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Nucleotide
Metabolism
Nucleotide Roles
• RNA and DNA monomers
• Energy: ATP
• Physiologic mediators
• cAMP levels → blood flow
• cGMP → second messenge
Biosynthetic Routes:
De novo and salvage pathways
Most organisms can synthesize purine and pyrimidrne
nucleotides from low-molecular-weight precursors in
amounts sufficient for their needs. These so-called de novo
pathways are essentially identical throughout the biological
world.
Salvage pathways involve the utilization of preformed purme
and pyrimidine compounds that would be otherwise lost to
biodegradation. Salvage pathways represent important sites
for manipulation of biological systems.
Diet (exogenous)
Figure 22.1: Overview of nucleotide metabolism.
Figure 4.3: Nucleosides and nucleotides
Nucleoside = Sugar + Base (no phosphate)
Nucleotide = Sugar + Base + Phosphate
purine pyrimidine
Nucleic Acid Degradation and the Importance
of Nucleotide Salvage
The salvage, or reuse, of purine and pyrimidine bases involves
molecules released by nucleic acid degradation
Degradation can occur intracellularly, as the result of cell death,
or, in animals, through digestion of nucleic acids ingested in the
diet.
In animals, the extracellular hydrolysis of ingested nucleic acids
represents the major route by which bases and nucleosides
become available. Catalysis occurs by endonucleases, which
function to digest nucleic acids in the small intestine. The
products are mononucleotides.
If bases or nucleosides are not reused for nucleic acid synthesis
via salvage pathways, the purine and pyrimidine bases are
further degraded to uric acid or b-ureidopropionate.
Figure 22.2: Reutilization of purine and pyrimidine bases.
Endonuclease
Phosphodiesterase
Nucleotidase
Phosphorylase
Purine Synthesis
Goal is to create AMP and GMP
• Ingredients:
• Ribose phosphate (HMP Shunt)
• Amino acids
• Carbons (tetrahydrofolate, CO2)
Figure 22.3: Low-molecular-weight
precursors to the purine ring.
Glycine
2 Glutamine
Asparate
10-formyl-THF
CO2
PRPP: A Central Metabolite in De Novo and
Salvage Pathways
5-Phospho-a-D-ribosyl-1-pyrophosphate (PRPP) is an
activated ribose-5-phosphate derivative used in both salvage
and de novo pathways.
PRPP
synthetase
Phosphoribosyltransferase
(HGPRT)
Purine synthesis from PRPP to inosinic acid
Purines are synthesized at the nucleotide level, starting with
PRPP conversion to phosphoribosylamine and purine ring
assembly on the amino group.
Control over the biosynthesis of inosinic acid is provided
through feedback regulation of early steps in purine
nucleotide synthesis. PRPP synthetase is inhibited by various
purine nucleotides, particularly AMP, ADP, and GDP, and PRPP
amidotransferase is also inhibited by AMP, ADP, GMP, and GDP.
Figure 22.4:
De novo biosynthesis
of the purine ring,
from PRPP to inosinic
acid.
1. PRPP amidotransferase
2. GAR synthetase
3. GAR transformylase
4. FGAR amidotransferase
5. FGAM cyclase
6. AIR carboxylase
7. SAICAR synthetase
8. SAICAR lyase
9. AICAR transformylase
10. IMP synthase
Figure 22.6: Pathways from inosinic acid to GMP and AMP.
Adenylosuccinate
synthetase
Adenylosuccinate
lyase
IMP
dehydrogenase
XMP
aminase
H
Inosine
Monophosphate
(IMP)
AMP
GMP
Summary
Purine Salvage
Purine degradation and
disorders of purine metabolism
Formation uric acid
All purine nucleotide catabolism yields uric acid.
Purine catabolism in primates ends with uric acid, which is
excreted. Most other animals further oxidize the purine ring,
to allantoin and then to allantoic acid, which is either
excreted or further catabolized to urea or ammonia.
Figure 22.7: Catabolism of purine nucleotides to uric acid.
Nucleotidase
PNP
(Muscle)
Xanthine
oxidase
Xanthine
oxidase
Xanthine
Hypoxanthine Uric acid
Nucleotidase
PNP
PNP: Purine nucleoside phosphorylase
Guanine
deaminase
ADA: Adenosine deaminase
ADA
Figure 22.8: Catabolism of uric acid
to ammonia and CO2
Excessive accumulation of uric acid: gout
Uric acid and its urate salts are very insoluble. This is an
advantage to egg-laying animals, because it provides a route
for disposition of excess nitrogen in a closed environment.
Insolubility of urates can present difficulties in mammalian
metabolism. About 3 humans in 1000 suffer from
hyperuricemia, which is chronic elevation of blood uric acid
levels well beyond normal levels. The biochemical reasons
for this vary, but the condition goes by a single clinical name,
which is gout.
Prolonged or acute elevation of blood urate leads to
precipitation, as crystals of sodium urate, in the synovial fluid
of joints. These precipitates cause inflammation, resulting in
painful arthritis, which can lead to severe degeneration of the
joints.
