Chemical Sense in Metabolism

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Lecture 25

• Chemical Sense in Metabolism

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Making and Breaking CC Bonds

• Homolytic reactions
• Heterolytic reactions

3
Making and Breaking CC Bonds

• Nucleophilic substitutions

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Nucleophilic Substitution Reactions

• SN1

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Carbocation
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Common Biological Nucleophiles
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SN2 Nucleophilic Substitution
?
?
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Reactivity is SN2 Reactions
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Leaving Group

• Must accommodate a pair of electrons
• And sometimes a negative charge

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Major Role of Phosphorylation

• Converts a poor leaving group (OH) into a good
  one (Pi, PPi)

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Acid Catalysis of Substitution Reactions
This H is often donated by an acidic
sidechain of enzyme
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Central Importance of Carbonyls

• 1. Can produce a carbocation
• 2. Can stabilize a carbanion

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Biological Carbonyls
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Aldol Condensation
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Aldol Condensation
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Aldol Condensation
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Aldolase Reaction

• Glycolysis and gluconeogenesis

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Claisen Condensation
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Claisen Condensation
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Thioesters in Biology

• In thioesters, the carbonyl carbon has more
  positive character than carbonyl carbon in oxygen
  ester.

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High-Energy Thioester Compounds
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Coenzyme A
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Fatty Acid Metabolism

• Uses Claisen condensation
• Thiolase acts in fatty acid oxidation for energy
  production

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Thiolase Role of Cys-SH
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Thiolase Role of Cys-SH
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Energy Diagram for Reaction

• is the transition state
• Pentacovalent carbon, for example

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Functional Groups on Enzymes

• Amino acid side chains
• Imidazole

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Functional Groups on Enzymes

• Coenzymes/cofactors
• Pyridoxal phosphate
• Metal ions and complexes
• Mg2, Mn2, Co2, Fe2, Zn2, Cu2, Mo3

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Enzyme Inhibitors and Poisons

• Chelating agents
• EDTA (divalent cations)
• CN (Fe2)
• Cofactor analogs
• Warfarin
• Suicide substrates

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Lecture 26

• ATP and Phosphoryl Group Transfers

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Phosphate Esters and Anhydrides
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Phosphoryl Group Transfers
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Phosphoryl (Not Phosphate) Transfers
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Nucleophilic Displacements
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ATP as a Phophoryl Donor

• 2 roles for ATP
• Thermodynamic
• Drive unfavorable reactions
• Mechanistic
• Offer 3 electrophilic phosphorous atoms for
  nucleophilic attack

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ATP as Phosphoryl Donor

• 3 points of nucleophilic attack

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Adenylyation Attack on ?-P
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Adenylation Attack on ?-P
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Pyrophosphorylation Attack on ?-P
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Phosphorylation Attack on ?-P
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Amino Acid Sidechains as Nucleophiles
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Enzymatic Phosphoryl Transfers

• Four classes
• Phosphatases
• Water is acceptor/nucleophile
• Phosphodiesterases
• Water is acceptor/nucleophile
• Kinases
• Nucleophile is not water
• Phosphorylases
• Phosphate is nucleophile

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Phosphatases Glucose-6-Phosphatase
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Phosphatases Glucose-6-Phosphate
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Phosphodiesterases RNAase
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Phosphodiesterases RNAase
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Kinases ?-Phosphoryl Transfer

• Transfer from ATP

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Kinases P-Enzyme Intermediates
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Kinases P-Enzyme Intermediates
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Kinases
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Pyruvate Kinase

• Makes ATP (?Gº? 31 kJ/mol) from PEP

?Gº? 62 kJ/mol
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Phosphoryl-Group Transfer Potential
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Significance of High-Energy P Compounds

• Drive synthesis of compounds below
• Phosphated compounds are more reactive
• Thermodynamically
• Kinetically
• If organism has ATP (etc), it can do work and
  resist entropy
• ?Cells must get ATP