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					 Biosynthesis and degradation of
          nucleotides
• Nucleotides are precursors of DNA and
  RNA, essential carriers of energy as ATP,
  GTP, NAD, FAD, CoA, etc., signaling
  mechanisms, and activated biosynthetic
  precursors.
• Two pathways lead to nucleotide synthesis
  – de novo
  – salvage
   de novo nucleotide synthesis
• Appears identical among all organisms
• Bases (guanine, etc.) are NOT intermediates
  in pathway
• Purine rings not synthesized and attached to
  ribose, assembled on the ribose
• Pyrimidine synthesized as orotate, attached
  to ribose phosphate and converted to
  nucleotides
  Pyrimidines and purines share
           precursors
• Phosphoribosyl pyrophosphate (PRPP) is a
  key intermediate for both (also involved in
  tryptophan and histidine synthesis also)
• Amino acids are important precursors,
  glycine for purines, and aspartate for
  pyrimidines
• Also, glutamine and aspartate serve as
  sources of amino groups in both purine and
  pyrimidine biosynthesis
  PRPP serves as the foundation
for purine nucleotide biosynthesis
Three atoms from glycine are
added to the new amino group
This chain is extended by formate
             addition
An amine group is donated by
        glutamine
The FGAM ring is closed to
       form AIR
AIR is carboxylated to CAIR
(unique because doesn’t use biotin)
A mutase rearranges the
     carboxylate
Aspartate donates an amino group in
    two steps to form AICAR
Another formate group is
donated, carried by THF
Ring closure forms Inosinate
           (IMP)
Summary of purine atom origins
IMP is converted to purine
       nucleotides
Regulation of purine biosynthesis
• Three major feedback loops
  – Primary regulation is AMP, GMP, and IMP
    inhibiting glutamine-PRPP amidotransferase
    (the first committed step)
  – IMP branchpoint to AMP and GMP is regulated
    independently by end products
  – Additional regulation is inhibition of PRPP
    synthesis (using ADP or GDP)
Pyrimidine biosynthesis from aspartate,
   PRPP, and carbamoyl phosphate
• Base (as orotate) is made first then attached
  to ribose 5-phosphate
• Orotate synthesis begins with aspartate
  reacting with carbamoyl phosphate to form
  a product which is cyclized to
  Dihydroorotate
• Dihydroorotate is oxidized to orotate, which
  reacts with PRPP
• This product can undergo subsequent
  reactions to form UMP, UTP, and CTP
      Pyrimidine biosynthesis
            regulation
• Mostly through the allosteric behavior of
  aspartate transcarbamoylase, which
  catalyzes the first step and is inhibited by
  CTP (inhibition can be prevented by ATP)
    Nucleoside monophosphates are
  converted to nucleoside triphosphates
• AMP  ADP (adenylate kinase)
• ATP + NMP  ADP + NDP (nucleoside
  monophosphate kinases)
• Nucleoside diphosphate kinase converts
  nucleoside diphosphates to triphosphates
  (generally ATP is phosphate donor)
 From these pathways, you note that
 ribonucleotides are being generated
• To get deoxyribonucleotides (precursors of
  DNA), the 2’ carbon atom must be reduced
• Accomplished by an interesting enzyme
  ribonucleotide reductase
• A pair of hydrogen atoms originating from
  NADPH are passed to ribonucleotide
  reductase by either glutaredoxin or
  thioredoxin to generate an activated enzyme
  intermediate
Ribonucleotide reductase catalytic
mechanism includes free radicals
   Regulation of ribonucleotide
            reductase
• Both activity and substrate specificity is
  modulated by binding of effector molecules
• At one binding site:
ATP activates enzyme;
dATP inactivates enzyme

A second binding site
monitors substrate binding
dTMP is generated from dUMP

				
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posted:2/27/2012
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