Nucleic acids metabolism

1. Nucleic acids metabolism Dr. Gamal Gabr, College of Pharmacy

2. OVERVIEW • Nucleotides serve as building blocks for RNA and DNA. • Nucleotides can serve as sources of energy (i.e., ATP), physiological signaling mediators (i.e., adenosine in control of coronary blood flow), secondary messengers (cAMP and cGMP), and allosteric enzyme effectors. • Nucleotides can be synthesized de novo, or from components “salvaged” from the deg-radation products of nucleic acids. Dr. Gamal Gabr, College of Pharmacy

3. de novo and salvaged Pathway • Nucleotides can be synthesized de novo, or from components “salvaged” from the degradation products of nucleic acids. • When in excess, nucleotides are degraded to products that can either be consumed by other pathways or excreted. • Defects in the pathways for de novo synthesis, salvage, and degradation of nucleotides result in clinical disorders, and many drugs target these pathways. Dr. Gamal Gabr, College of Pharmacy

4. Biosynthesis of purine nucleotides  The purine nucleotides are synthesised by most of the tissues.  The major site is the liver. This pathway operates in the cytoplasm.  The major pathway is denoted as de novo synthesis, because the purine ring is synthesis from different small components and from different sources.  During de novo synthesis, purine ring is build up on a ribose-5- phosphate molecule. Dr. Gamal Gabr, College of Pharmacy

5. Dr. Gamal Gabr, College of Pharmacy

6. The purine ring is constructed by a series of reactions that add the donated carbons and nitrogens to a preformed ribose 5-phosphate. Dr. Gamal Gabr, College of Pharmacy

7. PURINE NUCLEOTIDE SYNTHESIS Dr. Gamal Gabr, College of Pharmacy

8. De novo synthesis of pyrimidine nucleotides Dr. Gamal Gabr, College of Pharmacy

9. Degradation of purine nucleosides • The end product of purine nucleotide catabolism is uric acid (Urate). • This degradation is taking place mainly in the liver. • Normal blood level of uric acid ranges from 2-5 mg/dl in females, and 3-7 mg/dl in males. • Nucleic acid content is more in non vegetarian diet Dr. Gamal Gabr, College of Pharmacy

10. NUCLEOTIDE CATABOLISM AND SALVAGE • Nucleotide turnover occurs continuously in cells. Breakdown of DNA and RNA releases nucleoside 5’-monophosphates, which can be hydrolyzed by 5’-nucleotidases to yield nucleosides. Although both purine and pyrimidine nucleosides can be degraded to waste products that are excreted, the catabolic pathways have branch points in most cells at which the components of nucleotides can be salvaged. • Having shared catabolism and salvage pathways saves metabolic energy while preventing nucleotide pools from reaching toxic levels. Dr. Gamal Gabr, College of Pharmacy

11. Salvage pathway This pathway ensures the recycling of purines formed by degradation of nucleotides. Nucleosides and deoxy-nucleosides can also be salvaged.  PRPP is the starting material in this pathway. It is also a substrate for de novo synthesis. Hence , these two pathways are closely inter-related.  The pathway is of importance in tissues like RBCs and brain where the denovo pathway is not operating. Dr. Gamal Gabr, College of Pharmacy

12. DE NOVO RIBONUCLEOTIDE SYNTHESIS • Purine and pyrimidine nucleoside 5’-monophosphates can be synthesized de novo from PRPP and various carbon and nitrogen donors. • A few important drugs inhibit key steps in de novo purine nucleotide synthesis and as a result kill rapidly dividing cells. Dr. Gamal Gabr, College of Pharmacy

13. NUCLEOTIDE CATABOLISM AND SALVAGE Dr. Gamal Gabr, College of Pharmacy

14. PURINE SALVAGE Dr. Gamal Gabr, College of Pharmacy

15. Diseases associated with purine degradation • Gout • Gout is a disorder characterized by high levels of uric acid. The end product of purine catabolism in blood (hyperuricemia), as a result of either the overproduction or underexcretion of uric acid. • The hyperuricemia leads to the deposition of monosodium urate crystals in the joints, and an inflammatory response to the crystals, causing first acute and then to chronic gouty arthritis. Dr. Gamal Gabr, College of Pharmacy

16. Diseases associated with pyrimidine metabolism • Oroticaciduria • Excessive excretion of orotic acid in urine. It causes a characteristic form of anemia and may be associated with mental and physical retardation.. Dr. Gamal Gabr, College of Pharmacy