Doc Sange - SUMMARIZED

• Nitrogenous base


  • Purine and pyrimidine
  • Heterocyclic
  • Rings contain hydrogen
  • Possess the chemical properties of a base
  • Proton acceptor with proton at low pH associated with ring nitrogen
• Nitrogenous base types


  • Adenine (A)
  • Guanine (G)
  • Cytosine (C)
• Nucleosides


  • Also called N-glycosides
  • Structure: Nitrogenous base + Pentose Monosaccharide
• Nucleosides


  • Sugar is linked to 1 ring nitrogen atoms by a-N-glycosidic bond
  • 2 types: Ribonucleosides (D-ribose) and Deoxyribonucleosides (2-deoxy-D-ribose)
• Nucleotides


  • Structure: Nucleosides (Nitrogenous base + Pentose monosaccharide) + Phosphate groups
  • Most nucleotides are 5' (phosphate group is attached to 5'-hydroxyl group)
• Nucleobases


  • Pyrimidine
  • Purine
• Pyrimidine vs Purine


  • Pyrimidine: single ring, diazine

  Purine: double ring, pyrimidine + imidazole

  Pyrimidine is smaller, Purine is bigger

  Pyrimidine numbering is clockwise, Purine numbering is counterclockwise
• Nucleobases


  • Guanine
  • Adenine
  • Cytosine
  • Uracil
  • Thymine
• Nucleobase forms


  • X=H (base)

  X=RIBOSE (nucleoside)

  X=RIBOSE PHOSPHATE (nucleotide)
• Polynucleotides


  • Pentose moieties linked by phosphodiester bonds to form the backbone of RNA and DNA

  Directional 3' → 5' phosphodiester bonds

  Representation: 5'-base (G) at left, 3'-base (A) at right (GCUA)

  Terminal 5'-hydroxyl is phosphorylated (pGpCpUpA)
• Nucleotides


  Act as 2nd messengers (cAMP, cGMP)

  Serve as components of coenzymes (NAD, NADP, FAD, CoA)

  Act as energy source in the cell (ATP, GTP)

  Provide sulfate for sulfate conjugation of drugs

  Regulatory compounds for pathways in intermediate metabolism

  Serve as carriers of activated intermediates in the synthesis of carbohydrates, lipids, and conjugated proteins

  Serve as proton donors or proton receptors at pH values ~2/more units above or below neutrality
• Synthetic nucleotides


  Analogs of purines, pyrimidines, nucleosides, and nucleotides modified in heterocyclic ring or in sugar moiety

  Either inhibit enzymes essential for nuclei acid synthesis or they are incorporated into the nuclei acid

  Chemotherapeutic agents incorporated into DNA prior to cell division
• Synthetic nucleotides


  • 5-fluoro or 5-iodouracil

  1. deoxyuridine
  2. thioguanine and 6-mercaptopurine
  3. or 6-azaruridine
  4. or 6-azacytidine
  5. azaguanine

  Cytarabine
• Azathioprine


  Suppresses immunologic rejection, employed during organ transplantation
• Allopurinol


  Purine analog, treatment in hyperuricemia and gout, inhibits purine biosynthesis and xanthine oxidase activity
• Non-hydrolyzable nucleoside triphosphate analogs


  Elucidate the mechanisms of action of nucleoside triphosphate enzymes, natural nucleotides are hydrolyzed at rates usually preventing such studies
• Pseudouridine


  Post-translational modification of preformed nucleotides, nucleoside with D-ribose linked to C5 Uracil by a carbon-carbon bond rather than usual beta-N-glycosidic bond
• Conjugated double bonds of purine and pyrimidine derivatives absorb UV light, at pH 7 all common nucleotides absorb light at wavelength around 260 nm, explains how UV can exert mutagenic effects on DNA
• Processes that contribute to purine nucleotide biosynthesis


  • Synthesis from amphibolic intermediates (De Novo Synthesis)
  • Phosphoribosylation of Purine
  • Phosphorylation of Purine Nucleotides
• Liver is the major site of purine nucleotide biosynthesis, purine ring is constructed primarily in liver by a series of reactions that add the donated carbons and nitrogen to ribose sugar
• Steps in De Novo Nucleotide Synthesis


  5 steps need ATP

  2 steps – N10-formyl-THF (1-carbon donor)

  2 steps – glutamine (1-nitrogen)

  1 step – glycine (2-carbon, 1-nitrogen)

  1 step – aspartate (1-nitrogen)
• Steps in De Novo Nucleotide Synthesis


  • step 1 - Phosphoribosyl pyrophosphate
  • Step 2 - 5-phosphoribosylamine synthesis
  • Steps 3-12 Inosine monophosphate synthesis
• Inhibitors of purine nucleotide synthesis


  • Folic acid analogs (Methotrexate)
  • Glutamine analogs (Diazanorleucine)
  • Glutamine-depended enzymes (Azaserine)
  • Purine analogs (Allopurinol, Acyclovir)
  • PABA analogs (Sulfonamides)
• Pathogens that inhibit purine nucleotide synthesis: Varicella virus, Herpes zoster, Herpes labialis
• Disorders of purine metabolism

  • Lesch-Nyhan Syndrome
  • Von Gierke disease
  • Hypouricemia
  • Xanthine oxidase deficiency
  • Adenosine deaminase deficiency
• Disorders of pyrimidine metabolism


  • B-Hydroxybutyric aciduria
  • Orotic aciduria (Type 1 and Type 2)
• Drugs that may precipitate orotic aciduria

  • Allopurinol
  • 6-azauridine
• Methotrexate

  Control cancer by interfering with synthesis of nucleotides
• Diazanorleucine


  Antibiotic isolated from streptomyces with antineoplastic activity
• Azaserine


  Isolated from streptomyces, antifungal, antibacterial, antineoplastic
• Allopurinol


  Treatment for hyperuricemia and gout
• Acyclovir


  herpes zoster, varicella virus

  analog to dGTP

  synthetic inhibitors of DNA replication
• Sulfonamides


  Inhibits growth of rapidly dividing microorganisms

  synthetic inhibitor of purine synthesis
• Lesch-Nyhan syndrome


  Defect in xanthine-guanine PRT

  Frequent episode of uric acid lithiasis and self-mutation
• Von Gierke disease

  G6P deficiency
• Hypouricemia


  Xanthine oxidase deficiency
• Beta-hydrobutyric aciduria


  Deficiency of dihydropyrimidine dehydrogenase
• orotic aciduria


  Accompanies reye syndrome
• Type 1 orotic aciduria


  Deficiency of both PRT and orotidylate decarboxylase
• Type 2 orotic aciduria


  Deficiency of orotidylate decaarboxylase ONLY