Lecture 5 Purine catabolism & Gout (CBL) PDF

Faculty of Medicine Academic Year: 2024-2025 Year: 1 Semester: 1 Module: BLOOD and body fluids (blf) 103 Purine catabolism & gout By: Dr. Marwa Ali Assistant Professor of Medical Biochemistry and Molecular Biology Ain Shams university Medica...

Faculty of Medicine Academic Year: 2024-2025 Year: 1 Semester: 1 Module: BLOOD and body fluids (blf) 103 Purine catabolism & gout By: Dr. Marwa Ali Assistant Professor of Medical Biochemistry and Molecular Biology Ain Shams university Medical Biochemistry and Molecular Department: Biology 05/01/2025 2  Objectives By the end of this lecture the student will be able to: 1. Illustrate steps of purine catabolism 2. Demonstrate causes of hyperuricemia 3. Interpret biochemical basis of gout and its treatment 4. Correlate purine metabolism with immune diseases 3  Catabolism of Purine nucleotides 1-Dietary purine nucleotides are degraded to Uric Acid in intestinal mucosal cells. 2- Degradation of cellular nucleic acids after cell death or degradation of unstable RNA  Uric acid is the final product of human purine degradation and it is excreted in urine 2,6,8 tri-oxy-purine  AMP IMP GMP (remove phosphate group) (- P) (- P) Nucleosides Nucleosides Nucleosides (Adenine+ Ribose) (Hypoxanthine+ Ribose) (Guanine +Ribose) (remove amino (remove sugar group) group in form of Ribose1-p) Hypoxanthine Guanine Xanthine oxidase deaminase Xanthine Xanthine oxidase Uric acid Xanthine oxidase  Normal serum uric acid Male 3-7 mg/dl Female 2-6 mg/dl Exceeding normal level = Hyperuricemia  GOUT Is a disorder characterized by high level of uric acid Under-excretion Over-production Of uric Acid Of uric Acid 1- Under-excretion of uric acid Is the main cause in most patients with gout: 1- Inherited Excretory defect of the kidney 2- Excessive consumption of ethanol Because it decreases excretion of uric acid.  GOUT 2-Over-production of uric acid A-Primary Defect of one or more of enzymes of purine synthesis 1- Genetic defect of PRPP synthetase ( responsible for purine synthesis) So purines are synthesized in excess and degraded to uric acid 2-Lesch- Nyhan syndrome: a genetic defect in HGPRT leads to inability to reuse purines and so they are degraded to uric acid.  Lesch-Nyhan syndrome symptoms LNS is an X-linked recessive disease 1. Abnormally increased levels of uric acid 2. Mental retardation and neurological symptoms 3. Self-mutilating behaviors such as lip and finger biting and/or head banging.  In infants : Earlier urate crystal formation, due to increased levels of uric acid in the urine, leads to the presence of orange colored deposits (“orange sand”) in the diapers of infants with this disorder. This may be the first manifestation of Lesch-Nyhan syndrome, B-Secondary a cause outside the pathway of purine synthesis 1-Increase nucleic acids in diet by eating excess meat. 2-Increased cellular breakdown as in malignancy & treatment with anticancer drugs that destroy cancer cells. 3-Von-Gierke disease:a genetic disease (glucose 6- phosphatase deficiency )  Gout (hyperuricemia) Clinical picture : Arise from low solubility of uric acid in body fluids, so insoluble sodium Urate crystals precipitate into: joints kidneys soft tissues  1-Joints Deposition of needle shaped urate crystals in joints causing sever inflammation (gouty arthritis).  The big toe joint is most commonly affected. But the joints of the feet, ankles, knees, wrists, fingers, and elbows may also be involved. Acute attacks may be accompanied by fever. The joints are swollen, red , hot & painful  2-Kidney Deposition of sodium urate crystals in the kidney causing uric acid stones.  3- Soft tissue Nodular masses of sodium urate crystals (tophi) may be deposited ,under the skin. : The goals of treatment for gout are 1-Rapid pain relief in acute attacks. Prevention of future gout attacks and the -2 complications by decreasing formation.of uric acid 1-Acute attacks  Analgesics & anti-inflammatory  Cholchicine decreases movement of granulocytes into affected area 2-Xanthine oxidase inhibitors (Allopurinol): it is an analogue of hypoxanthine and acts as an competitive inhibitor to Xanthine Oxidase resulting into accumulation of hypoxanthine which is more soluble than uric acid It is used for long term therapy of gout 3-Decrease Uric acid level -Alkalinization of urine can increase solubility of uric acid in urine. 4-Dietry therapy Avoid purine rich foods: Red meat and liver Peas ,beans and lentils Beer & alcoholic beverages Coffee (contains xanthine) DRINK A LOT OF WATER  Advise the patient to eat Plenty of Fruits because they tend to have very few purines.  