Purine Metabolism Lecture Notes PDF

Lippincott’s illustrated reviews Chapter 22, Page 289 Lecture 3-4 Purine Metabolism 1  Specific Objectives By the end of this lecture students can be able to: Differentiate between de-novo synthesis and salvage of purine nucleotides. Follow th...

Lippincott’s illustrated reviews Chapter 22, Page 289 Lecture 3-4 Purine Metabolism 1  Specific Objectives By the end of this lecture students can be able to: Differentiate between de-novo synthesis and salvage of purine nucleotides. Follow the degradation pathways of purine nucleotides. Discuss some disorders in purine metabolism. 2  Synthesis Of Deoxyribonucleotides The nucleotides required for DNA synthesis, however, are 2'-deoxy -ribonucleotides, which are produced from ribonucleoside diphosphates by the enzyme ribonucleotide reductase. Most important Which enzyme is 3 Important Enzymes: Ribonucleotide reductase (inhibited by hydroxyurea). Thymidylate synthase (enzyme required in pyrimidine synthesis) (inhibited by 5-fluorouracil). Dihydrofolate reductase (inhibited by methotrexate (euk), trimethoprim 4 (prok), pyrimethamine (protozoa)). 5  Clinical Significance of synthetic inhibitors of purine synthesis Sulfonamides are designed to inhibit the growth of rapidly dividing microorganisms without interfering with human cell functions. 6  Sulfonamides (sulfa drugs) are structural analogs of para- aminobenzoic acid (PABA) that competitively inhibit bacterial synthesis of folic acid by inhibition of dihydropteroate synthase enzyme. Humans cannot synthesize folic acid, and must depends on external sources of this vitamin. Therefore, sulfa drugs do not interfere with human purine synthesis. 7  Methotrexate I It is structural analogs of folic acid used pharmacologically to control the spread of cancer by interfering with the synthesis of nucleotides by inhibition of dihydrofolate reductase and, therefore, of DNA and RNA. 8  Salvage pathway for purines Purines that result from the normal turnover of cellular nucleic acids can be converted to nucleoside triphosphates and used by the body. 9 10 o  Conversion of purine bases to nucleotides Two enzymes are involved: adenine phospho-ribosyl transferase (APRT) and hypoxanthine-guanine phospho-ribosyl transferase (HGPRT). Text Both enzymes use PRPP as the source of the ribose 5-phosphate group. 11  Lesch-Nyhan syndrome This syndrome is a rare, X-linked, recessive disorder associated with a virtually complete deficiency of HGPRT. This deficiency results in an inability to salvage of hypoxanthine and guanine, from which excessive amounts of uric acid, the end product of purine degradation, are produced. Lesch-Nyhan a heritable cause of hyperuricemia. 12  In patients with Lesch-Nyhan syndrome, the hyperuricemia (juvenile gout) frequently results in the formation of uric acid stones in the kidneys (urolithiasis) and the deposition of urate crystals in the joints and soft tissues. In addition, the syndrome is characterized by motor dysfunction, cognitive deficits, and behavioral disturbances that include self-mutilation (biting of lips and fingers). 13 14  Degradation of purine nucleotides Purine nucleotides from de novo synthesis are degraded in the liver primarily. The free bases are sent out from liver and salvaged by peripheral tissues. Degradationbof dietary nucleic acids occurs in the small intestine, where a family of pancreatic enzymes hydrolyzes the nucleic acids to nucleotides. 15 16  Inside the intestinal mucosal cells, purine nucleotides are sequentially degraded by specific enzymes to nucleosides and free bases, with uric acid as the end product of this pathway. Dietary purine bases are not used to any appreciable extent for the synthesis of tissue nucleic acids. Instead, they are generally converted to uric acid in intestinal mucosal cells. Most of the uric acid enters the blood, and is eventually excreted in the urine. 17  Importance of Uric acid Uric acid levels in the blood must be close to the saturation point not less because uric acid has many benefits. Uric acid may exert fundamental roles in tissue healing via initiating the inflammatory process that is necessary for tissue repair, scavenging oxygen free radicals (strong antioxidant ), and mobilizing progenitor endothelial cells. 18  Diseases associated with purine degradation I- Hyperuricemia The causes of this disorder refer to:  Excessive cell death.  Excessive alcohol consumption.  Excessive dietary nucleic acid.  Underexcretion by kidney. Genetic disease as:  Lesh-Nyhan syndrom  Glucose-6-phosphatase deficiency  Galactose uridyltransferase deficiency.  Fructose-1-P aldolase deficiency 19 Gout: Gout is a disorder characterized by high levels of uric acid— the end product of purine catabolism—in blood (hyperuricemia), as a result of either the overproduction or underexcretion of uric acid. 20  The hyperuricemia can lead to the deposition of monosodium urate crystals in the joints, and an inflammatory response to the crystals, causing first acute and then progressing to chronic gouty arthritis. 21  Nodular masses of monosodium urate crystals (tophi) may be deposited in the soft tissues, resulting in chronic tophaceous gout. Formation of uric acid stones in the kidney (urolithiasis) may also be seen. 22 Diagnosis of gout requires aspiration and examination of synovial fluid from an affected joint (or material from a tophus) using polarized light microscopy to confirm the presence of needle-shaped monosodium urate crystals. 23 Treatment of gout: Long-term therapeutic strategies for gout involve lowering the uric acid level below its saturation point, thereby preventing the deposition of urate crystals. Use of recombinant Urate oxidase is a potential therapeutic strategy to lower urate levels. [Note: Uric acid levels in the blood normally are close to the saturation point. One reason for this may be the strong antioxidant effects of uric acid.] 24  II- Hypouricemia 1- Xanthine Oxidase Deficiency (Xanthinuria) It is a genetic defect. Characteristic features are hypouricemia and liver damage. Patients often display renal symptoms because they excrete a large amounts of xanthine in urine. High-fluid-intake, allow-purine-food, and alkalization of urine are effective in this patients. 25 Freatment 26 2- Adenosine deaminase (ADA) deficiency ADA is expressed in a variety of tissues, but, in humans, lymphocytes have the highest activity of this cytoplasmic enzyme. A deficiency of ADA results in an accumulation of adenosine and deoxyadenosine, consequently, cells cannot make DNA and divide. In its most severe form, this autosomal recessive disorder causes a type of severe combined 0 immunodeficiency disease (SCID), involving a decrease in27 T cells, B cells, and natural killer (NK) cells. 28 29 30 Treatment Antibiotics and periodic injections of immunoglobulin will be life saving. Enzyme replacement therapy (ERT): Weekly intramuscular injections of bovine ADA were found to be beneficial. bone marrow transplantation (BMT): Bone marrow stem cells will increase both T and B cells in the patients. Without appropriate treatment, children with this disorder usually die by the age of two. 31 Reference Book: Champe, P. C., Harvey, R. A. and Ferrier, D. R., 2005. Biochemistry “Lippincott’s Illustrated Reviews”, 5th or 6th Edition 32