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U-M CHEM 451 - Introduction to Metabolism

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Metabolism: Food processingThe ChemistryMetabolism: group transfer reactionsOxidation/Reduction ReactionsElimination/DehydrationIsomerizationRearrangementsC-C bond formation and cleavageModern Studies of Metabolism: MetabolomicsPhenylketonuria and isotope labelingSynthesizing HemeATP: The energizer of the cellCHEM 451 1st Edition Lecture 11-12Outline of Last Lecture I. Enzyme catalyst overviewII. Acid-base catalysisa. General: keto-enol tautomerizationb. Example: RNAse AIII. Preferential binding of the transition statea. Example: lysozymeIV. Catalytic antibodies (abzymes)V. Electrostatic Catalysisa. Discussion of controversyVI. Metal ion catalysisVII. Covalent CatalysisVIII. Chapter 3 SummaryOutline of Current Lecture IX. Introduction to MetabolismX. Group Transfer ReactionsXI. Oxidation/ReductionXII. Elimination/Dehydration/Isomerization/RearrangementXIII. MetabolomicsXIV.Phenylketonuria and isotope labelingXV. ATP: The energizer of the cellCurrent LectureMetabolism: Food processingMetabolism = catabolism (degradation) + anabolism (biosynthesis)- Pyruvate is a central metabolite – perhaps an early - Acetyl-CoA: thioester; recall origin of life- Metabolic pathways are irreversibleo Usually there is one highly exergonic stepo Even if other steps in the pathway are unfavorable, completion of this step will push the pathway alongThese notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.o This is called the committed stepo The committed step is usually the most regulated – controls the most overall flux of the reaction.- Thus, catabolic and anabolic pathways must differ – couple ATP in an anabolic pathway- In eukaryotic cells, metabolic pathways occur in specific cellular locationso Reactions can be segregatedo Contrast to prokaryotes: everything is pretty much mixed togetherThe Chemistry- Metabolism is full of bond cleaving – activating nucleophiles via deprotonation, etc.- Electrophiles react with nucleophiles; may be protons, metal ions, but also carbonyl oxygen- Homolytic cleavage is rare in natureo Produces free radicals, which are toxico Free radicals are so reactive that they would destroy the cell- Heterolytic reactions: electron pair either stays with carbon to create carbanion, or is transferred to create carbocationMetabolism: group transfer reactions- Acylation reactions: keto compound (acid or aldehyde) is reacted with nucleophileo Reaction may also occur with Imine (Schiff base) – allowing for efficient acylation- Phosphoryl group reactions o Allow for coupling of ATP energy into metabolismo Trigonal-pyramidal transition, forms glucose-6-phosphate- Glycosyl reactions: exchange X group on glycosyl bond via nucleophilic substitutionOxidation/Reduction Reactions- NAD picks up hydride to become NADH or FAD picks up one electronDehydration, Eliminations, Isomerizations, and RearrangementsDehydration typically requires a secondary alcohol that loses a proton and a hydroxide to allow for elimination of water.Elimination/Dehydration- Creates C=C double bond and allows for addition of other things. - Concerted: Proton leaves at the same time as hydroxide; electrons between H-C and C-Oare in flight at the same time. Form pi-bond at the time- Stepwise mechanism via carbocation: lose hydroxide first, leaving behind a positively charged carbocation, which is neutralized by losing a proton and creating a double bond- You can also lose the proton first to create a carbanion. Consequently, the negative charge will redistribute to form the double bond. Isomerization- Sugar loses a proton (creates carbocation). Negative charge can be redistributed by resonance stabilization into keto-oxygen- If there is a second protonation, you have now changed the functionality from alcohol and aldehyde to alcohol and ketone.- This occurs by a simple deprotonation-protonation reaction.- Nature changes the reactivity of functional groups by deprotonation.Rearrangements- May use radical reactions, which are responsible for reorganizing the entire carbon scaffold- Can change a branched architecture to linearC-C bond formation and cleavage- Nature may chose an aldol condensation reaction to make or break bonds- α-carbon next to a ketone is slightly acidic (pKa~13)- Carbonyl oxygen activates the proton to be donated, consequently creating a resonance-stabilized carbanion.o This is the driving force to form a transient intermediate carbanion that has a nucleophilic carbon and an electrophilic carbon, forming a C=C double bond.o The key is having a nearby carbonyl- Variations: Claisen ester condensation, which builds fatty acids- Variation: β-keto acid has two keto-functionalities; activates bonds via electron-withdrawing power. This can lead to decarboxylationModern Studies of Metabolism: Metabolomics- Techniques used to trace carbon: NMR and mass spectrometryo Both can sense a single neutron difference- Standard experiment to study metabolismo Prepare an extract with all metaboliteso Analyze via 2D NMR, creating multidimensional o Grow a different sample labeled with C-13 and then feed to plant/animalo Compare the two samples, where one is metabolically active and one is inactiveo Very few peaks will have changed – subtract the two spectra to get negative peak- How do you do this?o Genetically manipulate an organismo Add a metabolic inhibitor – if you know a certain enzyme will inhibit a particular reaction and only the downstream reactions will be affected. Thus you can identify metabolic pathways.- Use these methods to identify genetic defects if you have a method to interfere with onestep in the metabolic pathway. Phenylketonuria and isotope labelingPhenylketonuria: individuals with this genetic disease cannot digest phenylalanine.- For the longest time, people thought the breakdown of phenylalanine included the formation of phenylpyruvate. This was wrong. Phenylpyruvate does not exist naturally in our bodies.- Tyrosine is made instead.- This was studied by labeling phenylalanine, and subsequently tyrosine was discovered in the pathway.Synthesizing Heme- Heme carries oxygen in the blood.- Complex porphyrin ring system with iron in the middle. - Add N-15 labeled amine in various different amino acids; only glycine showed up- Trace in a benign way to show that glycine is the building block of the porphyrin backbone of heme.ATP: The energizer of the cell- ATP is situated within many


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