Nucleotide metabolism
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NUCLEOTIDE METABOLISM. SITI ANNISA DEVI TRUSDA. Nucleotides are essential for all cells. DNA/RNA synthesis protein synthesiscells proliferate Carriers of activated intermediates in the synthesis of carbohydrate, lipids and protein

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NUCLEOTIDE METABOLISM

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NUCLEOTIDE METABOLISM

SITI ANNISA DEVI TRUSDA


Nucleotides are essential for all cells

  • DNA/RNA synthesisproteinsynthesiscells proliferate

  • Carriers of activated intermediates in the synthesis of carbohydrate, lipids and protein

  • Structural component of several essential coenzymes (coA,FAD,NAD+,NADP+)

  • cAMP,cGMP2nd messenger in signal transduction pathway

  • Important regulatory compound for many of the pathways of intermediary metabolism, inhibiting/activating key enzimes


Nucleotide structure

  • Consist of:

    • Nitrogenous base : purine & pyrimidine

    • Pentose monosaccharide

    • 1/2/3 phosphate groups

      DNA and RNA contain the same purine bases: A & G

      Pirimidine RNA : U & C

      DNA : T & C

      T& U differ by only one methyl group


Nucleosides

  • Pentose sugar + Nitrogen Base = Nucleosides

  • So, nucleotides = Nucleosides + Phosphate

  • If the sugar is ribose : ribonucleosides

  • If deoxyribose: deoxyribonucleosides

  • Ribonucleosides of A,G,C,U: Adenosine,Guanosine,Cytidine,Uridine

  • What are the deoxyribonucleosides for A,G,C,T?


Nucleotides

  • mono,di,tri esters of nucleosides

  • 1st phosphate group is attached by an ester linkage to the 5’OH of the pentosenucleoside 5’phosphate/5’-nucleoside

  • Type of pentose is added as prefix for nucleotide, can be ribose/deoxyribosee.g: 5’-ribonucleotide/5’-deoxyribonucleotide


  • 1 phosphate group + 5’-carbon of the pentosenucleosidemonophosphate(NMP) e.g AMP, CMP

  • 2 or 3 phosphate group added to the nucleosidenucleosidedi/triphosphatee.g ADP/ATP

  • The latter connected to the nucleotide by a high-energy bond

  • Phosphate groups(-) charge DNA/RNA=nucleic acids


  • So, what is :

    • Nucleoside?

    • Nucleotide?

    • Nucleic acid?


SYNTHESIS OF PURINE NUCLEOTIDES

  • Source of purine ring: aspartic acid, glycine, glutamine, CO2,N10-formylTHF

  • Synthesis of 5-phosphoribosyl-1-pyrophosphate (PRPP)

    an activated pentose for synthesis of purine/pirimidine & salvage of purine bases

    catalyzed by PRPP synthetase, from ATP & ribose 5-phosphate

    this enzyme is activated by inorganic phosphat (Pi), inhibited by purine nucleotides

    the sugar of PRPP is ribose ribonucleotides as end product of purinesynthetis


  • Purine synthesis is critical to fetal development, therefore defects in enzymes will result in a nonviable fetus.

  • PRPP synthetase defects are known and have severe consequences (next slide)

  • PRPP synthetasesuperactivity has been documented, resulting in increased PRPP, elevated levels of nucleotides, and increased excretion of uric acid.


Phosphoribosyl Pyrophosphate (PRPP) Synthetase Defects

  • PRPP deficiency results in convulsions, autistic behavior, anemia, and severe mental retardation.

  • Excessive PRPP activity causes gout (deposition of uric acid crystals), along with various neurological symptoms, such as deafness.


  • Synthesis of 5’-phosphoribosylamine

    Amide group of glutamine replaces the pyrophosphate group at C1 of PRPP

    the enzyme, glutamine:phosphoribosyl pyrophosphate amidotransferase is inhibited by the purine 5’-nucleotides AMP,GMP,IMP (end product)

    Committed step

    Rate of reaction also controlled by intracellular [] of glutamine and PRPP


  • Synthesis of inosinemonophosphate,the “parent” of purine nucleotide

    requires 4 ATP

    2 steps require N10 –formyltetrahydrofolate

  • Conversion of IMP to AMP and GMP

    2 step energy requiring pathway

    synthesis of AMP requires GTP as energy source

    synthesis of GMP requires ATP


  • Conversion of nucleoside monophosphates to nucleoside di and triphosphate

    AMP + ATP ↔ 2 ADP

    GMP +ATP ↔ GDP + ADP

    GDP + ATP ↔ GTP + ADP

    CDP + ATP ↔ CTP + ADP


Purine Synthesis


DAUR dr IMP  AMP & GMP

Adenilosuksinat synthetase

IMP dehidrogenase

XMP aminase

Adenilosuksinat lyase


Salvage Pathway of purines

  • Purines that result from the normal turnover of cellular nucleic acids/diet can be reconverted into nucleoside triphosphatessalvage pathway

  • 2 enzymes: Adenine phosphoribosyltransferase (APRT), and hypoxanthine-guanine phosphoribosyltransferase (HPRT)

  • Both needs PRPP as the source of the ribose 5-phosphate


Degradation of Purine Nucleotides

  • Purine Nucleotides from ingested nucleic acids or turnover of cellular nucleic acids is excreted by humans as uric acid.

