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Biochemistry II - Chem 473

II BIOENERGETICS AND METABOLISM


13 Bioenergetics and Biochemical Reaction Types 14 Glycolysis, Gluconeogenesis, and the Pentose Phosphate Pathway 15 Principles of Metabolic Regulation 16 The Citric Acid Cycle 17 Fatty Acid Catabolism 18 Amino Acid Oxidation and the Production of Urea 19 Oxidative Phosphorylation and Photophosphorylation 21 Lipid Biosynthesis 22 Biosynthesis of Amino Acids, Nucleotides, and Related Molecules 23 Hormonal Regulation and Integration of Mammalian Metabolism

III INFORMATION PATHWAYS


24 Genes and Chromosomes 25 DNA Metabolism 26 RNA Metabolism 27 Protein Metabolism 28 Regulation of Gene Expression

Life Needs Energy


Recall that living organisms are built of complex structures Building complex structures that are low in entropy is only possible when energy is spent in the process The ultimate source of this energy on Earth is the sunlight

O2, CO2 and Nitrogen Cycles

Energy Flows through ATP and redox carriers to couple Catabolic and Anabolic Pathways

Nonlinear Metabolic Pathways

microbiome

Glycan metabolism

Metabolism Is the Sum of All Chemical Reactions in the Cell


Series of related reactions form metabolic pathways

Some pathways are primarily energy-producing


Catabolism

Some pathways are primarily using energy to build complex structures


Anabolism or biosynthesis

CHAPTER 13 Bioenergetics and Reactions

Key topics:
Thermodynamics applies to biochemistry, too Organic chemistry principles are still valid Some biomolecules are high energy with respect to their hydrolysis and group transfers Energy stored in reduced organic compounds can be used to reduce cofactors such as NAD+ and FAD, which serve as universal electron carriers

Laws of Thermodynamics Apply to Living Organisms


Living organisms cannot create energy Living organisms cannot destroy energy Living organism may transform energy from one form to another In the process of transforming energy, living organisms must increase the entropy of the universe In order to maintain organization within the themselves, living systems must be able to extract useable energy from the surrounding, and release useless energy (heat) back to the surrounding

Free Energy, or the Equilibrium Constant Measure the Direction of Spontaneous Processes

Hydrolysis Reactions tend to be Strongly Favorable (Spontaneous) Isomerization Reactions Have Smaller Free Energy Changes Complete Oxidation of Reduced Compounds is Strongly Favorable

Review of Organic Chemistry


Most reactions in biochemistry are thermal heterolytic processes Nucleophiles react with electrophiles Heterolytic bond breakage often gives rise to transferable groups, such as protons Oxidation of reduced fuels often occurs via transfer of electrons and protons to a dedicated redox cofactors

Chemical Reactivity
Most reactions fall within few categories:
Oxidations-reductions (e- transfers)

Group transfers (H+, CH3+, PO32-)


Cleavage and formation of CC bonds Cleavage and formation of polar bonds Nucleophilic substitution mechanism Additionelimination mechanism Hydrolysis and condensation reactions Internal rearrangements Eliminations (without cleavage)

Group Transfer Reactions


Proton transfer, very common
Methyl transfer, various biosyntheses Acyl transfer, biosynthesis of fatty acids Glycosyl transfer, attachment of sugars Phosphoryl transfer, to activate metabolites, also important in signal transduction

Chemistry at Carbon
Covalent bonds can be broken in two ways Homolytic cleavage is very rare, heterolytic cleavage is common but does not occur for C-C bonds

Nucleophiles and Electrophiles in Biochemistry

Examples of Nucleophilic CarbonCarbon Bond Formation Reactions

Phosphoryl Transfer from ATP


ATP is frequently the donor of the phosphate in the biosynthesis of phosphate esters

Hydrolysis of ATP is Favorable Under Standard Conditions


Better charge separation in products Better solvation of products More favorable resonance stabilization of products

Actual G of ATP Hydrolysis Differs from G


The actual free energy change in a process depends on

The standard free energy


The actual concentrations of reactants and products The free energy change is more favorable if the reactants concentration exceeds its equilibrium concentration True reactant and the product are Mg-ATP and Mg-ADP, respectively G0 also Mg++ dependent

[ MgADP ] [ Pi ] G G ' RT ln [ MgATP2 ]


0

Actual ATP Concentration Depends on Tissue Type


Cellular ATP concentration is usually far above the equilibrium concentration, making ATP a very potent source of chemical energy

Several Phosphorylated Compounds Have Large G for Hydrolysis


Again, electrostatic repulsion within the reactant molecule is relieved The products are stabilized via resonance, or by more favorable solvation The product undergoes further tautomerization

Phosphates: Ranking by the Standard Free Energy of Hydrolysis


Reactions such as PEP + ADP =>
Pyruvate + ATP

are favorable, and can be used to synthesize ATP

Hydrolysis of Thioesters
Hydrolysis of thioesters, such as acetyl-CoA is strongly favorable Acetyl-CoA is an important donor of acyl groups
Feeding two-carbon units into metabolic pathways
Synthesis of fatty acids

In acyl transfers, molecules other than water accept the acyl group

Molecular Basis for Thioester Reactivity


The orbital overlap between the carbonyl group and sulfur is not as good as the resonance overlap between oxygen and the carbonyl group in esters

Oxidation-Reduction Reactions
Reduced organic compounds serve as fuels from which electrons can be stripped off during oxidation

Reversible Oxidation of a Secondary Alcohol to a Ketone


Many biochemical oxidation-reduction reactions involve transfer of two electrons In order to keep charges in balance, proton transfer often accompanies electron transfer In many dehydrogenases, the reaction proceeds by a stepwise transfers of proton ( H+ ) and hydride ( :H- )

NAD and NADP are Common Redox Cofactors


These are commonly called pyridine nucleotides They can dissociate from the enzyme after the reaction In a typical biological oxidation reaction, hydride from an alcohol is transferred to NAD+ giving NADH

Flavin Cofactors allow Single Electron Transfers

Permits the use of molecular oxygen as an ultimate electron acceptor


flavin-dependent oxidases

Flavin cofactors are tightly bound to proteins

Chapter 13: Summary


In this chapter, we learned that the rules of thermodynamics, and organic chemistry still apply to living systems. For example:
Group transfer reactions are favorable when the free energy of products is much lower than the free energy of reactants. In biochemical phosphoryl transfer reactions, the good phosphate donors are destabilized by electrostatic repulsion, and the reaction products are often stabilized by resonance. Unfavorable reactions can be made possible by chemically coupling a highly favorable reaction to the unfavorable reaction. For example, ATP can be synthesized in the cell using energy in phosphoenolpyruvate. Oxidation-reduction reaction commonly involve transfer of electrons from reduced organic compounds to specialized redox cofactors. The reduced cofactors can be used in the biosynthesis, or may serve as a source of energy for ATP synthesis.