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Pyrimidine Biosynthesis

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17 diapositives · 650 Views · Aug 10, 2014

Pyrimidine Biosynthesis. NOTABLES. Carbamoyl Phosphate Synthetase II. Aspartate Transcarbamylase (ACTase). 2 components to make ring. PRPP (to add ribose). 5’-UMP is the product. COO -. +. H 3 N-C-H. CH 2. CO 2. +. 2ATP. +. CH 2. O. C=O. H 2 N-C~OPO 3 =. NH 2.

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Pyrimidine Biosynthesis
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  1. Pyrimidine Biosynthesis NOTABLES Carbamoyl Phosphate Synthetase II Aspartate Transcarbamylase (ACTase) 2 components to make ring PRPP (to add ribose) 5’-UMP is the product

  2. COO- + H3N-C-H CH2 CO2 + 2ATP + CH2 O C=O H2N-C~OPO3= NH2 Carbamoyl-PO4 Synthetase II + 2ADP + PO4= L-Glutamine

  3. COO- + H3N-C-H CH2 O COO- O O H2N-C~OPO3= C H HN H2N C Pi HO CH2 H C C C H C H C N COO- N COO- H O OPO3 H O Energy L-Aspartate + Carbamoyl-PO4 Aspartate Transcarbamylase Dihydroorotate

  4. O H C NAD+ NADH + H+ C C N COO- H O H HN HN C H C C C H C N COO- H O O Dihydroorotate Orotate (Looks like uracil with a -COO- group)

  5. CH2OPO3= O O O H H C C C C OPP HO OH C C N N COO- COO- H CH2OPO3= HN HN O C C HO OH O O Orotate PRPP Orotate monophosphate

  6. O O H C C C C H C N H C COO- N CH2OPO3= CH2OPO3= HN HN O O C C HO OH HO OH O O CO2 5’-OMP Uridine 5’-monophosphate (5’-UMP)

  7. ODDS AND ENDS Nucleoside Monophosphate Kinase 5’-UMP + ATP UDP + ADP Adenylate kinase ADP + ADP 5’-AMP + ATP Guanylate kinase GDP + ADP GMP + ATP Nucleoside Diphosphate Kinase UDP + ATP UTP + ADP GDP + ATP GTP + ADP ? dADP + ATP dATP + ADP ADP + ATP ATP + ADP

  8. Summary of Pyrimidine Nucleotide Biosynthesis UTP CTP TTP dCTP dTTP 5’-UMP UDP UTP dUDP CTP CDP There is no TMP, TDP, TTP dUTP dCDP dCMP Rapid dUMP dCTP dTTP dTDP dTMP

  9. O O H H N N O O N N CH3 NH2 H N O N Cytosine Post Synthesis modifications 5’-UMP UDP UTP Glutamine Deoxy Thymidine synthesis requires THF Glutamate dUDP CTP dUMP R 5,10-Methylene THF Dihydrofolate dTMP Thymine R

  10. SALVAGING Can Purine and Pyrimidine nucleotides be synthesized by joining ribose to a free ring? Yes Why is this possible? Because some tissues like brain lack the ability to synthesize the purine ring from scratch. How is this accomplished? Synthase enzymes called ribosyltransferases combine the base with PRPP producing a nucleoside mono- phosphate.

  11. O O N N H H N N H2N H2N N N N N H CH2OPO3= O HO OH Hypoxanthine-Guanine Phosphoribosyl Transferase (HGPRT) + PPi PRPP Guanine Lesch-Nyhan Syndrome

  12. Adenosine O N C H N C C O H C C N N N H C H H N C C C C N N O H H O H2O2 O2 H H2O2 O2 N C H N C C =O C C N N O H H Hypoxanthine Nucleotidase Adenine Adenine deaminase Xanthine Oxidase Xanthine Uric Acid PURINE DEGRADATION Fully oxidized Purine

  13. H N H N O O H2 H2 -O- N N C C C =O C =O C C C C N N N N O O O H H H H O H C N C H N C H2N NH2 O C =O O C C C-C N N + O 4NH4 + 2CO2 H H H O- + CO2 Allantoin (other vertebrates) Uric Acid (primates, birds, reptiles, insects) Allantoic Acid (bony fishes) 2 (marine invertebrates) + Urea Glyoxylate (amphibians, cartilag. fish)

  14. Pyrimidine Catabolism NH4+ PO4 PO4 UMP dTMP NADP+ NADPH (d)Ribose-1-PO4 + H+ O HN H2N O H(CH3) C C C H(CH3) -O- C C H CH2 H C CH2 O O N H N H H Uridine or deoxythymidine CMP Cytidine Uracil (Thymine) Dihydrouracil (Dihydrothymine) Ureidopropionate (Ureidoisobutyrate)

  15. O H(CH3) -O- C CH CH2 N O COO- H2N H2N O H(CH3) -O- C COO- CH-(CH3) C C H(CH3) CH -O- C CH-(CH3) HS-CoA CH CH=O CH2 C=O H2 N CH2 O O NADH + H+ N S-CoA NAD+ + CO2 + NH4+ H2 (Methyl)malonyl semialdehyde Malonyl-CoA (Methylmalonyl-CoA) Succinyl-CoA

  16. Quiz 4 BIOSYNTHESIS of Nucleotides Take a sheet of paper. Put your name on it. Your task is to determine the minimum number of compounds required to make UTP. I The compounds that you select must be. (1) two amino acids that are closest to UTP in the pathway (2) one high energy source (3) one carbohydrate that is closest to UTP in the pathway Show how it is possible to synthesize UTP with only two of the compounds named above. II Part I is worth 1 points or 4 points total Part II is worth 4 points

  17. II. Answer: Select glutamine and ATP Pathway: Gln -> Glu -> Kg -> OAA ->Aspartate OAA -> PEP -> ->Glu-6P -> Ribose-5-P -> PRPP I Answers: 1. Amino acids: glutamine, aspartate 2. Energy source: ATP 3. Carbohydrate: Ribose or Ribose-5-PO4