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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)


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
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
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
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


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
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)


  • 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


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 of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2– 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 of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

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


Activation of folate of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2(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 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/postgrad/thftypes.gif (Jan 2008)


Serin is the principal donor of of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2methylene group

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


Folate in a metabolism 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.prema-eu.org/folatepathway/fig1.gif (Jan 2008)


Synthesis of purine nucleotides de novo i
Synthesis of purine nucleotides of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2 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 of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2de 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 of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  • 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 of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

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 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 pyrimidine nucleotides de novo i
Synthesis of pyrimidine nucleotides of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2de 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 of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2de 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 of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

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 of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  • 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 synthesis of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2of purine nucleotides

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


Regulation of synthesis of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2of 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 of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2


Degradation of purines and pyrimidines
Degradation of purines and pyrimidines of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  • 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 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.med.unibs.it/~marchesi/purine_degradation.gif (Jan 2008)


Uric acid keto and enol form
URIC ACID of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2keto 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



free Koolman, K.H.Rradicals

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)

    urine 0,48 – 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)



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