Purines and Pyrimidines Metabolism PDF

Almaaqal University Purines and Pyrimidine Metabolism Dr/ Wael Sobhy Darwish Biochemistry PhD  Purine and Pyrimidine Purines and pyrimidines are heterocyclic aromatic compounds, which, along with sugar and phosphate groups, form the i...

Almaaqal University Purines and Pyrimidine Metabolism Dr/ Wael Sobhy Darwish Biochemistry PhD  Purine and Pyrimidine Purines and pyrimidines are heterocyclic aromatic compounds, which, along with sugar and phosphate groups, form the important components of nucleotides. Purines include adenine and guanine, Pyrimidines include thymine (in DNA), uracil (in RNA), and cytosine. A nucleoside is formed from the linkage of a sugar with a nitrogen-containing base. Nucleotide Structure Nucleotide Structure  Biomedical Importance DNA – RNA ( Nucleic acid metabolism ) ATP – GTP (Energy Metabolism ) NADH – FADH( Co- enzymes ) S- Adenosyl – methionine (donor for methyl group ) UDP – glucronic acids ( donor for conjugation ; bilirubin glucronid ) cAMP – cGMP ( Hormone Signal ) Anticancer Drugs ( Mtx , 5Flu, 6-TG , 6-MG ) Antiviral drugs (Aciclovir , Lamivudine ) Gout Disease Treatment ( Allopurinol )  Purines & Pyrimidines Are Dietarily Nonessential Human tissues can synthesize purines and pyrimidines. Ingested nucleic acids and nucleotides, which therefore are dietarily nonessential, are degraded in the intestinal tract to mononucleotides, which may be absorbed or converted to purine and pyrimidine bases. Dietary source: Purines and pyrimidine present in the form of nucleic acid which is present in liver and meat, small amount in legumes, cereals and vegetables. Egg, milk and cheese are not contain nucleic acids. Tea, coffee, cocoa, and cola contain the methyl purines, caffeine, theobromine and theophylline  Purine and pyrimidine metabolism Digestion and absorption: 1-Pancreas: Pancreatic juice contains nucleases both ribonucleases and deoxyribonucleases (Rnase and Dnase), that hydrolyse nucleic acids into mononucleotides. 2-Intestine: Nucleotidases and intestinal phosphatases remove phosphate producing nucleotides. Nucleosidases hydrolyse nucleosides into free bases (purine or pyrimidine), and pentose (ribose or deoxyribose). Nucleotides and nucleosides are poorly absorbed from the small intestine, if absorbed- they are catabolized by the liver.  Purine and pyrimidine metabolism Although the humans ingest large amounts of nucleotides and bases they are not utilized for nucleic acid synthesis. Humans-and other vertebrates- can synthesized large amounts of purine and pyrimidine nucleotides de novo. So, purine and pyrimidine bases are not essential dietary components. Unabsorbed purines are converted to uric acid by intestinal bacteria which may be absorbed and subsequently excreted in urine.  Catabolism of purine Site : In liver (intracytoplasmic) Hypoxanthine is oxidized into xanthine, and further to uric acid by xanthine oxidase. Uric acid diffuses to the blood to be excreted by the kidney. Uric acid is the end product of purine base catabolism. In lower mammals uric acid is oxidized into highly water soluble allantion by uricase enzyme. In birds uric acid is the end product of protein catabolism. In fishes ammonia is the end product of protein catabolism (ammonotelic).  Gout Gout is a metabolic disorder that is related to excess production and deposition of uric acid crystals (hyperuricemia). Uric acid is the byproduct of purine nucleotide catabolism. Hyperuricemia is characterized by recurrent attacks of acute inflammatory arthritis. The formation of urate crystals leads to deposition of (sandy, nodular masses of urate crystals (Sodium urate crystals ), particularly in the joints which precipitates the episodes of gouty arthritis. Gouty arthritis is the most painful manifestation of gout and is caused when urate crystals interact with neutrophils triggering an inflammatory response.  Acute gouty arthritis can progress to chronic gouty arthritis and might develop renal stones composed mainly of uric acid and /or urates. Normal blood uric acid is 3-7mg/dl (males) and 2-6mg/dl (females). It is excreted in urine 0.7gm/day. This amount decreases in case of purine free diet.  Lesch-Nyhan Syndrome Lesch-Nyhan syndrome (also known as Nyhan’s syndrome, Kelley-Seegmiller syndrome and Juvenile gout ) is inherited as an X-linked recessive disorder. Since it is an X-linked disease it is found almost exclusively in males although affected females have been identified albeit very rarely. It is a disorder related to defects in the activity of the purine nucleotide salvage enzyme, hypoxanthine-guanine phosphoribosyl transferase.  Lesch-Nyhan Syndrome Causes: Caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT), produced by mutations in the HPRT gene. The lack of HGPRT causes a build-up of uric acid in all body fluids: both hyperuricemia and hyperuricosuria, which lead to problems such as severe gout and kidney problems, poor muscle control, and moderate mental retardation. These complications usually appear in the first year of life.  Lesch-Nyhan Syndrome Dystonia (involuntary spasms and muscle contractions) Violent flinging movements of the limbs Impaired kidney function Irritability Muscle weakness Speech impairment Hyperrefelxia (exaggeration of reflexes) Kidney stones Blood in the urine Pain and swelling in the joints Difficulty swallowing and eating Vomiting Lesch-Nyhan Syndrome  Hypouricemia It may be renal or metabolic. 1-renal: due to low renal threshold. 2-Metabolic: there is decreased uric acid formation due to deficiency of: A-adinosine deaminase, (adenosinuria). B-Xanthine oxidase, hypoxanthine and xanthine are excreted in excess in urine. Xanthine stone might be formed. C- purine nucleosidase. there is accumulation of guanosine and inosine leading to guanosinuria. D-Folic acid. There is decreased de novo synthesis of purines. Catabolism of pyrimidines: This occurs mainly in the liver. β -alanine is the major end product of both uracil and cytosine. β–aminoisobutyric is the major end product of thymine.  Disorder of pyrimidine metabolism β-amino isobutyric aciduria: This characterized by execretion of large amounts of β-aminoisobutyric in urine. Causes: This is the result of defective deamination of β-aminoisobutyric acid. The condition also occurs in cases of leukemia, and exposure to radiation due to increased DNA breakdown.  2-Hereditary orotic aciduria: Disorder Defective Enzyme Comments Orotic aciduria, Type I Orotate phosphoribosyl causes retarded growth, transferase and Orotidine 5'- and severe anemia caused phosphate decarboxylase by hypochromic (OMP decarboxylase). erythrocytes and megaloblastic bone marrow. Leukopenia is also common in orotic acidurias. Orotic aciduria, Type II OMP decarboxylase As type 1 The disorders can be treated with uridine and/or cytidine, which leads to increased UMP production via the action of nucleoside kinases. The UMP then inhibits CPS-II, thus attenuating orotic acid production. Orotic aciduria due to the urea cycle enzyme, increased mitochondrial OTC deficiency ornithine carbamoyl phosphate exits and (no hematologic transcarbamoylase, is augments pyrimidine component) deficient biosynthesis; hepatic encephalopathy drug induced orotic OMP decarboxylase allopurinol and 6-azauridine aciduria treatments cause orotic acidurias without a hematologic component; their catabolic by-products inhibit OMP decarboxylase