Metabolismo de Purinas_2025_Luis Alvarez_Biomoleculas 2
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Curso biomoleculas 2 de Ácidos Mucleicos para la Maestría en Genética y Biología Molecular. Dr. Luis Marat Alvarez Salas
Metabolismo de Purinas_2025_Luis Alvarez_Biomoleculas 2
- 1. METABOLISMO DE PURINAS BIOMOLÉCULAS II DR. LUIS MARAT ALVAREZ SALAS [email protected]
- 2. Biosynthesis of purine and pyrimidine nucleotides • Dietary purine and pyrimidine bases (nucleoproteins) are poorly absorbed and cannot be used for synthesis • Humans depend on the endogenous synthesis of purines and pyrimidines • All cells needs ribonucleosides, deoxyribonucleosides and their phosphates
- 4. Nucleotide Functions ATP drives innumerable energy-requiring functions GTP is used in protein synthesis UTP is used to activate sugars during polysaccharide synthesis CTP is used to activate precursors during lipid biosynthesis AMP is part of the structure of coenzymeA, NAD, NADP Signal transduction (GTP, cAMP) They are the building blocks of nucleic acids!
- 6. N N N H N NH2 adenine N H N N H N O hypoxanthine N H N N H N O N H2 guanine N H N H N O O N H xanthine Purine molecules
- 10. Significance of folic acid for synthesis of bases Folát Green food, liver, food yeast, egg yellow The effective form in organism of human is tetrahydrofolate C O – O C O O – CH2 CH2 CH NH C O NH C H2 H N N N OH N N H2
- 11. C O – O C O O – CH2 CH2 CH NH C O NH C H2 H N H N H N OH N N H2 C O – O C O O – CH2 CH2 CH NH C O NH C H2 H N H N N OH N N H2 (dihydro)folate reductase catalyzes both reactions in animals and some microorganisms folate tetrahydrofolate dihydrofolate NADPH + H+ NADP NADP NADPH + H+ Formation of tetrahydrofolate + +
- 12. THF Synthesis
- 14. N-5,N-10- methylen H4F – synthesis of thymine N-10-formyl H4F – synthesis of purine Using of tetrahydrofolate in synthesis of purines and pyrimidines N C H2 N N H2 C O – O CH2 CH2 CH C O O – NH C O C H2 H N H OH N N CH O N N H2 C O – O CH2 CH2 CH C O O – NH C O C H2 H N H N H OH N N
- 15. Ribose-5P + ATP PRPP + AMP PRPP-synthase Synthesis of phosphoribosyl diphosphate (PRPP) (kinase) P O O – O – P O O – O H O H O O P O – O – O
- 21. Atom assembly of purine rings
- 23. Synthesis of AMP and GMP (more detailed) IMP Asp GT P GDP + Pi fumarate AMP NAD+ NADH + H+ ATP AMP + PPi XMP GMP Gln Glu H2O N N O N N Ribose H P N N N CH CH2COO COO N N Ribose P - - N N NH2 N N Ribose P N N O O N N Ribose H P N N O H2N N N Ribose H P H H
- 29. Disorder Defect Nature of Defect Comments Gout PRPP synthetase increased enzyme activity due to elevated Vmax hyperuricemia Gout PRPP synthetase enzyme is resistant to feed-back inhibition hyperuricemia Gout PRPP synthetase enzyme has increased affinity for ribose-5-phosphate (lowered Km) hyperuricemia Gout PRPP amidotransferase loss of feed-back inhibition of enzyme hyperuricemia Gout HGPRTa partially defective enzyme hyperuricemia Lesch-Nyhan syndrome HGPRT lack of enzyme SCID ADAb lack of enzyme Immunodeficiency PNPc lack of enzyme Renal lithiasis APRTd lack of enzyme 2,8-dihydroxyadenine renal lithiasis Xanthinuria Xanthine oxidase lack of enzyme hypouricemia andxanthine renal lithiasis von Gierke's disease Glucose-6-phosphatase enzyme deficiency aHypoxanthine-guanine phosphoribosyltransferase; badenosine deaminase; cpurine nucleotide phosphorylase; dadenosine phosphoribosyltransferase
- 31. GOUT Primary Gout: Enzyme defect Secondary Gout 1.Over production of Uric acid (Cancer, Starvation,alcohol) 2.Decreased excretion of uric acid (renal failure, Lactic acidosis, alcohol)
- 32. GOUT Symptoms: Arthritis of Metatarsophalangeal joint Precipatated by high purine diet & alcohol Tophi – chronic cases Treatment: Decreased purine intake Allopurinol- xanthine oxidase inhibitor Probenacid – uricosurics Colchicine – anti inflammatory
- 33. LESCH- NYHAN SYNDROME X – linked disorder HGPRTase deficiency Self mutilation, mental retardation, nephrolithiasis
- 35. Inhibitors of purine synthesis (antineoplastic agents) • inhibitors of dihydrofolate reductase • glutamine analogs (azaserine) • 6-mercaptopurine- inhibition of conversion of IMP to AMP and GMP N N SH N N H mercaptopurine
- 36. PURINE NUCLEOTIDE ANALOGS Used as Anti cancer agents: Mercaptopurine Methotrexate Azaserine 6-TG (thioguanine) 8 AG (Azaguanine)
- 38. Mycophenolic acid Potent, reversible, uncompetitive inhibitor of IMP dehydrogenase Used in preventing graft rejection It blocks de novo formation of GMP supress the proliferation of T and B cells O O O OH O O H CH3 CH3 C H3