Nucleotide Metabolism Study Resources

Purines Synthesis Twa ways: -De novo; it begins with metabolic precursor. synthesis Af nucleotides ; aminoacids, R-5-P, CO2, one-carbon units • Salvage palhuny: synthesis of nucleotides by recycling their free bases or nucleosides released from nucle acids breakdown. • De Novo synthesis id purines raising storichis - It takes place mostly in cytosol of liver small intestine, and thymus - Starting material &s Phosphoribose (R-5-P) - The active donor of R-5-P is PPP (5-Phosphoribusy - 1- Payrophosphate finet product - End produet & the plea pathway is IMP which is synthesisted further to AMP GMP. * From all the vitamins, the most impprtant Vitamin for nucleotide synthesis is Vitamin B9 (folic acil) Por both, Rurines & pyramidines (because it has eXtra cabons Bito donate, groups to donate PARDISI ATP used : 7 ATP'S H2O Produced : 2H20 * Final product is always monophosphate (it more is needed it will be added) Regulation of dennovo synthesis 95 feedback inhibition; so most important regulators are the products (AMPS GTP) Stept: activation d ribose - 5-Phaphate • usage of two ATP to phosphorylate r- 5-P andform PRPP • enzymis used: ribose phosphate pypiphosphotinese • Iti s called a committed step Step 2: acquisition of purine atom N9 • Usage & Glutamine to tate one fits amines and caneringit to Glutamate • E removal 6l PP. (Pyrophosphate) & exchanging it with on a mine group (Ng) • enzyme used : PRPP amidotranferase Note: Step 1&2 are tightly regulated by feedback inhibition step 3: acquisition of purine atoms Cu, C5, 1 N7 • Use full usage of glycine to give its two carbons done amine group • usage ALATP molecule • Enzyme used: glycinemide synthetase Stept 4: acquisition of purine atom C8 • Usage A Vitamin 134B9 (type N° Formyl Hu Folare) to toke faring as a carbon and converting it to no Ha Folate ARDIS • Enzyme used: GAR Transformylase Step5: acquisition of purine atom N3 - Usage of another Glutamine to take one st its amines and converting it to Calutamite • this requines 1 more ATP molecuk Step 6: Closing the imida zole ring • closure of the ring, which requires 1 Atp molecule • Release A 1H20 molecule step 7: acquisition of C6 • Consumption of a co, molecule from bicarbonate HCO • Consumptionot 1 ATP • En zyme used : AIR carboXylase step8: guisition acquisition of N. • Usage of Aspartate by joining it to the C6 so it can donate its amine group • Usage of anothe ATP • Enzyme used : SALCAR Synthetase step 9: Elimintion a fumarate • The part of Aspartate without the amine group $ called Fumarate and it muds to be eliminated by an enzyme - Enzyme is called, adenylosuccinate, yase Step 10; acquisition of Cz • Again, N°-Formyl Hu Folate is used repto consume its Catom (Formyl) and Hu Folate is veleased adding a C atom caposition Ca • Enzyme used: AICAR transformylase Step 11: Ring closure to fern IMP • Ring gets closed by attatching C2 to amine grous, releasing an H20 molecule forming the lint product! (IMP) * One once formed, IMP is converted rapidly to AMPeGMP/i+ does not accumtate in cells) * Final Productis always a monophosplate, epiTe are In this processi adden te men our produced if requiel ATP'sused : 7 ATP'S Amino arids used: 4: Glutamate (usal twice), Glycine, As partite vitamin B9: Used twice AIn conversion of + IMP to AMP & GMP; IMP Adenso Succinate (Inosinale) (EMPattatchedto) GTP -portate Aspartate NAD IMP GDP+P, NADH MI* > XMP (Xanthylate) Oxygen is added on C → Adenglate (NMP) (amire gp on C 6)) ARDIS Fumarete GlutenoR Calycine Guangbte (GMP AMP+PP: o, is exchanges with me amine gP A Glycine • Most Imp. regulators of the de novo synthesis are: *Negative Fahibitors; AMP, GMP, GTP, - - etc 7 Positive regulators (activater) i PRPP → Salvage Pathway • Synthesising prit nucleotiles by recycling intermedine a purines or by degradation ot RINA or DNA • This pathway is significant becaus it uses almost ene energy so it is a