Case A 42-year-old male patient undergoing radiation therapy for prostate cancer develops severe pain in the metatarsal phalangeal joint of his right big toe. Monosodium urate crystals are detected by in fluid obtained from this joint. Uric acid crystals are present in his urine. This patient’s pain is directly caused by the overproduction of the end product of which of the following metabolic pathways? A. De novo pyrimidine biosynthesis. B. Pyrimidine degradation. C. De novo purine biosynthesis. D. Purine salvage. E. Purine degradation. What is the relation of radiation of this case? Radiation therapy caused cell death, with degradation of nucleic acids and their constituent purines  Adenosine deaminase deficiency ADA irreversibly deaminates adenosine, converting it to the related nucleoside inosine. Cells cannot make DNA and can’t divide In its sever form it affects T and B lymphocytes (sever combined immune-deficiency disease “SCID”) Symptoms of ADA deficiency Symptoms develop symptoms before 6 months of age. The earliest symptoms of ADA deficiency include pneumonia, chronic diarrhea, widespread skin rashes, developmental delay.  Purine nucleoside phosphorylase (pnp) deficiency This autosomal recessive deficiency is rarer and less severe than ADA deficiency. Affects only T-cells. Characterized by recurrent infections and neurodevelopmental delay.  MCQ Allopurinol is used in treatment of gout as it: A. Increases secretion of uric acid B. Is competitive analogue to hypoxanthine. C. Decreases activity of PRPP. D. Decreases urinary reabsorption of uric acid. E. Is competitive analogue to Adenine. Gout CBL  One painful joint Kareem is a 45-year-old man. He went to the clinic urgently complaining of a painful joint in his foot. Kareem said that the pain started 2 days ago and the joint is red and swollen Drug history: Thiazide Family history: irrelevant On Examination: Vital signs were normal ie. he is afebrile. No rash Joint exam: see the photo How can you reach a final diagnosis? (Investigations)  One painful joint The doctor asked Kareem to do CBC ESR C reactive protein Serum uric acid Results showed: ESR: 60 mm/hr White blood cell count: 14000/mm3 CRP: 24 Serum uric acid: 10 mg/dl Interpret Mild elevated: White blood cell count, ESR, CRP. = Inflammation Serum uric acid is elevated. = Acute Gouty Arthritis What are main causes of increased level of uric acid?  Hyperuricemia 1- Under-excretion of uric acid Is the main cause in most patients with gout: 1- Inherited Excretory defect of the kidney 2- Excessive consumption of ethanol Because it decreases excretion of uric acid.  Hyperuricemia 2-Over-production of uric acid A-Primary Defect of one or more of enzymes of purine synthesis 1- Genetic defect of PRPP synthetase (responsible for purine synthesis) So purines are synthesized in excess and degraded to uric acid 2-Lesch- Nyhan syndrome: a genetic defect in HGPRT leads to inability to reuse purines and so they are degraded to uric acid.  B-Secondary a cause outside the pathway of purine synthesis 1-Increase nucleic acids in diet by eating excess food rich in purines.. 2-Increased cellular breakdown as in malignancy & treatment with anticancer drugs that destroy cancer cells. 3-Von-Gierke disease:a genetic disease (glucose 6- phosphatase deficiency ) 4- Some drugs as thiazides: “thiazides” reduce the clearance of uric acid since they compete for the same transporter, and therefore raise the levels of uric acid in the blood  What are the pathological changes that result from gout?  GOUTY ARTHRITIS Etiology: Disturbance in purine metabolism increase in serum uric acid deposition of sodium urate crystals in tissues Primary gout: (known or unknown enzyme defect) heridetary predisposition Secondary gout: Due to excess nucleoprotein destruction as in chronic myeloid leukaemia GOUTY ARTHRITIS Tophus GOUTY ARTHRITIS  GOUTY ARTHRITIS Gouty nephropathy:  Tophi in the interstitial tissue of the kidney  Uric acid/ urate stones in the renal pelvis and calyces  Renal failure may occur How can manage Kareem ? 1-Acute attacks  Analgesics & anti-inflammatory  Cholchicine decreases movement of granulocytes into affected area  NSAID used as analgesic and anti-inflammatory 2-Xanthine oxidase inhibitors (Allopurinol): it is an analogue of hypoxanthine and acts as an competitive inhibitor to Xanthine Oxidase resulting into accumulation of hypoxanthine which is more soluble than uric acid It is used for long term therapy of gout 3-Decrease Uric acid level -Alkalinization of urine can increase solubility of uric acid in urine. 4-Dietry therapy Avoid purine rich foods: Red meat and liver Peas ,beans and lentils Beer & alcoholic beverages Coffee (contains xanthine) DRINK A LOT OF WATER  Advise the patient to eat Plenty of Fruits because they tend to have very few purines.  References 1- "Lippincott's Illustrated Reviews in Biochemistry" by P.C.Champe, R.A.Harvey and D.R.Ferrier 2- "Harper's Biochemistry" by R.K.Murray, D.K.Granner, P.A. Mayes and V.W.Rodwell. 52 Marwa Ali