Purines metabolism.pptx

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1. BIOCHEMISTRY [B. Pharm – I Yr.] Topic: Biosynthesis and Catabolism of Purine Nucleotides Umesh Kumar Assistant Professor Dept. of Pharm. Chemistry Hygia Institute of Pharmaceutical Education and Research

2. CONTENTS Biosynthesis of Purine nucleotides Introduction Biosynthesis of prine nucleotides Catabolism of Purine nucleotides Disorders of Purine nucleotides

3. Nucleotides Nucleotides consist of a nitrogenous base, a pentose and a phosphate. The pentose sugar is D-ribose in ribonucleotides of RNA while in deoxyribonucleotides (deoxynucleotides) of DNA, the sugar is 2-deoxy D-ribose. Nucleotides participate in almost all the biochemical processes either directly or indirectly. They are the structural components of nucleic acids (DNA, RNA), coenzymes, and are involved in the regulation of several metabolic reactions

4. The structures of major purines and pyrimidines found in nucleic acids are shown in the following image. DNA and RNA contain the same purines namely adenine (A) and guanine (G), Further, the pyrimidine cytosine (C) is found in both DNA and RNA. However, the nucleic acids differ with respect to the second pyrimidine base. DNA contains thymine (T) whereas RNA contains uracil (U). As is observed in the Fig,5.2, thymine and uracil differ in structure by the presence (in T) or absence (in U) of a methyl group. Purines and Pyrimidines

5. Biosynthesis of Purine Nucleotides It should be remembered that purine bases are not synthesized as such, but they are formed as ribonucleotides. The purines are built upon a pre-existing ribose-5-phosphate . Liver is the major site for purine nucleotide synthesis. Erythrocytes, polymorphonuclear leukocytes and brain cannot produce purines. Generally, pathway takes place for the synthesis of Inosine Monophosphate which is the parent nucleotide of purine nucleotides. For the synthesis of inosine monophosphate, the reaction takes place in total 11 steps.

6. Synthesis of AMP and GMP from IMP

7. Salvage Pathway for Purines The free purines (adenine, guanine and hypoxanthine) are formed in the normal turnover of nucleic acids (particularly RNA), and also obtained from the dietary sources. The purines can be directly converted to the corresponding nucleotides, and this process is known as 'salvage pathway ’.

8. Uric acid is the final excretory product of purine metabolism in humans. Uric acid can serve as an important antioxidant by getting itself converted to allatonin . Catabolism of Purine Nucleotides

9. Disorders of Purine Metabolism Hiperuricemia and Gout Uric acid is the end product of purine metabolism in humans. The normal concentration of uric acid in the serum of adults is in the range of 3-7 mg/dl. In women, it is slightly lower (by about 1 mg) than in men. The daily excretion of uric acid is about 500-700 mg. Hyperuricemia refers to an elevation in the serum uric acid concentration. This is sometimes associated with increased uric acid excretion (uricosuria). Gout is a metabolic disease associated with overproduction of uric acid. At the physiological pH, uric acid is found in a more soluble form as sodium urate. ln severe hyperuricemia, crystals of sodium urate get deposited in the soft tissues, particularly in the joints. Such deposits are commonly known as tophi. This causes inflammation in the joints resulting in a painful gouty arthritis. Sodium urate and/or uric acid may also precipitate in kidneys and ureters that results in renal damage and stone formation.

10. Historically, gout was found to be often associated with high living, over-eating and alcohol consumption. In the previous centuries, alcohol was contaminated with lead during its manufacture and storage. Lead poisoning leads to kidney damage and decreased uric acid excretion causing gout. Gout is of two types – Primary Gout Secondary Gout Primary Gout It is an inborn error of metabolism due to overproduction of uric acid. This is mostly related to increased synthesis of purine nucleotides. The following are the important metabolic defects (enzymes) associated with primary gout- PRPP synthetase PRPP glutamylamidotransferase HGPRT deficiency

11. HGPRT deficiency This is an enzyme of purine salvage pathway, and its defect causes Lesch-Nyhan syndrome . This disorder is associated with increased synthesis of purine nucleotides by a two-fold mechanism. Firstly, decreased utilization of purines (hypoxanthine and guanine) by salvage pathway, resulting in the accumulation and diversion of PRPP for purine nucleotides. Secondly, the defect in salvage pathway leads to decreased levels of IMP and CMP causing impairment in the tightly controlled feedback regulation of their production. Secondary gout Secondary hyperuricemia is due to various diseases causing increased synthesis or decreased excretion of uric acid. Increased degradation of nucleic acids (hence more uric acid formation) is observed in various cancers (leukemias, polycythemia, lymphomas, etc.) psoriasis and increased tissue breakdown (trauma, starvation etc.). The disorders associated with impairment in renal function cause accumulation of uric acid which may lead to gout.

12. THANK YOU HYGIA GROUP OF INSTITUTIONS GHAILA ROAD, GAAZIPUR BALRAM, FAIZULLAHGANJ, LUCKNOW