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Assessment 1.3
Nucleotide Metabolism: Purine Metabolism
Question | Answer |
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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) |
Synthesize nucleotides directly from amino acids and other precursors | |
The cell can interconvert between specific nucleotides | |
The basis for this "fixed" concentration of nucleotides is that de novo synthesis and salvage pathways are very rigidly controlled under normal conditions. | |
De Novo Purine Sythesis | synthesis of the purine nucleotides from other unrelated compounds (scratch) |
In practice purines, are synthesized using three components: amino acids (carbon & nitrogen donors), tetrahydrofolate (carbon donor), & carbon dioxide (carbon donor) | |
occurs entirely in the cytosol | |
not all cells are capable of de novo purine synthesis (white and red blood cells) | |
IMP: AMP & GMP are synthesized thru a common intermediate inosine monophosphate- IMP; requires a lot of energy | |
PRPP Synthesis: de novo synthesis and all savage pathways use a common reactant called phosphoribosylpyrophosphate (PRPP), Highly Regulated- inhibited by other nucleotides | |
PRA Synthesis: Once PRPP is available, de novo purine synthesis can occur, which begins with the synthesis of 5-phosphoribosylamine (PRA) | |
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. | |
There is no regulation of IMP synthesis after this step | |
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 | |
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 | |
GMP Synthesis- nitrogen comes from Glutamine, AMP Synthesis- nitrogen comes from Aspartate | |
Formation of Purine NTP- are formed from either AMP or GMP by the action of two enzymes, which this stage of synthesis is unregulated | |
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 |
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 | |
HGPRT reacts hypoxanthine or guanine with PRPP, APRT reacts adenine with PRPP | |
Purine Salvage Regulation | Regulated, the products inhibit the pathways, HGPRT is inhibited by IMP & GMP, APR is inhibited by AMP |
Use of this pathway inhibits the de novo synthesis pathwa by lowering the level of PRPP, raising the level of purine NTP | |
Nucleoside Salvage- only the sugar and base no phosphate group | specific enzymes, stray purine nucleosides can also be salvaged |
Purine Nucleotide Interconversion | advantageous for the cell to be able to interconvert between AMP & GMP which occurs indirectly thru IMP |
IMP can then be converted thru the de novo pathway to either AMP OR GMP as needed | |
Interconversion Regulation | Interconversion of nucleotides is regulated to maintain a suppply of both |
AMP conversion to IMP is inhibited by GTP & GDP but enhanced by ATP | |
GMP conversion is IMP is strongly inhibited by XMP but increase by GTP | |
XMP tell that the cell is actively making GMP | |
Purine Nucleotide Catabolism | Catabolism of Purines- the breakdown of purines follows a common path to uric acid; unregulated, nucleases breakdown either DNA or RNA |
Guanine Catabolism- guanosine, guanine and xanthine | |
Adenine Catabolism- look at page 22 of notes | |
Purine Catabolism- Xanthine is oxidized by xanthine oxidase to give uric acid which is then secreted | |
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 |
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) | |
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. | |
Hyperuricemia can be treated with allopurinol , there is no known treatment for the neurological symptoms |