Biosynthesis of Nucleotides and Nucleic Acids

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Biosynthesis of Nucleotidesand Nucleic Acids
Biosynthesis of purine nucleotides Biosynthesis
of pyrimidine nucleotides Polymerization of
nucleotides by the enzyme DNA polymerase
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Structures of Nucleotide Bases
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Nucleotide Structure
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5-phosphoribosyl-1-pyrophosphate (PRPP)
The ribose phosphate in the final nucleotide
product is obtained from the precursor
molecule5-phosphoribosyl-1-pyrophosphate (PRPP).
Ribose 5-phosphate
Ribose phosphatepyrophosphokinase
5-phosphoribosyl-1-pyrophosphate (PRPP)
Nucleotides
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Biosynthesis ofPurine Nucleotides
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Origin of the ring atoms of purines
HCO
HCO
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Step 1 An amino group donated by glutamine is
attached at carbon 1 of PRPP
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Step 2 Three atoms from glycine, an amino
acid,are added to what will become the
five-membered ring
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Step 3 The added glycine amino group is
formylated by N10-formyltetrahydrofolate
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Step 4 A nitrogen is donated by glutamine
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Step 5 Dehydration and ring closure producesthe
five-membered imidazole ring of the purine
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Step 6 A carboxyl group is added using
bicarbonate
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Step 7 A rearrangement transfers the carboxylate
from theexocyclic amino group to position 4 of
the imidazole ring
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Step 8 Aspartate is added to the carbonderived
from bicarbonate
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Step 9 The carbon skeleton of aspartate is
eliminated as fumarate
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Step 10 The final carbon atom is contributed
byN10-formyltetrahydrofolate
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Step 11 Ring closure produces inosinate (IMP)
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Inosinate monophosphate (IMP) is a purine ring
precursor
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Adenylate and Guanylate are synthesized from
Inosinate
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Adenylate and Guanylate are synthesized from
Inosinate
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Biosynthesis ofPyrimidine Nucleotides
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UTP and CTP
H
Synthesis of pyrimidines UTPand CTP
fromaspartate andcarbamoyl phosphate
OPO3
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Synthesis of pyrimidines UTPand CTP
fromaspartate andcarbamoyl phosphate
Dehydration and ring closure
Formation of a double bond
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Synthesis of pyrimidines UTPand CTP
fromaspartate andcarbamoyl phosphate
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Synthesis of pyrimidines UTPand CTP
fromaspartate andcarbamoyl phosphate

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Synthesis of deoxyribonucleotides
Ribonucleotides are used for RNA synthesis.For
DNA deoxyribonucleotides are needed. The 2
carbon of ribose is reduced to form
deoxynucleotides. Ribonucleotide reductase
catalyzes the reduction of 2 carbon.
H
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Synthesis of Thymidylate
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Catalysis by thymidylate synthase
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Nucleotide Biosynthesis and Cancer
Cancer cells, which are growing more rapidly than
normal cells have a requirement for the
synthesis of new DNA. Cancer cells, therefore,
are more sensitive to drugs that
inhibit nucleotide biosynthesis than a normal
cell. Many chemotherapeutic agents act by
inhibiting enzymes of nucleotide biosynthetic
pathways.
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Azaserine and Acivicin
Glutamine analogs azaserine andacivicin inhibit
glutamine amidotransferases, enzymes
thatprovide nitrogen for manynucleotide
biosynthetic pathways.
XMP-glutamineamidotransferase
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Thymidylate synthase and dihydrofolate reductase,
enzymes critical forthe synthesis of
thymidylate, are primary drug targets.
Methotrexate, an structural analog of
tetrahydrofolate, inhibits dihydrofolate
reductase. Fluorouracil inhibits thymidylate
synthase.
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Fluorouracil inhibits the enzyme thymidylate
synthase
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Methotrexate, an structural analog of
tetrahydrofolate, inhibits dihydrofolate
reductase
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Nucleotide Structure
Nucleotides are linked by phosphodiester bonds
between the 5-PO4 and the 3-OH.
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Phosphodiester bonds are formed by a nucleophilic
attack of a free 3-OH on the 5-a-PO4 of the
incoming dNTP.
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Requirements for DNA replication
The enzyme DNA polymerase. A DNA template to
guide synthesis. A primer, a short nucleotide
segment complementary to the template that can
provide a free 3-OH for synthesis. Primers are
often short RNA oligonucleotides
synthesized when and where needed by specialized
enzymes.