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Purine & pyrimidine metabolism and disorders
Purine and pyrimidine nucleotides play important roles in the body, including forming DNA and RNA and acting as carriers of energy and active intermediates. There are two pathways for nucleotide synthesis: de novo synthesis starting from metabolic precursors, and salvage pathways that recycle bases from nucleic acid breakdown. IMP is an important intermediate that is converted to AMP and GMP. Defects in purine metabolism can cause disorders like gout, kidney stones, and Lesch-Nyhan syndrome. Orotaciduria is a pyrimidine synthesis disorder caused by a deficiency in orotate-phosphoribosyltransferase.
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Purine & pyrimidine metabolism and disorders
- 1. PURINE & PYRIMIDINE METABOLISM& DISORDERS By DR KHALED SALEH ALGARIRi 2014
- 2. FUNCTIONS OF NUCLEOTIDES Polymerizeto make DNA and RNA Energy currency of the cell e.g. ATP, GTP Act as carriers of active intermediates in various metabolic pathways e.g. UDP-glucose in glycogen synthesis, SAM Component of coenzymes e.g. FAD, NADH, NADPH Act as 2nd messengers e.g. cAMP and cGMP Allosteric regulation of various metabolic pathways e.g. ATP inhibits PFK-1
- 3. There are twopathways leading to nucleotides De novo synthesis: The synthesis of nucleotides begins with their metabolic precursors: amino acids, ribose-5-phosphate, CO2, and one-carbon units. Salvage pathways: The synthesis of nucleotide by recycle the free bases or nucleosides released from nucleic acid breakdown.
- 4. Once formed, IMPis rapidly converted to AMP and GMP (it does not accumulate in cells).
- 5. IMP Synthesis -Significance IMP = serves as a precursor for synthesis of all other purine nucleotides such as adenine and guanosine monophosphate (AMP & GMP)and ATP.
- 6. Salvage Pathways forPurine Synthesis Purine bases created by degradation of RNA and DNA and intermediate of purines synthesis can be directly converted to the corresponding nucleotides. The significant of salvage pathway 1- Save fuel 2- Some tissues and organs such as brain and bone marrow are only capable of synthesizing nucleotides by Salvage pathways Broken down endogenous nucleotides = salvage pathways. Purine salvage pathways us one of two enzymes. Adenine phosphoribosyltransferase (APRT). Converts free adenine to AMP Hypoxanthine-guanine phosphoribosultransferase (HGPRT). Converts hypoxanthine to IMP Converts guanine to GMP
- 7. Purine Salvage Pathway N NN N NH2 O Guanine N NN O N Hypoxanthine O OHHO 2-O3POH2C N N N O N IMP O OHHO 2-O3POH2C N NN N NH2 O GMP . . Adenine AMP PRPP PPi adenine phosphoribosyl transferase PRPP PPi hypoxanthine-guanine phosphoribosyl transferase (HGPRT) Absence of activity of HGPRT leads to Lesch-Nyhan syndrome.
- 8. INOSINE 5’- MONOPHOSPHATE(IMP) GMP synthetase ATP + Gln AMP + Glu Guanosine monophosphate (GMP) Fumarate Adenylosuccinase Adenosine monophosphate (AMP) Adenylosuccinate GTP + Asp GDP + Pi Adenylosuccinate synthetase NAD+ NADH IMP dehydrogenase Xanthine monophosphate (XMP)
- 9. DEGRADATION OF PURINENUCLEOTIDES Guanase NH3 Xanthine Xanthine oxidase Guanine Ribose 5’ Phosphorylase Ribose Hypoxanthine Uric Acid (excreted) Xanthine oxidase Adenosine deaminase IMPAMP deaminase AMP GMP Guanosine Pi5’ NucleotidasePi Inosine Pi Adenosine 5’ Nucleotidase IMP is the precursor for both AMP and GMP
- 10. DISEASES ASSOCIATED WITHDEFECTS IN PURINE METABOLISM HYPERURICEMIA GOUT LESCH-NYHAN SYNDROME KIDNEY STONES SEVERE COMBINED IMMUNODEFECIENCY (SCID)
- 11. HYPERURICEMIA Characterized by plasmaurate (uric acid) level greater than 7.0 mg/dL Normal plasma levels Females = 2.4 - 6 mg/dL Males = 3.4 - 7 mg/dL
- 12. HYPERURICEMIA •Primary Hyperuricemia: aninnate defect in purine metabolism and/or uric acid excretion •Secondary Hyperuricemia: increased availability of purines due to medications/ medical conditions or through diet.
- 13. GOUT Gout is causedby precipitation of sodium urate crystals in the joints resulting in inflammation and pain.
- 14. Progression of Hyperuricemiato Gout Stage 1: Asymptomatic hyperuricemia. At a serum urate concentration greater than 6.8 mg/dL, urate crystals may start to deposit in the joints. No evidence that treatment is required. Stages 2 : Acute gout. If sufficient urate deposits develop around joints, and if the local environment or some trauma triggers the release of crystals into the joint space, an inflammatory response occurs. These flares can be self-resolving but are likely to recur. Stage 3: Intercritical periods. These are the intervals between attacks. During these periods, crystals may still be present at a low level in the synovial tissue and fluid, resulting in future attacks. Stage 4: Advanced gout. If crystal deposits continue to accumulate, patients may develop chronically stiff, swollen joints and tophi. This advanced stage of gout is relatively uncommon generally avoidable with therapy.
