Disorders of Purine Metabolism  Lecturer:     Dr. G. K. Maiyoh     Department of MedicalBiochemistry, School of Medicine, ...
Overview•   Introduction•   Purine (types)•   Purine functions•   Sources of purines•   Metabolic disorders•   Nucleotide ...
WHAT ARE PURINES?• Purines are heterocyclic  compound consisting of  a pyrimidine ring fused  to an imidazole Ring March 2...
Purines• Other minor purine base include:1. Xanthine2. Hypoxanthine3. Uric acid• The above occur in free state in the cell...
PURINES7 1,3-Dimethylxanthine(theophylline) found in   TEA8 3,7-Dimethylxanthine(theobromine)found in   COCOA9 1,3,7-Trime...
FunctionsKey functions include;Provision of Energy e.g. ATP, GTPBuilding blocks for DNA and RNA (along side  pyrimidines...
Sources of purineENDOGENOUS•       They may be synthesized DE NOVO  from small moleculesEXOGENOUS•        They may be deri...
Metabolic disorders of purines• They cover a broad spectrum of illnesses with  various presentations. Examples of  present...
Major Categories of Disorders    Two major types of disorders occur;          i.  Those that arise from a Blockage in puri...
Nucleotide degradation•   Nucleic acids can survive the acid of the stomach•   They are degraded into nucleotides by pancr...
Catabolism of purines                   ADA  Major pathways of purine   catabolism in animals.  March 21, 2013         GKM...
Catabolism of purines•Purine nucleotide degradation refers to a regulated series of reactionsby which purine ribonucleotid...
Uric Acid (2,6,8-trioxypurine) • This is the end product of purine metabolism in   humans • Accumulation of uric acid in b...
Excretion of uric acid• Uric acid is filtered through the glomeruli and most is  reabsorbed in the proximal tubules.• More...
Excretion of uric acid• 75% urate leaving the body is in urine• The remaining 25% passes into the intestinal  lumen,where ...
HYPERURICAEMIA• This is increase in blood levels of uric acid that  is greater than 0.42 mmol/l in men and more  than 0.36...
Conditions that lead to Increased         Uric acid Production      – Malignancies      – Reyes Syndrome      – Downs Synd...
Factors contributing to Hyperuraecimia• Increased synthesis of purines(primary Gout)• Secondary GOUT (Other disorder in wh...
Factors contributing to Hyperuraecimia• Sex(plasma uric acid is higher in male than  females)• Obesity (Obese people tends...
Other causes may include:• Eclampsia• Lead toxicity• Chronic alcohol ingestion• NOTE Hypouricaemia is not an important  ch...
Management of disorders     Management of disorders of purine nucleotide     degradation is dependent upon modifying the ...
Common treatment for gout: allopurinol      Allopurinol is an analogue of hypoxanthine that strongly inhibits      xanthin...
In born errors of Uric Acid Metabolism1. Phosphorybosylpyrophosphate synthase (PRS)   superactivity    There are two form;...
2. Adenylosuccinase deficiency      • Due to lack of the enzyme adenylosuccinate        lyase      • In general, affected ...
Disorders due to purine catabolismMarch 21, 2013           GKM/MUSOM/NSP 210:PATH.2012.2013   25
Myoadenylate Deaminase Deficiency• Also called muscle adenosine monophosphate  deaminase deficiency• This is a genetic dis...
Xanthine Oxidase Deficiency       (XANTHINURIA)• This is a rare hereditary disorder in which  there is a deficiency of liv...
Xanthine Oxidase Deficiency (Xanthinuria)•Xanthine oxidase deficiency, is an inheritedmetabolic disorder in which there is...
Adenosine Deaminase Deficiency   • This is a genetic disorder that impairs the immune        system and is the basis of se...
Disorders due to salvage pathway     A salvage pathway is a pathway in which nucleotides (Purine and     pyrimidine) are s...
Lesch-Nyhan Syndrome• Lesch-Nyhan syndrome is a metabolic disorder    caused by a deficiency of an enzyme (HPRT)    produc...
Gout• Characterised by the accumulation of  monosodium urate crystal deposits which  result in inflamation in joints and s...
Gout• Commonly monoarticular (Affecting the  metatarsophalangeal joint of the big toe.• However deposits of sodium urates ...
Figure 28-29 The Gout, a cartoon by James Gilroy (1799).Page 1097              Gout is a disease characterized by elevated...
Types of Gout• Primary Gout     – Occurrence: Middle aged men (mostly)     – Cause: Overproduction of Uric Acid           ...
Types of Gout• Secondary Gout      – Occurrence: Children      – Cause: other condition in which there is rapid        tis...
