Question | Answer |
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 |