01:694:301 Lecture Notes - Lecture 25: Thymidylate Synthase, Methylene Group, Pteridine

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Chapter 25‘Nucleotide Biosynthesis’
Nucleotides are activated precursors of nucleic acids; important DNA replication,
transcription;
o Overall nucleotides and their derivatives are essential for many life processes and
pathways
! Ex: ATP " adenine nucleotide (universal currency of energy); GTP also energy source
o Glycine and asparate are used in ring systems present nucleotide assembly
KNOW the nomenclature in Table 25.1 (736)
Nucleotides can be synthesized by
de novo
and
salvage pathways
KNOW that the synthesis of Thymidylate (TMP) from dUMP (Fig. 25.13) uses CH2-THF and
produces DHF
o Thymidylate is formed by the ‘methylation’ of dUMP (
deoxyuridylate
): dUMP " TMP
o N5,N10-methyleneTHF is used as the methyl donor; rxn catalyzed by
thymidylate synthase
! Methyl group needs to be attached to C-5 on dUMP ring but C-5 weak nucleophile
! TMP synthase adds thiolate from cys side chain to ring creating nucleophile that can
attack methylene group on THF
! 5-membered ring opens and activated dUMP attacks methylene creating C-C bond
! Hydride ion is finally transferred from THF " methylene " creating methyl group
! THF after losing methylene group and H " dihydrofolate (DHF)
! THF must then be regenerated for further synthesis of TMP
Regeneration is catalyzed by
DHF reductase
(NADPH " NADP+)
Hydride ion transferred from nicotinamide ring to pteridine ring
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