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synthesis of pyrimidines and purines follows two different pathways.
Instead of uric acid secretion, guanine and IMP can be used for recycling purposes and nucleic acid synthesis in the presence of PRPP and aspartate (NH3 donor).
Degradation of nucleotides
Nucleotides of a cell undergo continuous turnover. Purines are catabolized and the end product is uric acid. Gout is a disease characterized by elevated levels of uric acid in body fluids. Sodium urate crystals are precipitated in the joints and soft tissues to cause painful arthritis. In Lesch-Nyhan syndrome, HGPRT deficiency occurs, leading to excessive uric acid production through PRPP accumulation. Gout is treated by allopurinol administration. Animal cells degrade pyrimidine nucleotides to their component bases by dephosphorylation, deamination and glycosidic bond cleavages to give rise to carbon dioxide, ammonia, β-alanine and β-amino isobutyrate.
Synthesis of Purine Ribonucleotides
The synthesis of the pyrimidines CTP and UTP occurs in the cytoplasm and starts from the condensation of aspartate with carbamoyl-phosphate to form orotic acid.
The covalent linkage between the ribose and pyrimidine occurs at position C1 of the ribose unit, which contains a pyrophosphate, and N1 of the pyrimidine ring. (EC 188.8.131.52) catalyzes the net reaction: Orotate + 5-Phospho-alpha-D-ribose 1-diphosphate = Orotidine 5'-phosphate + Pyrophosphate (C01103) is decarboxylated by (EC 184.108.40.206).
BIOSYNTHESIS AND CATABOLISM OF PYRIMIDINE NUCLEOTIDES.
Pyrimidines are synthesized first from aspartate and carbamoyl-phosphate in the cytoplasm to the common precursor ring structure (C00295), onto which a phosphorylated ribosyl unit is covalently linked.
While pyrimidine rings can be degraded completely to CO2 and NH3 (urea excretion), purine rings are degraded to the metabolically inert (C00366).
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There are 4 purines and 4pyrimidines that are of concern to us.
Nucleotides play a variety of important roles in all cells. They are the activated precursors of DNA and RNA. ATP, an adenine nucleotide, is a universal currency of energy in biological systems. GTP is an essential carrier of chemical energy. Adenine nucleotides are components of the coenzymes NAD+, NADP+, FMN, FAD and Coenzyme A. UDP-Glucose in Glycogen synthesis and CDP-diacylglycerol in Phosphoglyceride synthesis are the nucleotide derivatives that act as activated intermediates. Cyclic AMP is a ubiquitous mediator for the action of many hormones. All cells can synthesize nucleotides from simple building blocks (de novo synthesis) or by the recycling of pre-formed bases (Salvage pathway). Nucleotides are phosphate esters of pentoses in which a nitrogenous base is linked to C1’ of the sugar residue. A nucleotide without the phosphate group is known as a nucleoside. The major purine components of nucleic acids are adenine and guanine residues. The major pyrimidine residues are those of Cytosine, Uracil and Thymine. Pyrimidines are bound to ribose through N 1 atoms.
synthesis of purines is most active in liver.
Synthesis of purine ribonucleotides
IMP is synthesized from ribose 5-phosphate. There are 11 reactions in the formation of IMP. IMP is converted to GMP and AMP with the help of ATP and GTP respectively. Nucleoside monophosphates are converted to nucleoside diphosphates by base specific monophosphate kinases. Purine nucleotide synthesis is regulated by feedback inhibitor – AMP, GMP and IMP. An important regulatory factor is the availability of PRPP. Salvage pathway for purines is observed in RBC and the brain. Free purines are salvaged by APRTase and HGPRTase enzymes
Synthesis of pyrimidine ribonucleotides
Pyrimidine ring is synthesized as free pyrimidine and then it is incorporated into the nucleotide. 6 reactions are involved in the synthesis of UMP. UDP and UTP are synthesized from UMP with the help of ATP. CTP is formed by adding an amino group from glutamine. Pyrimidine can also be salvaged using PRPP. In orotic aciduria, excretion of large amount of orotic acid is observed. It results from the deficiency of either orotate phospho ribosyl transferase or OMP decarboxylase.
Pyrimidine synthesis occursin a variety of tissues.
Formation of deoxyribonucleotides
Ribonucleotide reductase catalyzes the synthesis of deoxyribonucleotide. The reductant is NADPH. Thioredoxin transfers electrons from NADPH for reduction of 2’-OH of ribose. dTMP is formed by thymidylate synthase by methylation of deoxy uridine monophosphate.
Nucleotide Metabolism – Purines and Pyrimidines
Nucleotides are the components of many enzyme cofactors. Adenosine is a part of their structure in a variety of enzyme cofactors serving a wide range of chemical functions. Coenzyme A is synthesized from pantothenic acid and ATP.
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