Synthesis of Purine Nucleotides

the atoms of the purine ring are contributed by a number of compunds:

• amino acids (apartic acid, glycine, glutamine)

• CO2

• N10-formyltetrahydrofolate

liver —> by a series of reactions that add the donated carbons + nitrogens to a performed ribose 5-phosophate

in the pentose phosphate pathway

1. Synthesis of 5-phosphoribose-1-pyrophosphate (PRPP)

2. Synthesis of 5-phosphoribosylamine

3. Synthesis of inosine monophosphate (“parent” purine nucleotide)

4. Synthetic inhibitor of purine synthesis

5. Conversion of IMP to AMP and GMP

6. Conversion of nucleoside monophosphate to nucleoside diphosphate and triphosphate

7. Salvage pathway for purines

synthesis of 5-phosphoribosyl-1-pyrophosphate (PRPP)

an “activated pentose” which participates in the synthesis + salvage of purines + pyrimidines

ATP and ribose 5-phosphate

ribose phosphate pyrophosphokinase (PROO synthetase)

• The X-linked enzyme is activated by inorganic phosphate

• is inhibited by purine nucleotides (end-product inhibition)

Synthesis of 5´-phosphoribosylamine

PRPP + glutamine

• the amid group of glutamine replaces the pyrophosphate group attached to C1 of PRPP

phosphoribosylpyrophosphate amidotransferase

intracellular concentration of PRPP —> any small change in PRPP concentration causes a proportional change in rate of the reaction

• the purine 5´-nucleotides AMP + GMP (end-product inhibition)

Synthesis of inosine monophosphate (= “parent” purine nucleotide)

9

• ATP as an energy source

• 2 steps require N10-formyltetra-hydrofolate

• inhibit the growth of rapidly dividing microorganisms without interfering with human cell functions (sulfonamides)

• are used pharmalcologically to control the spread of cancer by interfering with the synthesis of nucleotides —> and therfore the synthesis of DNA + RNA (analogs of folic acid —> eg: methotrexate)

• inhibitors of human purine synthesis are extremly toxic to tissues —> especially to developing structures (fetus) or to cell types that normally replicate rapidl (bone marroe, skin, GIT, immune system, hair follicles)

• patients receiving those anticancer drugs can experience adverse effects —> anemia, scaly skin, GIT disturbances, immunodeficiencies, hair loss

conversion of IMP to AMP and GMP

• conversion uses a 2-step energy-requiring pathway

• AMP —> guanosine triphosphate (GTP)

• GMP —> ATP

• the first reaction of the conversion is inhibited by the end products of the pathway (either AMP or GMP)

• if both AMP + GMP are present in adequate amounts the new synthesis pathway of purine synthesis is turned off at the amidotransferase step (PRPP —> 5´-phosphoribosylamine)

• the druff is a reversible-inhibitor of IMP dehydrogenase

• the drug deprives rapidly proliferating T + B cells of key components of nucleuc acids

• is an immonr-suppressant used to prevent graft rejection

the concversion of the mucleoside monophosphates to nucleoside diphosphates and nucleoside triphosphates

they are synthesized from the corresponding nucleoside monophosphate by base-specific nucleoside mono-phosphate kinases

AMP + ATP —> 2 ADP

GMP + ATP —> GDP + ADP

• adenylate kinase (particular active in liver + muscles -> there is an high amount of ATP)

• guanylate kinase

maintains equilibrium among AMP, ADP, ATP

nucleosides diphosphate and triphosphate are interconverted by the enzyme “nucleoside diphosphate kinase” —> the enzyme has a broas specificity

• purines that result from a normal turnover of cellular nucleic acids or the small amount that is obtained from the diat and not degraded and then converted to nuceosides triphosphates by the body

• adenin phosphoribosyltransferase (APRT)

• hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

  
  

• the enzymes APRT + HGPRT use PRPP as the source of the ribose 5-phosphate group

• this group is transfered to the purine base —> formation of nucleotides

irreversible

• the release of pyrophosphate from PRPP + its subsequent hydrolysis by pyrophospatese makes the reaction irreversible

• an X-linked recessive inherited disorder associated with a virtually complete deficiency of HGPRT enzyme —> therfore patient is not able to salvage hypoxanthine or guanine

• this enzyme deficiency leads to increased levels of PRPP + decreased levels of IMP and GMP —> this increases de novo purine synthesis

• increased de novo purine synthesis results in excessive production of uric acid + characteristic neurological features (self-mutilation and involuntary movements)

• other symptoms: formation of uric acid stones in kidneys (urolithiasis) + deposition of urate ctrystals in the joints (gouty arthritis)

• motor dysfunction, cognitive deficits, behavioral disturbances