Nucleotide Metabolism: Purine Metabolism
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| THe stock of nucleotides is maintained at essentially a constant level by many metabolic pathways | Salvage bases from other cellular processes (from scratch)
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| Synthesize nucleotides directly from amino acids and other precursors
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| The cell can interconvert between specific nucleotides
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| The basis for this "fixed" concentration of nucleotides is that de novo synthesis and salvage pathways are very rigidly controlled under normal conditions. |
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| De Novo Purine Sythesis | synthesis of the purine nucleotides from other unrelated compounds (scratch)
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| In practice purines, are synthesized using three components: amino acids (carbon & nitrogen donors), tetrahydrofolate (carbon donor), & carbon dioxide (carbon donor)
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| occurs entirely in the cytosol
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| not all cells are capable of de novo purine synthesis (white and red blood cells)
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| IMP: AMP & GMP are synthesized thru a common intermediate inosine monophosphate- IMP; requires a lot of energy
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| PRPP Synthesis: de novo synthesis and all savage pathways use a common reactant called phosphoribosylpyrophosphate (PRPP), Highly Regulated- inhibited by other nucleotides
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| PRA Synthesis: Once PRPP is available, de novo purine synthesis can occur, which begins with the synthesis of 5-phosphoribosylamine (PRA)
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| Regulation of PRA Synthesis: COMMITTED STEP, IMP must be formed after this step, this enzyme is the rate limiting step for de novo synthesis (can only occur as fast as you make PRA); Highly Regulated, PRPP is an activator; IMP,GMP, & AMP are inhibitos.
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| There is no regulation of IMP synthesis after this step
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| IMP Utilization: Conversion of IMP to AMP and GMP is regulated_ each product regulates its own synthesis, AMP inhibits AMP synthesis & GMP inhibits GMP synthesis
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| Synthesis of AMP from IMP requires GTP as an energy source, Synthesis of GMP from IMP requires ATP as an energy source. This reciprocal arrangement ensure that when there is a sufficient ATP in the cell GMP will be synthesized from IMP and vice versa
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| GMP Synthesis- nitrogen comes from Glutamine, AMP Synthesis- nitrogen comes from Aspartate
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| Formation of Purine NTP- are formed from either AMP or GMP by the action of two enzymes, which this stage of synthesis is unregulated
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| Purine Salvage Biosynthesis | Stray purine nucleobases can be reused to give nucleotides , much more energetically favorable than de novo purine sythesis, de novo and salvage parthways are interconnected to provide a near constant amount of nucleotides
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| Two nucleotides are responsible for purine nucleobase salvage: hypoxanthine-guanine phosphoribosyl transferase (HGPRT) & adenine phosphoribosyl (APRT). Both catalyze the reaction of their respective nucleobases with PRPP to give the nucleotide
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| HGPRT reacts hypoxanthine or guanine with PRPP, APRT reacts adenine with PRPP
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| Purine Salvage Regulation | Regulated, the products inhibit the pathways, HGPRT is inhibited by IMP & GMP, APR is inhibited by AMP
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| Use of this pathway inhibits the de novo synthesis pathwa by lowering the level of PRPP, raising the level of purine NTP
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| Nucleoside Salvage- only the sugar and base no phosphate group | specific enzymes, stray purine nucleosides can also be salvaged
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| Purine Nucleotide Interconversion | advantageous for the cell to be able to interconvert between AMP & GMP which occurs indirectly thru IMP
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| IMP can then be converted thru the de novo pathway to either AMP OR GMP as needed
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| Interconversion Regulation | Interconversion of nucleotides is regulated to maintain a suppply of both
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| AMP conversion to IMP is inhibited by GTP & GDP but enhanced by ATP
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| GMP conversion is IMP is strongly inhibited by XMP but increase by GTP
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| XMP tell that the cell is actively making GMP
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| Purine Nucleotide Catabolism | Catabolism of Purines- the breakdown of purines follows a common path to uric acid; unregulated, nucleases breakdown either DNA or RNA
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| Guanine Catabolism- guanosine, guanine and xanthine
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| Adenine Catabolism- look at page 22 of notes
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| Purine Catabolism- Xanthine is oxidized by xanthine oxidase to give uric acid which is then secreted
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| Defects in Metabolism | Gout- defect in purine metabolism; hyperuricemia- uric acid overproduction & blood and urine concentration are elevated. uric acid is very poorly soluble which causes sodium urate crystals are deposited in joints and in the kidneys
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| Caused by: increased de novo synthesis and purine catabolism and decrease in purine salvage. Allopurinol is the usual treatment(is a xanthine oxidase and prevents the formation of uric acid)
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| Lesch Nyhan Syndrome- defect of purine nucleotide salvage, the cause of this disease is a severe or complete deficiency of HGPRT. HGPRT is located on the x chromosome so this disease is exclusively limited to males.
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| Hyperuricemia can be treated with allopurinol , there is no known treatment for the neurological symptoms
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