Lecture 25 Chemical Sense in Metabolism

Making and Breaking C–C Bonds Homolytic reactions Heterolytic reactions

Making and Breaking C–C Bonds Nucleophilic substitutions

Nucleophilic Substitution Reactions S N 1

Carbocation

Common Biological Nucleophiles

S N 2 Nucleophilic Substitution –– ––

Reactivity is S N 2 Reactions

Leaving Group Must accommodate a pair of electrons –And sometimes a negative charge

Major Role of Phosphorylation Converts a poor leaving group ( – OH) into a good one (P i, PP i )

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

Central Importance of Carbonyls 1. Can produce a carbocation 2. Can stabilize a carbanion

Biological Carbonyls

Aldol Condensation

Aldolase Reaction Glycolysis and gluconeogenesis

Claisen Condensation

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

“High-Energy” Thioester Compounds

Coenzyme A

Fatty Acid Metabolism Uses Claisen condensation Thiolase acts in fatty acid oxidation for energy production

Thiolase: Role of Cys-SH

Energy Diagram for Reaction ‡ is the transition state –Pentacovalent carbon, for example

Functional Groups on Enzymes Amino acid side chains – –Imidazole –

Functional Groups on Enzymes Coenzymes/cofactors –Pyridoxal phosphate Metal ions and complexes – Mg 2+, Mn 2+, Co 2+, Fe 2+, Zn 2+, Cu 2+, Mo 3+

Enzyme Inhibitors and Poisons Chelating agents –EDTA (divalent cations) –CN – (Fe 2+ ) Cofactor analogs –Warfarin Suicide substrates

Lecture 26 ATP and Phosphoryl Group Transfers

Phosphate Esters and Anhydrides

Phosphoryl Group Transfers

Phosphoryl (Not Phosphate) Transfers

Nucleophilic Displacements

ATP as a Phophoryl Donor 2 roles for ATP –Thermodynamic Drive unfavorable reactions –Mechanistic Offer 3 electrophilic phosphorous atoms for nucleophilic attack

ATP as Phosphoryl Donor 3 points of nucleophilic attack

Adenylyation: Attack on  -P

Adenylation: Attack on  -P

Pyrophosphorylation: Attack on  -P

Phosphorylation: Attack on  -P

Amino Acid Sidechains as Nucleophiles

Enzymatic Phosphoryl Transfers Four classes –Phosphatases Water is acceptor/nucleophile –Phosphodiesterases Water is acceptor/nucleophile –Kinases Nucleophile is not water –Phosphorylases Phosphate is nucleophile

Phosphatases: Glucose-6- Phosphatase

Phosphatases: Glucose-6- Phosphate

Phosphodiesterases: RNAase

Kinases:  -Phosphoryl Transfer Transfer from ATP

Kinases: P-Enzyme Intermediates

Kinases

Pyruvate Kinase Makes ATP (∆Gº= –31 kJ/mol) from PEP ∆Gº= –62 kJ/mol

Phosphoryl-Group Transfer Potential

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