Gout results from overproduction of purine nucleotides,
leading to excessive uric acid synthesis, or from impaired uric
acid excretion through the kidney
Several known genetic alterations in purine metabolism lead
to purine oversynthesis, uric acid overproduction, and gout.
Gout can also result from mutations in PRPP amidotransferase
that render it less sensitive to feedback inhibition by purine
nucleotides. Another cause of gout is a deficiency of the
salvage enzyme hypoxanthine-Guanine
phosphoribosyltransferase (HGPRT).
Many cases of gout are successfully treated by the
antimetabolite allopurinol, a structural analog of
hypoxanthine that strongly inhibits xanthine oxidase.
This inhibition causes accumulation of hypoxanthine and
xanthine, both of which are more soluble and more readily
excreted than uric acid.
Figure 22.9: Enzymatic abnormalities in three types of gout.
HGPRT:hypoxanthine-guanine phosphoribosyltransferase
APRT: adenine phosphoribosyltransferase
Loss of
feedback
inhibition
Elevated
levels
Decreased levels
Lesch-Nyhan syndrome: HGPRT defficiency
Lesch-Nyhan syndrome is a x-linked trait, because the
structural gene for HGPRT is located on the X chromosome.
• Excess uric acid production (“juvenile gout”)
• Excess de novo purine synthesis (↑PRPP, ↑IMP)
Patients with this condition display a severe gouty arthritis,
but they also have dramatic malfunction of the nervous
system, manifested as behavioral disorders, learning
disabilities, and hostile or aggressive behavior, often self-
directed.
At present, there is no successful treatment, and afflicted
individuals rarely live beyond 20 years.
Severe combined immune deficiency (SCID)
Patients with a hereditary condition called severe combined
immunodeficiency syndrome are susceptible, often fatally, to
infectious diseases because of an inability to mount an
immune response to antigenic chanllenge.
In this condition, both B and T lymphocytes are affected.
Neither class of cells can proliferate as they must if antibodies
are to be synthesized. In many cases the condition is caused
from a heritable lack of the degradative enzyme adenosine
deaminase (ADA).
The deficiency of ADA leads to
accumulation of dATP which is
known to be a potent inhibitor of
DNA replication.
A less severe immunodeficiency results from the lack of
another purine degradative enzyme, purine nuceloside
phosphorylase (PNP). Decreased activity of this enzyme
leads to accumulation primarily of dGTP. This accumulation
also affects DNA replication, but less severely than does
excessive dATP.
Interestingly, the phosphorylase deficiency destroys only
the T class of lymphocytes and not the B cells.
purine metabolism.ppt

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purine metabolism.ppt

  • 2. Nucleotide Roles • RNA and DNA monomers • Energy: ATP • Physiologic mediators • cAMP levels → blood flow • cGMP → second messenge
  • 3. Biosynthetic Routes: De novo and salvage pathways Most organisms can synthesize purine and pyrimidrne nucleotides from low-molecular-weight precursors in amounts sufficient for their needs. These so-called de novo pathways are essentially identical throughout the biological world. Salvage pathways involve the utilization of preformed purme and pyrimidine compounds that would be otherwise lost to biodegradation. Salvage pathways represent important sites for manipulation of biological systems. Diet (exogenous)
  • 4. Figure 22.1: Overview of nucleotide metabolism.
  • 5. Figure 4.3: Nucleosides and nucleotides Nucleoside = Sugar + Base (no phosphate) Nucleotide = Sugar + Base + Phosphate
  • 7. Nucleic Acid Degradation and the Importance of Nucleotide Salvage The salvage, or reuse, of purine and pyrimidine bases involves molecules released by nucleic acid degradation Degradation can occur intracellularly, as the result of cell death, or, in animals, through digestion of nucleic acids ingested in the diet. In animals, the extracellular hydrolysis of ingested nucleic acids represents the major route by which bases and nucleosides become available. Catalysis occurs by endonucleases, which function to digest nucleic acids in the small intestine. The products are mononucleotides. If bases or nucleosides are not reused for nucleic acid synthesis via salvage pathways, the purine and pyrimidine bases are further degraded to uric acid or b-ureidopropionate.
  • 8. Figure 22.2: Reutilization of purine and pyrimidine bases. Endonuclease Phosphodiesterase Nucleotidase Phosphorylase
  • 9. Purine Synthesis Goal is to create AMP and GMP • Ingredients: • Ribose phosphate (HMP Shunt) • Amino acids • Carbons (tetrahydrofolate, CO2)
  • 10. Figure 22.3: Low-molecular-weight precursors to the purine ring. Glycine 2 Glutamine Asparate 10-formyl-THF CO2
  • 11. PRPP: A Central Metabolite in De Novo and Salvage Pathways 5-Phospho-a-D-ribosyl-1-pyrophosphate (PRPP) is an activated ribose-5-phosphate derivative used in both salvage and de novo pathways. PRPP synthetase Phosphoribosyltransferase (HGPRT)
  • 12. Purine synthesis from PRPP to inosinic acid Purines are synthesized at the nucleotide level, starting with PRPP conversion to phosphoribosylamine and purine ring assembly on the amino group. Control over the biosynthesis of inosinic acid is provided through feedback regulation of early steps in purine nucleotide synthesis. PRPP synthetase is inhibited by various purine nucleotides, particularly AMP, ADP, and GDP, and PRPP amidotransferase is also inhibited by AMP, ADP, GMP, and GDP.
