Catabolism of Purine Nucleotides PDF

Catabolism of Purine Nucleotides DR:ADIL KHALIL  1 n Orotic acid would be an intermediate n A. Synthesis of guanine B. Synthesis of uracil n A. A only n B. B only n C. Both A and B n D. Neither A or B  2 n T...

Catabolism of Purine Nucleotides DR:ADIL KHALIL  1 n Orotic acid would be an intermediate n A. Synthesis of guanine B. Synthesis of uracil n A. A only n B. B only n C. Both A and B n D. Neither A or B  2 n The following enzymes are involved in the catabolism of AMP to uric acid. The correct order of their use is: 1. A deaminase 2. A nucleoside phosphorylase 3. A nucleotidase 4. Xanthine oxidase n A. 1, 2, 3, 4. n B. 1, 3, 2, 4 n C. 1, 4, 2, 3 n D. 3, 2, 1, 4 n E. 3, 1, 2, 4  3 n The major control of de novo pyrimidine nucleotide synthesis in man is: n A. feedback inhibition of glutamine-PRPP amidotransferase. n B. feedback inhibition of aspartate transcarbamylase. n C. availability of N-acetyl glutamate. n D. substrate availability. n E. competitive inhibition of carbamoyl phosphate synthetase II.  4 n Which of the following would NOT be expected to contribute to hyperuricemia (gout)? n A. Unusually high levels of PRPP n B. Inhibition of xanthine oxidase n C. Unusually high turnover of nucleic acids n D. High activity of adenosine deaminase n E. Deficiency of HG-PRT  5 n Direct sources of purine ring atoms in the de novo synthesis of IMP include: 1. glutamine. 2. a component of the tetrahydrofolate one- carbon pool. 3. aspartate. 4. glycine. n A. 1, 2 and 3 n B. 1 and 3 n C. 2 and 4 n D. 4 only n E. All four n Three enzymes n 1. Deaminase …. To remove the amino group n Adenine …..inosine , Guanine ……xanthine n 2. Nucleosidase ……. To remove p n GMP …….Guanosine (nucleoside) n 3.Phosphorylase ……to remove the ribose n Guanosine ….. Guanine Disorders of Purine Metabolism -severe combined immunodeficiency syndrome due to defect in a denosine deaminase enzyme characterized by deficiency in B and T lymphocyte.the baby should stay in sterile media all his life.  Severe Combined Immunodeficiency Syndrome (SCIDS). Purine degradation defect. Fatal disorders due to defects in cellular and humoral immune function in patients with autosomal recessive form of the disorder. Adenosine deaminase and nucleoside phosphorylase enzyme deficiency = > accumulation of adenosine, deoxyadenosine, and dATP, and ATP depletion in the lymphoid tissue. Lymphocyte function compromised. Conclusion: the purine normal metabolism pathway is critical for normal immune system function. Disorders of Purine Metabolism n Gout: n Metabolic disease. n This clinical condition is characterized by Hyperuricaemia (Hyperuricaemia is the biochemical finding). n The normal serum uric acid is: 3-9 mg/dL in ♂ 2-7 mg/dL in ♀ Causes of hyperuricaemia: 1. Uric acid production: 2. Uric acid excretion (chronic renal disease, lactic acidosis, drugs). 3. PRPP synthase defects: 4. HGPRT deficiency. 5. Von Gierke disease  Over-activity X-linked Gout PRPP synthase ( Vmax) recessive Resistance X-linked Gout PRPP synthase to feedback recessive inhibition Low km for Probably X- Gout PRPP synthase ribose-s-p linked recessive Partial X-linked Gout HGPRTase deficiency recessive Lesch-Nyhan Complete X-linked HGPRTase Syndrome deficiency recessive Immunodefic- Severe Autosomal Adenosine deaminase iency deficiency recessive Complete Autosomal Xanthinuria Xanthine oxidase deficiency recessive HGPRT deficiency: 1. Partial. 