Lecture 5: Pyrimidine Metabolism PDF

Lippincott’s illustrated reviews Chapter 22 – Page 299 Lecture 5 Pyrimidine Metabolism 1  Specific Objectives By the end of this lecture students can able to know: Synthesis of pyrimidine nucleotides. Degradation of pyrimidine nucleotides. Disord...

Lippincott’s illustrated reviews Chapter 22 – Page 299 Lecture 5 Pyrimidine Metabolism 1  Specific Objectives By the end of this lecture students can able to know: Synthesis of pyrimidine nucleotides. Degradation of pyrimidine nucleotides. Disorders in pyrimidine metabolism. 2 3  A. Synthesis of carbamoyl phosphate The regulated step of this pathway in mammalian cells is the synthesis of carbamoyl phosphate from glutamine and CO2, catalyzed by carbamoyl phosphate synthetase (CPS) II. First SXES 4 CPS II is inhibited by UTP urdine and is activated by PRPP. (UTP, the end product of this pathway, which can be converted into the other pyrimidine nucleotides), 5 6  B. Synthesis of orotic acid The second step in pyrimidine synthesis is the formation of carbamoylaspartate, catalyzed by aspartate transcarbamoylase. The pyrimidine ring is then closed hydrolytically by dihydroorotase. dihydrate The resulting dihydroorotate is oxidized to produce orotic acid. The enzyme that produces orotate, dihydroorotate dehydrogenase, is associated with the inner mitochondrial membrane. All 7 other enzymes in pyrimidine biosynthesis are cytosolic. 8  C. Formation of a pyrimidine nucleotide The completed pyrimidine ring is converted to the nucleotide orotidine 5'-monophosphate (OMP) ( the parent pyrimidine mononucleotide) then to uridine monophosphate (UMP) by bifunctional enzyme UMP synthase. Enzyme Yucatite PRPP is again the ribose 5-phosphate donor. [Note: Both purine and pyrimidine synthesis thus require glutamine, aspartic acid, and PRPP as essential precursors.] 9 10 Orotic aciduria Orotic aciduria is a rare genetic defect—may be caused by a deficiency of one or both activities of bifunctional enzyme UMP synthase, resulting in orotic acid in the urine, poor growth, megaloblastic anemia. red cells Large 11 12 13  End Ammonia product 14 β-alanine and β -aminoisobutyrate, can serve as precursors acetyl CoA and succinyl CoA, respectively. important in Krebs Ammonia and carbon dioxide can form urea 14 which excrete with urine Urea is from the end product of pyrimidine nucleotides 15 Reference Book: Champe, P. C., Harvey, R. A. and Ferrier, D. R., 2005. Biochemistry “Lippincott’s Illustrated Reviews”, 5th or 6th Edition 16