  • 13.
  • 14. Figure 22.4: De novo biosynthesis of the purine ring, from PRPP to inosinic acid. 1. PRPP amidotransferase 2. GAR synthetase 3. GAR transformylase 4. FGAR amidotransferase 5. FGAM cyclase 6. AIR carboxylase 7. SAICAR synthetase 8. SAICAR lyase 9. AICAR transformylase 10. IMP synthase
  • 15.
  • 16. Figure 22.6: Pathways from inosinic acid to GMP and AMP. Adenylosuccinate synthetase Adenylosuccinate lyase IMP dehydrogenase XMP aminase H Inosine Monophosphate (IMP) AMP GMP
  • 17.
  • 20.
  • 21.
  • 22. Purine degradation and disorders of purine metabolism Formation uric acid All purine nucleotide catabolism yields uric acid. Purine catabolism in primates ends with uric acid, which is excreted. Most other animals further oxidize the purine ring, to allantoin and then to allantoic acid, which is either excreted or further catabolized to urea or ammonia.
  • 23. Figure 22.7: Catabolism of purine nucleotides to uric acid. Nucleotidase PNP (Muscle) Xanthine oxidase Xanthine oxidase Xanthine Hypoxanthine Uric acid Nucleotidase PNP PNP: Purine nucleoside phosphorylase Guanine deaminase ADA: Adenosine deaminase ADA
  • 24. Figure 22.8: Catabolism of uric acid to ammonia and CO2
  • 25.
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  • 28. Excessive accumulation of uric acid: gout Uric acid and its urate salts are very insoluble. This is an advantage to egg-laying animals, because it provides a route for disposition of excess nitrogen in a closed environment. Insolubility of urates can present difficulties in mammalian metabolism. About 3 humans in 1000 suffer from hyperuricemia, which is chronic elevation of blood uric acid levels well beyond normal levels. The biochemical reasons for this vary, but the condition goes by a single clinical name, which is gout.
  • 29. Prolonged or acute elevation of blood urate leads to precipitation, as crystals of sodium urate, in the synovial fluid of joints. These precipitates cause inflammation, resulting in painful arthritis, which can lead to severe degeneration of the joints. Gout results from overproduction of purine nucleotides, leading to excessive uric acid synthesis, or from impaired uric acid excretion through the kidney Several known genetic alterations in purine metabolism lead to purine oversynthesis, uric acid overproduction, and gout. Gout can also result from mutations in PRPP amidotransferase that render it less sensitive to feedback inhibition by purine nucleotides. Another cause of gout is a deficiency of the salvage enzyme hypoxanthine-Guanine phosphoribosyltransferase (HGPRT).
  • 30. Many cases of gout are successfully treated by the antimetabolite allopurinol, a structural analog of hypoxanthine that strongly inhibits xanthine oxidase. This inhibition causes accumulation of hypoxanthine and xanthine, both of which are more soluble and more readily excreted than uric acid.
  • 31. Figure 22.9: Enzymatic abnormalities in three types of gout. HGPRT:hypoxanthine-guanine phosphoribosyltransferase APRT: adenine phosphoribosyltransferase Loss of feedback inhibition Elevated levels Decreased levels
  • 32. Lesch-Nyhan syndrome: HGPRT defficiency Lesch-Nyhan syndrome is a x-linked trait, because the structural gene for HGPRT is located on the X chromosome. • Excess uric acid production (“juvenile gout”) • Excess de novo purine synthesis (↑PRPP, ↑IMP) Patients with this condition display a severe gouty arthritis, but they also have dramatic malfunction of the nervous system, manifested as behavioral disorders, learning disabilities, and hostile or aggressive behavior, often self- directed. At present, there is no successful treatment, and afflicted individuals rarely live beyond 20 years.
  • 33. Severe combined immune deficiency (SCID) Patients with a hereditary condition called severe combined immunodeficiency syndrome are susceptible, often fatally, to infectious diseases because of an inability to mount an immune response to antigenic chanllenge. In this condition, both B and T lymphocytes are affected. Neither class of cells can proliferate as they must if antibodies are to be synthesized. In many cases the condition is caused from a heritable lack of the degradative enzyme adenosine deaminase (ADA). The deficiency of ADA leads to accumulation of dATP which is known to be a potent inhibitor of DNA replication.
  • 34. A less severe immunodeficiency results from the lack of another purine degradative enzyme, purine nuceloside phosphorylase (PNP). Decreased activity of this enzyme leads to accumulation primarily of dGTP. This accumulation also affects DNA replication, but less severely than does excessive dATP. Interestingly, the phosphorylase deficiency destroys only the T class of lymphocytes and not the B cells.