HBG 15 ( Nucleic Acid)

• Nucleosides/nucleotides:

  • Pyrimidine nucleosides: Cytidine, Thymidine, Uridine
  • Purine nucleosides: Adenosine, Guanosine
• Functions of nucleotides:

  • Precursors for nucleic acids (A, C, G, T, U)
  • Structural moieties for coenzymes (NAD+, FAD, coenzyme A)
  • Energy-rich compounds (ATP, GTP)
  • Intermediate in biosynthetic pathways (UDP-glucose, CDP-diacylglycerol)
  • Second messenger (cAMP, cGMP)
• Biosynthesis of nucleotides:

  • Common precursor for both de novo and salvage synthesis
  • PRPP provides ribose-5-phosphate to purines and pyrimidines synthesis
  • R5P is synthesized through PPP (pentose phosphate pathway)
• Degradation of nucleotides:

  • Degradation of purine nucleotides leads to uric acid formation
  • Salvage synthesis of GMP does not require ATP
  • De novo synthesis of GMP requires energy in the form of ATP
  • Rate-limiting steps occur at the first 2 steps
• De novo purine synthesis:

  • Purine rings are built on ribose
  • Aspartate provides atoms for purine synthesis
  • ATPs are required
  • CTP and UTP function as inhibitors
  • Orotidine 5’ monophosphate is the first nucleotide being synthesized
• Feedback inhibition:

  • PRPP synthetase is feedback inhibited by purine-5’-nucleotides (mainly ADP & GDP)
  • PRPP amidotransferase is feedback inhibited allosterically by ATP, ADP, AMP, GTP, GDP, and GMP
• Nucleotide salvage:

  • In the liver, nucleotides can be converted to nucleosides or free bases and transported to other cells
  • Most cells can salvage existing bases to generate nucleotides for RNA and DNA synthesis
• Nucleotide synthesis:

  • Adenine phosphoribosyl transferase (APRT) and Hypoxanthine guanine phosphoribosyl transferase (HGPRT) add Ribose-5’-Phosphate from PRPP to a free base to generate nucleotide
  • Deficiency of HGPRT causes Lesch-Nyhan Syndrome
• Deficiency of HGPRT causes Lesch Nyhan Syndrome
• Building the purine ring onto the sugar involves 11 steps with simple metabolites
• Purines: PRPP, IMP, AMP, GMP, ADP, GDP, ATP, GTP
• Building the free pyrimidine ring involves Orotate, OMP, UMP, UTP, CTP, UDP
• Nucleoside diphosphate kinase involves PRPP in 4 steps for the 1st pyrimidine nucleotide
• The base is synthesized first before it is attached to the R5P moiety supplied by PRPP
• Atoms of the ring come from Asp + carbamoyl phosphate (derived from CO2 + Gln)
• Step 1: Carbamoyl-P is synthesized in the cytosol from 1x Gln, 2x ATP & 1x CO2 by carbamoyl-Phosphate synthetase II (CPS II)
• Orotic acid (orotate) is converted to the 1st pyrimidine (OMP) through several steps involving Asp, Carbamoyl aspartate, ATCase, Ribose-5-P, PRPP, Orotate phosphoribosyl transferase
• Uridine monophosphate (UMP) is produced from orotidine 5’-monophosphate (OMP) through decarboxylation
• Thymidine nucleotides only exist in deoxyribose form
• Conversion of pyrimidine bases to nucleosides is done by non-specific pyrimidine nucleoside phosphorylase
• Thymine phosphorylase adds a deoxyribose residue to thymine
• Specific nucleoside kinases catalyze the phosphorylation of nucleosides to form nucleotides
• Synthesis of dTTP requires dUMP, which is converted to dTMP by thymidylate synthase
• N5,N10-methylene THF donates a methyl group and becomes DHF
• DHF is converted back to THF by dihydrofolate reductase, a target for chemotherapy
• Thymidine nucleotides are dephosphorylated to nucleosides, then cleaved to produce R1P + free bases (cytosine, uracil & thymine)
• Cytosine is deaminated to uracil, which is converted to CO2, NH4+, and β-Ala
• Thymine is converted to CO2, NH4+, and β-aminoisobutyrate
• Hyperuricemia is characterized by abnormally high levels of uric acid in the serum
• Causes of hyperuricemia include under excretion, overproduction & intake of uric acid, and excessive alcohol consumption
• Treatment for hyperuricemia includes anti-inflammatory agents, XO inhibitors, and uricosuric agents
• Lesch Nyhan Syndrome is an inherited disease caused by mutations of the gene encoding for hypoxanthine guanine phosphoribosyl transferase I (HGPRT I)
• Patients with Lesch Nyhan Syndrome are usually treated with ALLOPURINOL to reduce uric acid production
• Lesch Nyhan Syndrome is an autosomal recessive disorder with deficiencies in Orotate phosphoribosyl transferase and Orotidine 5’-P decarboxylase
• Pyrimidine cannot be synthesized in Lesch Nyhan Syndrome