  • Humans excrete about 0.6 g uric acid every 24 hours.

  • Degradation of dietary nucleic acids occurs in the small intestine by pancreatic enzymes


Digestion of dietary nucleic acids

  • In the stomach: low pH denatures DNA&RNA

  • In small intestine: break down phosphodiester bond by endonuclease(pancreas)  oligonucleotide

  • By phosphodiesterase(exonucleasenon spesific enzyme)  mononucleotide

  • By phosphomonoesterase (nucleotidase)result:nucleosideand orthophosphate.

  • Nucleosidaphosphorylase result: baseand ribose-1-phosphate.


  • The nucleoside then absorbed by intestinal mucosal cells

  • If the base or nucleoside is unused, it will be reused in salvage pathways, the base will be degraded:

    uric acid ureidopropionic

    (purin) (pyrimidine).


Diseases associated with purine degradation


Gout

  • Elevated uric acid levels in the blood

  • Uric acid crystals will form in the extremities with a surrounding area of inflammation. This is called a tophus and is often described as an arthritic “great toe”.

  • Can be caused by a defect in an enzyme of purine metabolism or by reduced secretion of uric acid into the urinary tract.

tophus


Adenosine Deaminase (ADA) and Purine Nucleoside Phosphorylase (PNP) Deficiency.

  • accumulation of adenosine wich is converted to its ribonucleotide or deoxyribonucleotide form by cellular kinases

  • As dATP level rise, ribonucleotidereductase is inhibited↓ production of all deoxyribose containing nucleotidescells cannot make DNA and divide.

  • Most severe form: severe combined immunodeficiency disease (SCID)lack of T and B cells


  • A deficiency of either ADA or PNP causes a moderate to complete lack of immune function.

  • Affected children cannot survive outside a sterile environment.

  • They may also have moderate neurological problems, including partial paralysis of the limbs.

  • When a compatible donor can be found, bone marrow transplant is an effective treatment.


Lesch-Nyhan Syndrome

  • Hypoxanthine Guanine Phosphoribosyltransferase (HGPRT) deficiency

  • X-linked genetic condition

  • Severe neurologic disease, characterized by self-mutilating behaviors such as lip and finger biting and/or head banging

  • Up to 20 times the uric acid in the urine than in normal individuals. Uric acid crystals form in the urine.

  • Untreated condition results in death within the first year due to kidney failure.

  • Treated with allopurinol, a competitive inhibitor of xanthineoxidase.


SYNTHESIS OF DEOXYRIBONUCLEOTIDES

  • Deoxyribonucleotides required for DNA synthesis (2’-deoxyribonucleotides)

  • Enzyme: ribonucleotidereductase

  • Inhibitor : dATP

  • Needed a coenzyme : thioredoxin

  • Thioredoxin is regenerated by thioredoxinreductase

  • Regulation of ribonucleotide reduction is controlled by allosteric feedback mechanisms.


PYRIMIDINE SYNTHESIS AND DEGRADATION

  • Source of pyrimidine ring: glutamine, CO2, aspartic acid

  • Synthesis of carbamoyl phosphate

    from glutamine & CO2, enzyme: carbamoyl phosphate synthetase II (CPS II), inhibited by UTP

    activated by ATP and PRPP


  • Synthesis of orotic acid

    formation of carbamoylaspartatedihydroorotateorotic acid (mind the enzymes!!)

  • Formation of a pyrimidine nucleotide : orotidine 5’-monophosphate (OMP)the parent of pyrimidine mononucleotide

    OMPUridinemonophosphate (UMP)

  • Synthesis of uridinetriphosphate and cytidinetriphosphate

    CTP is produced by amination of UTP

  • Synthesis of thymidinemonophosphate from dUMP


Orotatfosforibosiltransferase

Orotidilate dekarboksilase

CTP synthetase

UMP kinase

Nukleosida diphosphat kinase


Pyrimidine Synthesis

Production of Uridine 5’-monophosphate (UMP) from orotate is catalyzed by the enzyme UMP synthase


Orotic Aciduria

  • Deficiency in UMP synthetase activity

  • Due to the demand for nucleotides in the process of red blood cell synthesis, patients develop the condition of megaloblastic anemia, a deficiency of red blood cells.

  • Pyrimidine synthesis is decreased and excess orotic acid is excreted in the urine (hence the name oroticaciduria)


Degradation of pyrimidine nucleotides

  • Unlike the purine rings, which are not cleaved in human cells, the pyrimidine ring can be opened and degraded to highly soluble structures, such as β-alanine, and β-aminoisobutyrate, which can serve as precursors of acetyl coA and succinylcoA


SALVAGE OF PYRIMIDINES

Pyrimidine salvage defects have not been clinically documented


Nucleic Acid Metabolism Overview


HaturNuhun

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