Other conditions that could lead togout• Any other condition that may lead to  either;      – Decreased uric acid clearanc...
Hereditary disorders associatedwith gout• These include 3 key enzymes resulting in  hyperuricemia• These are;      1. Seve...
Hereditary disorders associatedwith gout - cnt• 1st two are caused by hyperuricemia due to  purine nucleotide and uric aci...
Familial Juvenile Gout (Familial Juvenile     Hyperuricemic Nephropathy (FJHN)• Due to severe renal hypoexcretion of uric ...
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Disorders of purine metabolism

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The metabolism and associated disorders of purine metabolism

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Disorders of purine metabolism

  1. 1. Disorders of Purine Metabolism Lecturer: Dr. G. K. Maiyoh Department of MedicalBiochemistry, School of Medicine, MUMarch 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 1
  2. 2. Overview• Introduction• Purine (types)• Purine functions• Sources of purines• Metabolic disorders• Nucleotide degradation• Uric acid and hyperuricemia• In-born errors of Uric acid metabolism• Disorders due to purine catabolism• Disorders due to salvage pathwayMarch 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 2
  3. 3. WHAT ARE PURINES?• Purines are heterocyclic compound consisting of a pyrimidine ring fused to an imidazole Ring March 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 3
  4. 4. Purines• Other minor purine base include:1. Xanthine2. Hypoxanthine3. Uric acid• The above occur in free state in the cells4 N6 –Methyladenine5 N6 N6 Dimethyladenine6 N7-Methylguanine• Occur in mamalian RNAMarch 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 4
  5. 5. PURINES7 1,3-Dimethylxanthine(theophylline) found in TEA8 3,7-Dimethylxanthine(theobromine)found in COCOA9 1,3,7-Trimethylxanthine(caffiene ) found in coffeeThis are pharmacologically importantMarch 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 5
  6. 6. FunctionsKey functions include;Provision of Energy e.g. ATP, GTPBuilding blocks for DNA and RNA (along side pyrimidines)Basic conenzymes i.e. NAD and NADHPlay role in signal transduction e.g GTP, cAMP, cGMPMarch 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 6
  7. 7. Sources of purineENDOGENOUS• They may be synthesized DE NOVO from small moleculesEXOGENOUS• They may be derived from the breakdown of ingested nucleic acid,mostly from cell-rich meat• Plant diets generally poor in purinesMarch 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 7
  8. 8. Metabolic disorders of purines• They cover a broad spectrum of illnesses with various presentations. Examples of presentations include; • Hyperuricemia • Acute renal failure • Gout • Unexplained neurologic defects (seizures, muscle weakness e.tc) • Developmental disorders • Compulsive self injury and aggression • Immune deficiency • DeafnessMarch 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 8
  9. 9. Major Categories of Disorders Two major types of disorders occur; i. Those that arise from a Blockage in purine nucleotide degradation pathway ii. Arising from increased activity of nucleotide degradation pathwayMarch 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 9
  10. 10. Nucleotide degradation• Nucleic acids can survive the acid of the stomach• They are degraded into nucleotides by pancreatic nucleases and intestinal phosphodiesterases in the duodenum.• Components cannot pass through cell membranes, so they are further hydrolyzed to nucleosides.• Nucleosides may be directly absorbed by the intestine or undergo further degradation to free bases and ribose or ribose-1-phosphate by nucleosidases and nucloside phosphorylase. nucleosidase Nucleoside + H2O Nucleoside base + ribose phosphorylase Nucleoside + Pi base + ribose-1-P
  11. 11. Catabolism of purines ADA Major pathways of purine catabolism in animals. March 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 11
  12. 12. Catabolism of purines•Purine nucleotide degradation refers to a regulated series of reactionsby which purine ribonucleotides and deoxyribonucleotides are degradedto uric acid in humans.•As indicated earlier, two major types of disorders occur in this pathway; • A block of degradation occurs with syndromes involving;- • immune deficiency. •myopathy or •renal calculi. •Increased degradation of nucleotides occurs with syndromes characterized by;- • hyperuricemia and gout, •renal calculi, •anemia or acute hypoxia. March 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 12
  13. 13. Uric Acid (2,6,8-trioxypurine) • This is the end product of purine metabolism in humans • Accumulation of uric acid in blood is reffered to as hyperuricemia • Uric acid is highly insoluble therefore a very slight alteration in the production or solubility will increase levels in blood. • Due to poor solubility, levels in blood are usually near the maximal tolerable limitsMarch 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 13
