WEEK 11 (Purine Metabolism) Flashcards
What are the different Nucleotide roles in the body?
- RNA and DNA monomers
- ATP (energy)
- Physiologic mediators
- GTP (second messenger pathways)
- cAMP levels (blood flow)
- cGMP (second messenger pathways)
What are De novo pathways?
When organisms synthesise purine and pyrimidine nucleotides from low-molecular-weight precursors in amounts sufficient for their needs
What are Salvage pathways?
The utilisation of pre-formed purine and pyrimidine compounds that would be otherwise lost to biodegradation
What does a Nucleoside and a Nucleotide consist of?
Nucleoside = Base + Sugar
Nucleotide = Base + Sugar + Phosphate
What are the two different Purines?
Adenine & Guanine
What are the three different Pyrimidines?
Cytosine, Uracil & Thymine
What does the salvage/reuse of purine and pyrimidine bases involve?
Molecules released by NUCLEIC ACID DEGRADATION
Degradation can occur INTRACELLULARLY (as a result of cell death) or through DIGESTION of nucleic acids ingested in diet
Describe the route in animals by which bases and nucleosides become available
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 digest nucleic acids in the small intestine and produce MONONUCLEOTIDES
What happens to bases and nucleosides not reused for nucleic acid synthesis via salvage pathways?
The purine and pyrimidine bases are further degraded to URIC ACID or β-ureidopropionate
Describe the reutilisation of purine and pyrimidine bases
1) ENDONUCELASES cleave nucleic acids to form OLIGONUCLEOTIDES
2) PHOSPHODIESTERASES cleave oligonucleotides to form NUCLEOSIDE MONOPHOSPHATES
3) NUCLEOTIDASES hydrolyse mononucleotides forming NUCLEOSIDES
4) PHOSPHORYLASES hydrolyse nucleosides into NUCLEOBASES (uric acid & β-ureidopropionate)
What is the aim of Purine synthesis?
To generate AMP and GMP
What is needed to create AMP and GMP in Purine synthesis?
- Ribose phosphate (HMP Shunt)
- Amino acids
- Carbons (CO2 & Tetrahydrofolate)
What is 5-Phospho-α-D-ribosyl-1-pyrophosphate (PRPP)?
5-Phospho-α-D-ribosyl-1-pyrophosphate (PRPP) is an activated ribose-5-phosphate derivative used in both SALVAGE and DE NOVO PATHWAYS
Describe how Inosinic acid biosynthesis can be controlled from PRPP
PURINES are synthesised 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 (AMP, ADP & GDP) and PRPP AMIDOTRANSFERASE is inhibited by AMP, ADP, GMP & GDP.
How is GMP formed from Inosine Monophosphate (IMP)?
INOSINE MONOPHOSPHATE (IMP) is converted into XANTHOSINE MONOPHOSPHATE (XMP) via IMP DEHYDROGENASE. XMP is then converted to GMP using XMP AMINASE.
How is AMP formed from Inosine Monophosphate (IMP)?
INOSINE MONOPHOSPHATE (IMP) is converted into ADENYLOSUCCINATE via ADENYLOSUCCINATE SYNTHETASE. Adenylosuccinate is then converted to AMP using ADENYLOSUCCINATE.
What is Ribavirin?
- An antiviral
- Inhibits IMP dehydrogenase
- Blocks conversion IMP to GMP
- Inhibits synthesis of guanine nucleotides (purines)
What is Mycophenolate?
- An Immunosuppressant
- Inhibits IMP dehydrogenase
Describe the summary pathway from ribose phosphate to AMP & GMP
Ribose phosphate from HMP shunt is converted to PRPP. PRPP is then converted to IMP using Aspartate, Glycine, Glutamine, THF & CO2. IMP is then converted to AMP & GMP.
What are the properties of Purine Salvage?
- Salvages bases are ADENINE, GUANINE & HYPOXANTHINE
- Converts back into nucleotides (AMP, GMP & IMP)
- Requires PRPP
Describe the formation of IMP from Hypoxanthine
Hypoxantine & PRPP are converted to Inosine Monophosphate (IMP) using HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE (HGPRT)
Describe the formation of GMP from Guanine
Guanine & PRPP are converted to Guanine Monophosphate (GMP) using HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE (HGPRT)
Describe the formation of AMP from Adenine
Adenine & PRPP are converted to Adenosine Monophosphate (AMP) using ADENINE PHOSPHORIBOSYLTRANSFERASE (APRT)
What does Purine nucleotide catabolism form?
URIC ACID which is excreted
[some animals further oxidise the purine rings to ALLANTOIN and then to ALLANTOIC ACID which is either excreted or further catabolised to UREA/AMMONIA]
What are the properties of 6-Mercaptopurine
- Chemotherapy agent
- Mimics hypoxanthine/guanine
- Added to PRPP by HGPRT forming Thioinosinic acid
- Inhibits multiple steps in de novo synthesis
- decrease in IMP/AMP/GMP
What are the properties of Azathioprine
- Immunosuppressant
- Converted to 6-MP
What are the effects of Uric acid?
- Uric acid and its Urate salts are very INSOLUBLE
- Insolubility provides a route for egg-laying animals for getting rid of excess nitrogen in a closed environment
- HYPERURICEMIA (GOUT) in humans which is a chronic elevation of blood uric acid levels
What can prolonged or acute elevation of blood urate lead 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
What is Gout?
HYPERURICEMIA (GOUT) in humans which is a chronic elevation of blood uric acid levels
CAUSES:
- Overproduction of PURINE NUCLEOTIDES leading to excessive URIC ACID SYNTHESIS or from impaired URIC ACID EXCRETION through the kidney.
- Mutations in PRPP AMIDOTRANSFERASE that make it less sensitive to feedback inhibition by purine nucleotides
- Deficiency of HGPRT
TREATMENT:
- ALLOPURINOL which strongly inhibits XANTHINE OXIDASE
[inhibition causes accumulation of HYPOXANTHINE and XANTHIN which are more soluble and readily excreted than uric acid]
Describe Lesch-Nyhan syndrome
Lesch-Nyhan syndrome is an X-linked trait caused by HGPRT deficiency (HGPRT gene is located on the X chromosome).
CAUSES:
- Excess uric acid production
- Excess de novo purine synthesis
- Increased PRPP & IMP
SYMPTOMS:
- Severe gouty arthritis
- Malfunction of the nervous system
- Behavioural disorders, learning disabilities, hostile/aggressive behaviour
NO TREATMENT (individuals rarely live beyond 20 years)
Describe Severe Combine Immune Deficiency (SCID)
Patients are susceptible (often fatally) to infectious diseases because of an inability to mount an immune response; Both B and T lymphocytes are affected.
In many cases the conditions is caused by a lack of the degradative enzyme ADENOSINE DEAMINASE (ADA). Deficiency of ADA leads to accumulation of dATP which is known to be a potent inhibitor of DNA replication.
Describe the immunodeficiency resulting from the lack of Purine nucleoside phosphorylase (PNP)
Decreased activity of this enzyme leads to accumulation of dGTP. This accumulation affects DNA replication but less severely than excessive dATP.
The phosphorylase deficiency destroys only the T class of lymphocytes and not the B cells.
