Nucleotide Metabolism
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1 Nucleotide Metabolism
2 Nucleotide Synthesis De Novo Pathway Synthesize purine and pyrimidine nucleotides from low M.W. precursors Salvage Pathway synthesize nucleotides from nucleosides of nucleobases NB: important targets for therapy of microbial or parasitic diseases
3
4 Nucleic Acid Degradation Intracellular Degradation Turnover of unstable RNA; cell death; ingested nucleic acids Extracellular Degradation Major route by which nucleosides or nucleobases become available in animals
5 Nucleic Acid Degradation endonucleases oligonucleotides phosphodiesterases mononucleotides nucleotidases ortho PO 4 ; nucleosides nucleoside phosphorylase base; ribose-1-p
6 Nucleoside Phosphorylase
7
8 PRPP is a Central Metabolite in De Novo and Salvage Pathways An intermediate in histidine and tryptophan biosynthesis Synthesis of nucleoside-5 -phosphate (nucleotide) from free bases
9
10 Low Molecular Weight Precursors to the Purine Ring Feedback regulation of early steps PRPP synthetase ( ) by AMP, ADP, GDP PRPP amidotransferase ( ) by AMP, GMP (synergistic inhibition)
11 Pathways from inosinic acid to GMP and AMP Energy drive is from GTP/ATP A way to control the proportion of IMP that go to adenine and guanine nucleotide synthesis (reciprocal substrate relation)
12 Conversion of Nucleoside Monophosphate to the Triphosphate Step 1- Specific ATP-Dependent Kinase Guanylate kinase Adenylate kinase Step 2 Non-Specific ATP-Dependent Nuceloside diphosphokinase
13 Control of Purine Biosynthesis
14 Primates uric acid Most mammals further oxidize the purine ring to allantoin and to allantoic acid or further to urea
15 Enzymatic abnormalities that lead to hyperuricemia and gout by elevating the rate of de novo purine nucleotide biosynthesis
16 Gout Excessive accumulation of uric acid 3/1000 suffer from HYPERURICEMIA Urate ppt. causes inflammation in the joints Painful arthritis Allopurinol inhibits xanthine oxidase Solubility: hypoxanthine/xanthine > uric acid
17
18 De Novo Synthesis of Pyrimidine Nucleotides Pyrimidine ring is assembled as a free base Unbranched pathway Aspartate transcarbamoylase ( ) by CTP (+) by ATP
19 Pyrimidine Ring
20 Control of Pyrimidine Biosynthesis
21 Catabolic Pathways in Pyrimidine Nucleotide Metabolism
22 Overview of Deoxyribonucleotide Biosynthesis
23 Overview of Deoxyribonucleotide Biosynthesis Close regulatory relationships between DNA synthesis and dntp metabolism Conversion of ribose to deoxyribose Conversion of uracil to thymine
24 Mechanism for Reduction of a Ribonucleoside Diphosphate by rndp Reductase Replacement of the 2 -hydroxyl moiety of the sugar by a hydride ion retention of configuration Ribonucleoside diphosphate reductase (rndp)
25 Reductive electron transport sequences in the action of ribonucleoside diphosphate reductase
26 Ribonucleoside Diphosphate Reductase Both activity and specificity being regulated To maintain balanced pools of DNA precursors (1) Activity Sites Low affinity binding of ATP or datp ATP binding (+) datp binding ( )
27 Ribonucleoside Diphosphate Reductase (2) Specificity Sites High affinity binding of ATP, datp, dgtp or dttp Modulates the activities of enzyme toward different substrates Maintain a balanced rate of production of dntps
28 Salvage and De Novo Synthetic Pathways to Thymine Nucleotides
29 Relationship between thymidylate synthase and enzymes of tetrahydrofolate metabolism
30 Thymidylate Synthesis: A Target Site for Cancer Chemotherapy Rapidly dividing cells (eg. cancer cells) require an abundant supply of deoxythymidylate for DNA synthesis Thymidylate synthase & Dihydrofolate reductase TARGET ENZYMES
31 Thymidylate Synthesis: A Target Site for Cancer Chemotherapy Fluorouracil fluorodeoxyuridylate (F-dUMP) suicide inhibition of thymidylate synthesis
32 Thymidylate Synthesis: A Target Site for Cancer Chemotherapy Aminopterin and methotrexate inhibit dihydrofolate reductase Acute leukemia Choriocarcinoma Rapidly growing tumors
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