01:694:301 Lecture Notes - Lecture 25: Thymidylate Synthase, Methylene Group, Pteridine
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14 Nov 2018
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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