#20. Made by: rahmeh alsukkar & Enas Omar & Ahmad Abudayyeh 29/11/2016. Record 27

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1 #20 Made by: rahmeh alsukkar & Enas Omar & Ahmad Abudayyeh 29/11/2016 Record 27

2 Nucleotide Metabolism de Novo pathway synthesis from different sources salvage Pathway as recycling in salvage pathway : عندم يحدث breakdownل خاي ا لل, RBCs مك ن ت من ال ال DNA RNA تتحط ينتج من basis هذه ال basis ا يحدث losssing في ال urine بدل ذل يحدث ل عم يه ال من reabsorption ث يض ف ل مجم ع ت جديده لنحصل ع ى مركب ت اخرى مط به ** PRPP phosphate ribose pyrophosphate slide ( ) Two types of pathways lead to nucleotides: the de novo pathways and the salvage pathways. De novo synthesis of nucleotides begins with their metabolic precursors: amino acids, ribose 5-phosphate, CO2, and NH3. Salvage pathways recycle the free bases and nucleosides released from nucleic acid breakdown.

3 Salvage and de Novo Pathways The purine ring structure is built up one or a few atoms at a time, attached to ribose throughout the process. The pyrimidine ring is synthesized as orotate, attached to ribose phosphate, and then converted to the common pyrimidine nucleotides required in nucleic acid synthesis. Although the free bases are not intermediates in the de novo pathways, they are intermediates in some of the salvage pathways. * in de novo pathway the glycine is the main amino acid بسايد رق م كل مرك ش بعطي ; يعني مثا : glycine N7,C4 and c5 N10-formyl-tetrahydrofolate C2 and C8 Glutamine N3 and N9 asparatate N1 ** note that N10-formyl-tetrahydrofolate come from folic acid.

4 ** the aim of purin and pyrimidine synthesis is to build up of DNA and RNA ** phospho ribose byrophosphate is an activated ribose. كم في ال glucose ك ن UDP ه ال active glucose ** THF tetra hydrofuran slide (6,7,8,9,10,11) de Novo Pathway for Purine Nucleotide Synthesis The synthesis of the purine ring is more complex. The only major component is glycine, which donates C-4 and C-5, as well as N-7. All of the other atoms in the ring are incorporated individually. C-6 comes from HCO3. Amide groups from glutamine provide the atoms N-3 and N-9. The amino group donor for the inclusion of N-1 is aspartate, which is converted into fumarate in the process, in the same way as in the urea cycle. Finally, the carbon atoms C-2 and C-8 are derived from formyl groups in N10- formyl-tetrahydrofolate

5 The Purine Ring System Is Assembled on Ribose Phosphate Glutamine phosphoribosyl amidotransferase catalyzes this reaction. De novo purine biosynthesis, like pyrimidine biosynthesis, requires PRPP, but for purines, PRPP provides the foundation on which the bases are constructed step by step. The initial committed step is the displacement of pyrophosphate by ammonia, rather than by a preassembled base, to produce 5-phosphoribosyl-1-amine, with the amine in the β configuration.

6 de Novo Purine Biosynthesis Inosinate Formation GMP ا AMP *ال ) phosphate IMP (Inosin mono الن تج يكمل في احدى الطري ين لينتج ام ** note that step 1 in the AMP production pathway require ATP while step 1 in GMP pathway require NAD+ * سايد رق م نعرف كل خط ه ش بتحت ج ش بط ع من ر ن بين الطري تين. ** XMP xanthine mono phosphate ** purine and pyrimidine synthesis in the de novo pathway are step by step slide (12.13)

7 Generating AMP and GMP كل المك ن ت ال ي بتط ع بترجع تعمل ام : 1. Negative feed back inhibiton for the IMP using adenylosuccinase pathway or AMP dehydrogenase or 2. Inhibits the ribose bi phosphate to prevent the synthesis. ** remember that the main function in pentose phosphate pathway is to give ribose bi phosphate and NADPH ** the metabolic end product of the purin catabolism is Uric acid not urea * in some animals the reaction continuous to give urea ** the end product in birds is the uric acid not urea because urea need water for exertion.