fuel saver • Takes place mostly in the brain and bore marrow which are organs and tissues that could only produce nucleotides using this way • Two phosphoryl transterases are west involved - APRT (Adenine phosphoribes transferase) for Adenine - HGPRT (Hypothine Guanite phosphoriboy) transterase) for Enanine & Hypoxanthine Adenine. (APRT) / PRPP Hypo kanthine . (HGPRT) → AMP PRPP PPe IMP Guanine GMP ARDIS (HGPRT) * Absena of HGPRT Will cause Lesch-Nyhan syndrome • Final product of purine degredation is unic acid (28 20195 <2,698 -trioxypurine) * it is more souble than the rest of purines - when rio acid conc. A in our body, GOUT will leform in He body (by formahon ot crystals in soft tissue jex. in joints, Kidneytabess.. - The reason of uric acid conc. I is that purines are degraded / concumption of a bot of nucleoproteins. - GOUT can be treated by decreasing conc. & Uric acid, which is produced by the aid of an enzyme called Xanthive oxidase, so if we block the enzyme, uric acid production can be reduced → suicide inhibitor Allopurino, a kindot purine that is very similar to hypotentine, just the place of Nitrogen is diffevent. So, the enZyme can not distinguish it. when providing this drug, the enzyme can be decieved and it will block Hyporantine Prom forming Zantine, So uric acid production will get reduced -People with lech-Nayhan, which have solvage pathay nit vorte in them, which means they can not produce neates, also ta might have gouts and this is because they can not use salvage pathway because conthe enzymes are not working hence the cells can not work well, so the brain is affected. Since they can not be used by brain tells, they go to other cells to produce nuck did in delicat places by de nove syntesis, so this is a bad effect sinceit is het usehul by the brain, in which production of nuclecides a since is is a+ ellfatos, it will to to the rest of the & body hence more vic acid = Producing Gouts. - In a condition of cancer, many cells get produced (un wanted cells), 5o as a Strategy of anti-canargus treatement, drugs senich are responsible for producing nucleotides in the brain goes get #inhibited, hence interfering in the metabolism of nucleoties Hence by using andogues, Bwhich are similar to structure & something but are not the same structure, of folic acids, amino acids to try to stop these procases from occuring, te in anattempt to treat cancer Synthesis of Pyrindine Egoluis Nucleotides • Shorter pathway than purines • Pyrimiine rings are made first, then altatched to ribose-P (unlike purine biosynthesis * only 2 Precursors (Asparatate and glutamine, plus HCO;) contrbute to the 6-membered ring • requires 6 steps • First product is UMP (uridine monophosphate) • Structural difference between DNA &RNA is that in RNA, C #2 has a Hydroxyl group (-OTH) binded to it whe in DNA, C H2 does not have, hence why its called deoxyfibase • The reason why DNA does not have the (- OH) binded to it is that if it was there, it would prevent DNA from being double stranded • So it has reduced (DNA) and oxidized (RNA) form. • Theoredoxine is ena coenzyme that provides e/H/a kinalanes that are required to change ribose to deoxyribose "Enzyme used is reductase • D-Phosphate form Carbanayl Phosphate synthetase (CPS) exists in 2 types -CSI, a mitochondriul enzyme, is dedicatedto urea cycle and arginine biosynthesis - CPS-II , a cytosaic enzyme used in pyrimidine synthe sisto # TH is a commited step in animals HCO3- + Glutamine + 2ATP + H2O --Carbamoyl Phosphate Synthetase II--> Carbamoyl Phosphate + 2ADP + Pi + Glutamate Carbamoyl Phosphate + Aspartate --Aspartate Transcarbamylase (ATCase)--> Carbamoyl Aspartate Step: synthesis of Carbamoyl Aspartate Dihydroorotate Step: Synthesis of Carbamoyl Aspartate Step3 ring closure Dihydroorotate OH Step: decarboxylation of OMP Dihydroorotate Uridine Monophosphate (UMP) acquisition of moiety Orotate Orotate monophosphate (OMP) CO2 PRPP PP