- 15. Underexcretion of uricacid Diet rich in purines/alcohol; deficient in dairy products Increased purine degradation Increased PRPP Synthetase activity overproduction of PRPP = increased purine synthesis = increased purine degradation = increased uric acid production Decreased/partial HGPRT activity 1) Deficiency of HGPRT = increased HX and G 2) Deficiency of HGPRT = accumulation of PRPP = increased purine synthesis = increased uric acid levels 3) Deficiency of HGPRT = decreased IMP and GMP = decreased inhibitors for purine synthesis GOUT - Causes
- 16. Colchicine –reduces inflammation Allopurinol– inhibits uric acid synthesis Low purine diet - Foods that are high in purine include: Red meat and organ meats (eg. liver) Yeasts and yeast extracts (eg. beer and alcoholic beverages) Asparagus, spinach, beans, peas, lentils, oatmeal, cauliflower and mushrooms Avoid caffeine and alcohol Keep hydrated GOUT - Treatment
- 17. HN HC N C C C N H CH N O Hypoxanthine HN HC N C C C N H N H C O Allopurinol Allopurinol – asuicide inhibitor used to treat Gout Xanthine oxidase Xanthine oxidase
- 19.
- 20. Gout: accumulation of uricacid salts in joints
- 21. Gout: tophuses – accumulationof uric acid salts in cartilages, under skin.
- 22. KIDNEY STONES When uricacid is present in high concentrations in the blood, it may precipitate as a salt in the kidneys. The salt can form stones, which can in turn cause pain, infection, and kidney damage.
- 23.
- 24. Lesch-Nyhan Syndrom: isa inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase. LNS is present at birth in baby boys. Hypoxanthine and guanine are not used in the salvage pathway of purine nucleotides synthesis. Hypoxanthine and guanine are not utilizied repeatedly but converted into uric acid. Symptoms: - severe gout -severe mental and physical problems - self-mutilating behaviors
- 25. SEVERE COMBINED IMMUNODEFICIENCY (SCID) Adenosinedeaminase deficiency Accumulation of dATP = inhibition of ribonucleotide reductase =B and T cells unable to divide
- 26. Pyrimidine Ribonucleotide Synthesis UridineMonophosphate (UMP) is synthesized first CTP is synthesized from UMP Pyrimidine ring synthesis completed first; then attached to ribose-5-phosphate N1, C4, C5, C6 : Aspartate C2 : HCO3 - N3 : Glutamine amide Nitrogen
- 27. 2 ATP +HCO3 - + Glutamine + H2O CO O PO3 -2 NH2 Carbamoyl Phosphate NH2 C N H CH CH2 C COO O HO O Carbamoyl Aspartate HN C N H CH CH2 C COO O O Dihydroorotate HN C N H C CH C COO O O Orotate HN C N C CH C COO O O HH CH2 OH OH H H O O2- O3P Orotidine-5'-monophosphate (OMP) HN C N CH CH C O O HH CH2 OH OH H H O O2- O3P Uridine Monophosphate (UMP) 2 ADP + Glutamate + Pi Carbamoyl Phosphate Synthetase II Aspartate Transcarbamoylase (ATCase) Aspartate Pi H2O Dihydroorotase Quinone Reduced Quinone Dihydroorotate Dehydrogenase PRPP PPi Orotate Phosphoribosyl Transferase CO2 OMP Decarboxylase Pyrimidine Synthesis
- 28. UMP UTPand CTP Nucleoside monophosphate kinase catalyzes transfer of Pi to UMP to form UDP; nucleoside diphosphate kinase catalyzes transfer of Pi from ATP to UDP to form UTP CTP formed from UTP via CTP Synthetase driven by ATP hydrolysis Glutamine provides amide nitrogen for C4 in animals
- 29. UTP and CTPbiosynthesis UDP ADP UTP ATP ADP UMP ATP kinase kinase
- 30. Degradation of Pyrimidines CMPand UMP degraded to bases similarly to purines by Dephosphorylation Deamination Glycosidic bond cleavage Uracil reduced in liver, forming -alanine Converted to malonyl-CoA fatty acid synthesis for energy metabolism
- 31. OROTACIDURIA inherited disorder ofpyrimidine synthesis caused by a deficiency of the enzyme of orotate-phosphoribosyltransferase and decarboxylase. Symptoms: –excess of orotic acid and its excretion with urine (1.0-1.5 g) -mental and physical retardation -megaloblastic anemia
- 32. – Treatment: patientsare fed uridine U UMP UDP UTP UTP inhibits carbamoyl phosphate synthase II, preventing the biosynthesis and accumulation of orotic acid O OHOH CH2 O P O P O -O -O O- - O3PO O C NH O HN COOC C H C O PPi Orotate 5-phosphoribosyl-1-pyrophosphate (PRPP)
- 33.