8 ** HGPRT Hypoxanthine-guanine phosphoribosyltransferase slide (14,15,16,17)

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10 Salvage Pathways Economize Intracellular Energy Expenditure Two salvage enzymes with different specificities recover purine bases. Adenine phosphoribosyltransferase catalyzes the formation of adenylate In purine synthesis we use 5 ATP. In this reaction adenine is added to the activated ribose PRPP. In salvage pathway recycling of bases takes place. Bases undergo resynthesis, such as iron & hemoglobin in RBCs ( span life =120 days). When degradation of RBCs occurs iron & hemoglobin are reabsorbed by the kidneys to be used later. whereas hypoxanthine-guanine phosphoribosyltransferase (HGPRT) catalyzes the formation of guanylate as well as inosinate (inosine monophosphate, IMP), a precursor of guanylate and adenylate Pyrimidine Nucleotides Are Made from Aspartate, PRPP, and Carbamoyl Phosphate The common pyrimidine ribonucleotides are cytidine 5- monophosphate (CMP; cytidylate) and uridine 5-monophosphate (UMP; uridylate), which contain the pyrimidines cytosine and uracil. De novo pyrimidine nucleotide Biosynthesis proceeds in a somewhat different manner from purine nucleotide synthesis; the six-membered pyrimidine ring is made first and then attached to ribose 5-phosphate. In purines the common ribonucleotide is IMP ( inosine monophosphate ).

11 In the first step of the carbamoyl phosphate synthesis pathway, bicarbonate is phosphorylated by ATP to form carboxyphosphate and ADP. Ammonia then reacts with carboxyphosphate to form carbamic acid and inorganic phosphate. Another pathway to synthesize carbamoyl phosphate is the reaction between ammonia and carbon dioxide ( in urea cycle ). Carbamoyl phosphate reacts with aspartate to form carbamoylaspartate in a reaction catalyzed by aspartate Transcarbamoylase. Carbamoylaspartate then cyclizes to form dihydroorotate which is then oxidized by NAD+ to form orotate. Aspartate transcarbamoylase : is an allosteric enzyme which has a quaternary structure and contains six catalytic units. Aspartate is the main product of pyrimidine nucleus.

12 Orotate reacts with PRPP to form orotidylate, a pyrimidine nucleotide. This reaction is driven by the hydrolysis of pyrophosphate. The enzyme that catalyzes this addition, pyrimidine phosphoribosyltransferase Pyrimidine synthesis Glutamine is used to give ammonia. Carbamoyl phosphate reacts with aspartate to yield N-carbamoylaspartate in the first committed step of pyrimidine biosynthesis. This reaction is catalyzed by aspartate transcarbamoylase. By removal of water from N-carbamoylaspartate, a reaction catalyzed by dihydroorotase, the pyrimidine ring is closed to form L-dihydroorotate. This compound is oxidized to the pyrimidine derivative orotate, a reaction in which NAD is the ultimate electron acceptor.

13 Salvage pathway is easy because we just add a base to a sugar, while de novo synthesis is more complicated because we add components step by step to get purines and pyrmidines. Once orotate is formed, the ribose 5-phosphate side chain, provided once again by PRPP, is attached to yield orotidylate. Orotidylate is then decarboxylated to uridylate, which is phosphorylated to UTP. CTP is formed from UTP by the action of cytidylate synthetase. de Novo Pathway for Pyrimidine Nucleotide Synthesis. Carbamoyl phosphate synthetase 2 is an enzyme used in this pathway but carbamoyl phosphate synthetase 1 catalyzes reactions in urea cycle. Carbamoyl phosphate is an intermediate in both urea cycle and pyrimidine nucleotide synthesis. Aspartate is the main amino acid component in pyrimidine synthesis. Glycine is the main amino acid component in purine nucleotide. Aspartate is found in both pyrimidines & purines. PRPP is an intermediate in pyrimidines & purines. The C-2 and N-3 atoms in the pyrimidine ring come from carbamoyl phosphate, where as the other atoms of the ring come from aspartate. The pyrimidine ring is made up of three components:

14 the nitrogen atom N-1 and carbons C-4 to C-6 are derived from aspartate, carbon C-2 comes from HCO3-, and the second nitrogen (N-3) is taken from the amide group of glutamine. GTP will inhibit aspartate transcarbamoylase. UMP will inhibit carbamoyl phosphate synthetase. **Source of purins in food: homos, organs meat and some fish. **The goal of chemotherapy is to inhibit the synthesis of purines and pyrimidines in cancer cells so that it will die because it will lack DNA and RNA. تم قراءة باقي السايدات كما هي دون اضافات