BIOC/DENT/PHCY 230 LECTURE 6 Lecture 6: Nitrogen Metabolism III Amino acids as a source of nitrogen for biosynthesis of specialised compounds and nucleotides Understand why amino acids are precursors for specialised compounds and nucleot ides. Be familiar with the notable features of de novo biosynthesis of purines and pyrimidines. Be aware of the benefits of nucleot ide salvage pathways. Note the very different end products of purine and pyrimidine degr adat ion. Know that the product from purine degradat ion is uric acid and why it can cause medical problems. Explain some of the benefits t o medicine of understanding nitrogen metabolism. Nucleotides found in DNA and RNA used for energy (ATP and GTP) building blocks for coenzymes (NADH) Building blocks for nucleotides Two classes of bases Two types of ribose Synthesis of nucleotides nucleotide bases can be recycled or synthesised de novo purine bases are synthesised on ribose pyrimidine bases are synthesised independent of ribose Synthesis of PRPP PRPP contributes ribose phosphate to nucleotides formation catalysed by PRPP synthetase AMP PRPP synthetase is allosterically inhibited by AMP, ADP and GDP. De novo purine synthesis Glutamine donates an amide to initiate purine synthesis A whole glycine is added to the nitrogen The coenzyme tetrahydrofolate donates a formyl group Glutamine donates a second amide Imidazole ring is closed in an energy dependent reaction Aspartate is added in an energy dependent reaction This is analogous to the urea cycle Ring closure Tetrahydrofolate donates a second formyl group Origins of purine base IMP can be converted to GMP and AMP De novo pyrimidine synthesis The pyrimidine base is synthesised before being attached to ribose ring closure and oxidation Ribose is now added via PRPP UMP can be used to synthesise CTP Origins of pyrimidine base Comparison of purine and pyrimidine biosynthesis purines pyrimidines Base synthesis on ribose free Amino acids gln(2), asp, asp gln gly Other molecules ATP formate(2) HCO3- 5 carbamoyl phosphate 2 (AMP,GMP) CMP 3 (UMP) Ribonucleotides are used as precursors for deoxyribonucleotides ATP dATP GTP dGTP CTP dCTP UTP dUTP Ribonucleotide reductase Thymidine nucleotides are derived from dUMP Tetrahydrofolate donates a methyl group Degradation of pyrimidine nucleotides CTP UTP b-alanine, NH3, CO2 Degradation of purine nucleotides Free ammonia is also produced in muscle during severe muscle activity ATP ADP + Pi 2ADP ATP + AMP AMP IMP + NH4+ AMP deaminase Degradation of purine nucleotides GOUT uric acid is quite insoluble excess uric acid can crystallise in joints gout can be treated with allopurinol allopurinol is a competitive inhibitor of xanthine oxidase The take home message nucleotides have a number of functions they can be synthesised de novo if required some steps are analogous with the urea cycle amino acids provide many of the components synthesis is regulated by the concentrations of various nucleotides synthesis is energetically expensive the degradation of excess purines can cause gout