1-16-09 Nuc Metab slides

1-16-09 Nuc Metab slides - Section II Nucleotide Metabolism...

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Section II: Nucleotide Metabolism Function of Nucleotides O O OH OH N N NH O N NH 2 P O P O P O O O O O O O O OH N N N N NH 2 O O P O O O O OH OH P O P O O O O O N + CH 3 CH 3 C H 3 N N O NH 2 CDP-Choline GTP 3'-5' cAMP Coenzymes Activated Metabolites NA Precursors Energy Currency Signalling Regulatory Mols
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Nucleotide Metabolic Pathways Nucleotides and derivatives of them are such critically important metabolites that: ● exo genous and endo genous NA breakdown products are not wasted but are efficiently re-used at the cellular/organism levels -these pathways are known as SALVAGE or REUTILIZATION) ● they are synthesized from scratch using simple precursors (shown) in multi-step pathways –this is known as De Novo biosynthesis Metabolism of nucleotides is pretty complicated –consider: Figure 22.1 Note: The color key is Orange for Ribonucleotide and Blue for Deoxyribonucleotide biosynthesis respectively and NOT the two distinct types of pathway (Salvage (reutilization) and De Novo ) but…he key is close to representing the latter B y the end of this section you will be able to re-color this figure to show the two types of biosynthesis and hopefully will understand nucleotide metabolism better!
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Salvage (Reutilization) and Catabolic Pathways –Overview Fig 22.2 Nucleotide and derivatives are in constant metabolic flux and demand for NA synthesis is high Exogenous and endogenous NA’s turn-over (degrade) naturally and help supply demand When demand is met, excess is catabolized and excreted Fig 22.2 is largely accurate but it lacks detail for our purposes and does contain a few errors
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Nucleotide Metabolism – The “Big” Picture Revised Fig 22.2 Looks complex? It is ……. But not overly difficult if you break it up into: Salvage Pathways Catabolism De Novo Pathways
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O N H N O O CH 3 H OH O H P O O O OH O H OH O H O P O O O N H N O O CH 3 Salvage (Re-utilization) RXN's (I) Nucleoside Phosphorylase + + Thymine + 2'Deoxyribose β -1 Phosphate Pi + Thymidine BASE + PHOSPHORYLATED SUGAR PHOSPHATE + NUCLEOSIDE Re-utilization Phosphorlytic Cleavage The specific example is Thymidine Phosphorylase salvages thymine or related analogs (more later) uses deoxy ribose-1-phosphate as a co-substrate (what about uridine phosphorylase?) reaction is reversible so the same phoosphorylase can catalyze biosynthesis (shown) or nucleoside (analog) degradation (more later) Understand the role and learn the balanced equation for nucleoside phosphorylases
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O OH OH O P O O O O P O P O O O O O O OH OH O P O O O OH Salvage RXN's (II) a) PRPP Synthetase b) Phosphoribosyltransferase + + Ribose 5-Phosphate + ATP PRPP + AMP ATP AMP 5- P hospho α -D- R ibosyl 1- P yro p hosphate PRPP is a major metabolite for: Base salvage (next) De novo purine biosynthesis (more later) Histidine biosynthesis (PHCY062) The synthetase and PRPP are examples of a
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