  14. 14. Excretion of uric acid• Uric acid is filtered through the glomeruli and most is reabsorbed in the proximal tubules.• More than 80% of uric acid formed in the urine is derived from distal tubular secretion• Urinary excretion is slightly lower in males than females,which may contribute to the higher incidence of hyperuricaemia in men• Renal secretion may be enhanced by uricosonic drugs(e.g probenecid or sulfinpyrazone),which block tubular urate reabsorption
  15. 15. Excretion of uric acid• 75% urate leaving the body is in urine• The remaining 25% passes into the intestinal lumen,where it is broken down by intestinal bacteria(URICOLYCIS)
  16. 16. HYPERURICAEMIA• This is increase in blood levels of uric acid that is greater than 0.42 mmol/l in men and more than 0.36mmol/l in women• It can occur by two mechanisms:• 1 Increased production(Over Production)• 2 Decreased Excretion (under excretors)
  17. 17. Conditions that lead to Increased Uric acid Production – Malignancies – Reyes Syndrome – Downs Syndrome – Sickle cell anemia – Glycogen storage diseases types I,III, IV and V – Hereditary fructose intolerance – Gout – AcylCoA dehydroginase defficiencyMarch 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 17
  18. 18. Factors contributing to Hyperuraecimia• Increased synthesis of purines(primary Gout)• Secondary GOUT (Other disorder in which there is rapid tissue break down or rapid cellular turnover)• Increase intake of purines• Increase turnover of Nucleic Acids• Increased rate of urate formation• Reduced rate of Excretion
  19. 19. Factors contributing to Hyperuraecimia• Sex(plasma uric acid is higher in male than females)• Obesity (Obese people tends to high plasma level of urate)• Diet (subject with high protein diet ,which is also rich in NUCLIEC acids and who do have high alcohol consumption have high levels of plasma urate• Genetic factor(These are very important factor in high plasma urate levels)
  20. 20. Other causes may include:• Eclampsia• Lead toxicity• Chronic alcohol ingestion• NOTE Hypouricaemia is not an important chemical disorder in itself
  21. 21. Management of disorders Management of disorders of purine nucleotide degradation is dependent upon modifying the specific molecular pathology underlying each disease state.March 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 21
  22. 22. Common treatment for gout: allopurinol Allopurinol is an analogue of hypoxanthine that strongly inhibits xanthine oxidase. Xanthine and hypoxanthine, which are soluble, are accumulated and excreted.March 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 22
  23. 23. In born errors of Uric Acid Metabolism1. Phosphorybosylpyrophosphate synthase (PRS) superactivity There are two form; i. The severe form which appears in infancy ii. The mild form which presents in adolescence • In both forms, kidney or bladder stone is often the first symptom. • Gout and impairment of kidney function may develop if the condition is not adequately controlled with medication and dietary restrictions. March 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 23
  24. 24. 2. Adenylosuccinase deficiency • Due to lack of the enzyme adenylosuccinate lyase • In general, affected individuals may have a mix of neurological symptoms, which usually includes abnormalities with cognition and movement, autistic features, epilepsy, muscle wasting, and feeding problems.March 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 24
  25. 25. Disorders due to purine catabolismMarch 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 25
  26. 26. Myoadenylate Deaminase Deficiency• Also called muscle adenosine monophosphate deaminase deficiency• This is a genetic disease that interferes with the muscle cells processing of ATP, the key energy molecule of a cell.• The lack of an enzyme that converts ATP to inosine and ammonia may present no symptoms or it may cause exercise-induced cramping.• The disorder is diagnosed through the accumulation of ammonia or inosine monophosphate in muscle tissue• Treatment typically consists of exercise modulation.March 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 26
  27. 27. Xanthine Oxidase Deficiency (XANTHINURIA)• This is a rare hereditary disorder in which there is a deficiency of liver xanthine oxidase• The catabolism of purine stops with xanthine- hypoxanthine stones.• The blood uric acid is very low and there is a high level of urinary excretion of xanthine• There is reduced excretion of urinary uric acid
  28. 28. Xanthine Oxidase Deficiency (Xanthinuria)•Xanthine oxidase deficiency, is an inheritedmetabolic disorder in which there is deficiency of anenzyme needed to process xanthine, a substancefound in caffeine and related substances.•If left untreated, xanthinuria can lead to kidney stoneformation and subsequent urinary tract diseases.•Additionally, this condition can lead to muscledisorders, due to deposits of xanthine in muscletissue.•Treatment of the condition involves avoiding foodsand drinks that contain xanthine derivatives, such ascoffee, tea and colas and maintaining a high fluid 28March 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013
