 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

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


Metabolism of purines and pyrimidines

Synthesis of purine nucleotides

CYTOPLASM

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


Metabolism of purines and pyrimidines

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


Metabolism of purines and pyrimidines

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


Metabolism of purines and pyrimidines

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)


Metabolism of purines and pyrimidines

cytostatics

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


Metabolism of purines and pyrimidines

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)


Metabolism of purines and pyrimidines

Derivatives of tetrahydrofolate

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


Metabolism of purines and pyrimidines

Serin is the principal donor of methylene group

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


Metabolism of purines and pyrimidines

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

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

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

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


Metabolism of purines and pyrimidines

Synthesis of pyrimidine nucleotides

CYTOPLASM

mitochondrion

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


Metabolism of purines and pyrimidines

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


Metabolism of purines and pyrimidines

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 nucleotides de novo i

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

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)


Metabolism of purines and pyrimidines

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

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)


Metabolism of purines and pyrimidines

Regulation of synthesisof purine nucleotides

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


Metabolism of purines and pyrimidines

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 synthesis1

Regulation of nucleotide synthesis


Degradation of purines and pyrimidines

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)


Metabolism of purines and pyrimidines

Degradation of purines

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


Uric acid keto and enol form

URIC ACIDketo and enol form

  • salts of uric acid = urates

  • pH of blood: mononatrium urate


Metabolism of purines and pyrimidines

The figure was adopted from Color Atlas of Biochemistry / J. Koolman, K.H.Röhm. Thieme 1996. ISBN 0-86577-584-2


Degradation of pyrimidines

Degradation of pyrimidines


Metabolism of purines and 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

Principal differences between metabolism of purines and pyrimidines


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