Purine. Degradation And Metabolism Flashcards
What is uric acid?
End product of purine breakdown (adenine, guanine, hypoxanthine)
- Normally excreted in urine
- low solubility
- high blood uric acid levels (hyperurecemia) , mono sodium urate precipitates in joint(synovial) fluid causing arthritis (gouty arthritis)- ‘Needle shaped crystals’
- Monosodium urate deposits in soft tissues as ‘tophi’
- Renal stones of uric acid
Explain the formation of uric acid
- AMP (nucleotide) converted to adenosine (nucleoside)
- Adenisine (adenine-ribose) is deaminase (removal of ammonia to form inosine (hypoxanthine-ribose) by adenosine deaminase
- Ribose is formed by purine nucleoside phosphorylase (PNP) to form hypoxanthine (purine base)
- Hypoxanthine—> Xanthine—> uric acid by xanthine oxidase
- Guanine—> xanthine by guanase and later forms uric acid by xanthine oxidase
End product of purine degradation (adenine, hypoxanthine, and guanine)
Blood uric acid levels are close to saturation limits
Summarize dietary nucleic acids and purine bases
- Dietary nucleic acids (DNA and RNA) in meat/ beer digested to free purine bases in intestine
- Dietary purine bases directly form uric acid and excreted in ursine (not reused by salvage path2ay)
- Patuents with hyperurecemia advused to modify diet and reduce nucleic acid (dietary purine content)-Avoid meat and beer
Explain hyperurecemia due to Underecxretion
- Uric acid levels in blood close to saturation point
- Blood uric acid levels above 6.8 mg/dL
- Monosodium urate crystals in joints and soft tissues-Gout
- Hyperurecemia May be caused by
- underexcretion of uric acid (more common)
- cause not def8ndd- makes and obesity (more common)
- renal disease
- lactic acidosis (urate competes with lactate fir excretion)
- overproduction of uric acid
Explain hyperurecemia by overproduction of uric ac8d
-Idiopathic (cause not known) - males and obesity (risk factors)
- PRPP synthetase gene mutations (increased Vmax and decreased Km) leads to elevated PRPP concentrations (activator of purine synthesis) - overactive enzyme
- Excessive tumor of purines
-HGPRT Deficiency (Lisch-Nyhan syndrome)—> less recycling (salvage) of purine bases and elevated PRPP concentrations —> stimulates purine biosynthesis —>. Increased DNA and RNA breakdown)
Inherited disorders: Von Gierke’s disease, hereditary fructose intolerance
Describe the management of hyperurecemia
-Colchicine and anti-inflammatory agents like (NSAID and cortisol) reduces pain and inflammation
Urate lowering therapy (lower uric acid levels)
- Allopurinol (hypoxanthine analog) converted to oxypurinol
- Non-competitive irreversible inhibitor
- Hypoxanthine and xanthine more soluble than urate - Febuxostat (xanthine oxidase inhibitor)
Increase uric acid excretion (uricosuric agent ) probenecid
Decrease meat and alcohol
-dietary bases form uric acid
Explain the effect of adenosine deaminase deficiency (SCID)
Inherited disorders of purine degradation
- A 4 month old male /female. With a 2. Monthhustry 9f persistent cough
- Antibiotics but no 8mprovement
- Respiratory distress due to pneumonia
- Serum immunoglobin levels very low
- T and B cell function severely compromised
- Autosomal recessive SCID
Explain the effect of ADA deficiency
- adenosine deaminase (ADA) deficiency affects lymphocytes
- Adenosine accumulates—> hincreased (dATP) levels —> inhibits ribonucleotides reductase—> reduced lymphocyte cell division
- Decrease T-cell and B-cell immunity
- Repeated infections, fatal, life threatening infections
Treatment: enzyme replacement or bone marrow
Gene therapy successful
Explain purine nucleoside phosphorylase defuc7ency
- Inherited deficiency of PNP (purine degradation) less common
- less severe immunodeficiency involving T cells
- repeated infections
- Lab tests ind8cate T-cell deficiency
What 8s th3 function 9f thiopurine methyl transferase?
It catalyzes a methylation reaction to inactivate a drug- this c9nvetts meracptourine to inactivated form
Mercaptourine is metab9lized to compounds that inhibit synthesis of purine
Thiopurine methyltransferase enzyme is encoded by the TPMT gene (this figure is wrong, check DLA
Summarize pyrimidine biosynthesis
Pyrimidine bases
-uracil (RNA), cytosine, thymine (DNA)
Donors of C and N atoms for pyrimidine are
Aspartate, glutamine and CO2
Thymidine synthesis requires methylene tetrahydrofolate (THF)
Pyrimidine ring is initially assembled, and ribose- phosphate added later (compare to purine biosynthesis)
One carbon needed for thymidine biosynthesis
How is pyrimidine biosynthesis regulated?
- CPS-II (carbamoyl phosphate synthetase-II) regulatory step (compare to CPS-I of urea cycle)
- CPS-II inhibited by UTP (endproduct) by feedback inhibition
- CPS-II activated by ATP (ensures equal concentration of purines and pyrimidine nucleotudes) and PRPP
- OPRT and OMP decarboxylase (UMP synthase)
How is CTP formed?
- UTP forms CTP by CTP synthetase
- Uracil and cytosine (UDP and CDP() synthesized in ribonucleotide form
- CDP and UDP form de9cy ribonucleotides by ribonucletide reductase
Explain thymidine synthesis
- Thymidine monophosphate synthesized from dUMP by thymidykate synthase
- remember dna doesn’t have uracil
- Reqquires methylene tetrahydrofolate (THF) - one car in donor
- Methylene tetrahydrofolate converted to dihydrofolate
- Dihydrofolate converted THF by dihydrifilate reductase
- dTMP: ONLY pyrimidine that needs methylene tetrahydrofolate
Explain anticancer drugs that inhibit thymidine synthesis
- 5 fluorouracil converted to 5 fluoro- dUMP
- irreversibly binds thymidykate synthase and inactivates it (suicide inhibitor)
-folate analog (methotrexate) competitively inhibits dihydrifilate reductase and prevents THF formation
(Methotrexate inhibits purine abs thymidine biosynthesis )