  29. 29. Adenosine Deaminase Deficiency • This is a genetic disorder that impairs the immune system and is the basis of severe combined immunodeficiency, or SCID. • Children diagnosed with SCID are typically deficient in almost all immune protection from pathogens and are vulnerable to chronic infections caused by "opportunistic" organisms that ordinarily do not cause disease in healthy people with a normal immune response. • Symptoms of SCID include pneumonia and chronic diarrhea, with impeded growth compared to healthy children. • Additionally, neurological problems such as developmentalGKM/MUSOM/NSPmotor function disorders andMarch 21, 2013 delay, 210:PATH.2012.2013 29
  30. 30. Disorders due to salvage pathway A salvage pathway is a pathway in which nucleotides (Purine and pyrimidine) are synthesized from intermediates in the degradative pathway for nucleotides.There are two critical enzyme defficiencies;I. Hypoxanthine guanige phosphorybosyltransferase (HPRT) defficiency – May be total (Lesch-Nyhan syndrome ) or partal defficiency Partial HPRT-deficient patients present with symptoms similar to total but with a reduced intensity, and in the least severe forms symptoms may be unapparent.I. Adenine phosphorybosyltransferase (APRT) defficiency – The disorder results in accumulation of the insoluble Purine 2,8- dihydroxyadenine. – It can result in nephrolithiasis (kidney stones), acute renal failureMarch 21, 2013and permanent kidney damage. GKM/MUSOM/NSP 210:PATH.2012.2013 30
  31. 31. Lesch-Nyhan Syndrome• Lesch-Nyhan syndrome is a metabolic disorder caused by a deficiency of an enzyme (HPRT) produced by mutations in a gene located on the X chromosome.• The disease is marked by a buildup of uric acid in all body fluids that results in conditions known as hyperuricemia and hyperuricosuria.• Symptoms often include severe gout, impaired muscular control, moderate mental retardation and kidney problems.• These complications frequently emerge in the first year of life. Neurological symptoms can include March 21, 2013 grimacing, GKM/MUSOM/NSP 210:PATH.2012.2013 facial involuntary writhing and repetitive31
  32. 32. Gout• Characterised by the accumulation of monosodium urate crystal deposits which result in inflamation in joints and surrounding tissues.• Presentation – Hyperuricemia – Uric acid nephrolithiasis – Acute inflamatory arthritis March 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 32
  33. 33. Gout• Commonly monoarticular (Affecting the metatarsophalangeal joint of the big toe.• However deposits of sodium urates may aslo occur in; – The elbows – Knees – Feet – Helix of the earMarch 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 33
  34. 34. Figure 28-29 The Gout, a cartoon by James Gilroy (1799).Page 1097 Gout is a disease characterized by elevated levels of uric acid in body fluids. Caused by deposition of nearly insoluble crystals of sodium urate or uric acid. March 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 34
  35. 35. Types of Gout• Primary Gout – Occurrence: Middle aged men (mostly) – Cause: Overproduction of Uric Acid Decreased renal excretion or both Biochemical Etiology: Not clearly known and is considered a polygenic diseaseMarch 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 35
  36. 36. Types of Gout• Secondary Gout – Occurrence: Children – Cause: other condition in which there is rapid tissue breakdown or cellular turnover – Such condition leads to either; • Increased production of Uric acid • Decreased clearance of Uric acidMarch 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 36
  37. 37. Other conditions that could lead togout• Any other condition that may lead to either; – Decreased uric acid clearance or – Increase in production These may include; Also; • Malignancy therapy •Excessive purine intake •Alcohol intake • Dehydration •Carbohydrate ingestion • Lactic acidosis • Ketoacidosis • Stavation • Diuretic therapy • Renal failureMarch 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 37
  38. 38. Hereditary disorders associatedwith gout• These include 3 key enzymes resulting in hyperuricemia• These are; 1. Severe HPRT defficiency (Lesch-Nyhan syndrome) • Also Partial HPRT defficiency 1. Superactivity of PP-ribose-p synthetase 2. Glucose -6-phosphatase defficiency (glycogen storage disease type 1)March 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 38
  39. 39. Hereditary disorders associatedwith gout - cnt• 1st two are caused by hyperuricemia due to purine nucleotide and uric acid overproduction• The 3rd due to excess uric acid production and impaired uric acid secretionMarch 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 39
  40. 40. Familial Juvenile Gout (Familial Juvenile Hyperuricemic Nephropathy (FJHN)• Due to severe renal hypoexcretion of uric acid• Presentation usually occurs at puberty to the 3rd decade – Has also been reported in infancy Characteristics – Hyperuricemia – Gout – Familial renal disease – Low urate clearance relative to GFRMarch 21, 2013 GKM/MUSOM/NSP 210:PATH.2012.2013 40
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