2. Complete (Lesch-Nyhan Syndrome HGPRT deficiency leads to hyperuricaemia via three mechanisms PRPP PPi H IMP HGPRT G GMP PRPP PPi n Accumulation of hypoxanthine and guanine à enter the catabolic pathway. n Accumulation of the 2nd substrate PRPP à Enter De Novo synthesis of purines à Production of purines à catabolism of purine à Uric acid formation. n Low IMP and low GMP à loss of negative feed back inhibition on PRPP synthase and PRPP glutamyl amido-transferase à increase purine biosynthesis. Patients with complete deficiency of HGPRT presents with Lesch-Nyhan Syndrome n The pt. present with mental retardation, spastic paraplegia, choreoathetosis and self-mutilation  Von Gierke’s Disease n Impairment of glycogenolysis and gluconeogensis. n Hepatomegaly (enlarged liver). n Biochemical findings: n Hypoglycaemia (especially fasting hypoglycaemia hypoglycaemia occur in early morning). n Hyperlipidaemia n Ketosis n Lactic acidosis (impaired gluconeogensis)  Conversion of G-6-P to Glucose n Enzyme: Glucose-6-Phosphatase n No ATP used n Hyperuricaemia (accumlation of glucose- 6-p enter ppp production of Ribose-5-p Nucleic acid synthesis Nucleic acid catabolism Uric acid production). n Increased production of uric acid can be secondary to leukaemia, cancer and psoriasis. n Decreased urate excretion follows chronic renal diseases, lactic acidosis, drugs (e.g. Diuretics).  Pathogenesis of Gouty Inflammation n Urate crystals stimulate the release of numerous inflammatory mediators in synovial cells and phagocytes n The influx of neutrophils is an important event for developing acute crystal induced synovitis n Chronic gouty inflammation associated with cytokine driven synovial proliferation, cartilage loss and bone erosion n Symptoms and signs of gout result from tissue deposition of monosodium urate crystal in soft tissues and joints. n Major clinical manifestations include: 1- Acute gouty arthritis. 2- Chronic gouty arthritis. 3- Nephrolithiasis and urolithiasis. 4- Chronic renal disease (hyperuricaemic nephropathy Non- Pharmacologic Treatments n Immobilization of Joint n Ice Packs n Abstinence of Alcohol n Consumption can increase serum urate levels by increasing uric acid production. When used in excess it can be converted to lactic acid which inhibits uric acid excretion in the kidney n Dietary modification n Low carbohydrates n Increase in protein and unsaturated fats n Decrease in dietary purine-meat and seafood. Dairy and vegetables do not seem to affect uric acid  Pharmacological treatment n Urate Lowering drugs n Goal is for serum urate concentration to 6mg/dL or less n Start of therapy can precipitate acute attack; therefore, may need to use colchicine as a long as six months n Xanthine oxidase inhibitors n Allopurinol: blocks conversion of xanthine to uric acid. n Start typically 300mg/day and titrate weekly 100mg/day until optimal urate levels achieved. n Start lower doses with renally impaired patients n Uricosuric drugs n Probenecid or Sulfinpyrazone: increase renal clearance of uric acid by inhibiting tubular absorption  Problem (1) n A six year old boy presented with mental deficiency, choreoathetosis, spastic paraplegia and aggressive tendency to bite his fingers and lips. Questioning revealed family history of similar condition. n Investigations showed: n Hb 12 g/dl, TWBCs 4000, ESR 13, Blood urea 25 mg/dl, serum uric 15 mg/dl. n Questions: n discuss  Problem (2) n A pt suffering from leukaemia (cancer of the WBC) was put on chemotherapy followed by radio-therapy in the hope of producing a remission (improvement of signs and symptoms). Treatment is intended primarily to check the rapid cell division and it usually results in the breakdown of large numbers of WBC. The table below shows some investigations carried out in on this pt before, during and 3 weeks after the anticancer treatment.  WBC 10- Serum uric Blood urea Hb (%) 9 /mm2 acid mg/dl mg/dl Before 40 250000 8.0 30 treatment During 40 250000 14.0 35 treatment After 60 50000 16.0 150 treatment (a) How is uric acid produced in the human body? (b) Explain in biochemical terms the changes observed in uric acid level in this patient (c) Account for the change in the urea level after treatment (d) What other condition do you know in which a high blood uric acid is observed?