Chapter 1 The Foundations of Biochemistry. Why do we study biochemistry? 21 st Century: Integrated (fusion) Science BIO is the core ! BIO Physics Chemistry.

Chapter 1

The Foundations of Biochemistry

Why do we study biochemistry?

21st Century: Integrated (fusion) Science

BIO is the core !

BIO

Physics

Chemistry

Mathematics

Nanotechnology

IT & ETEngineering

Properties of Life

Biochemistry – Molecular Logic of Life Understanding the physical and chemical laws governing life

Simple elements and compounds

Biomolecules Life

Properties of life Chemical complexity and microscopic organization

Systems for extracting, transforming, and using energy from the environment

Self replication and self assembly

Sensing and responding to environmental changes

Defined functions for each components and their regulated interactions

Evolution

Contents

The foundations of biochemistry Chapter 1

Cellular foundations

Chemical foundations

Physical foundations

Genetic foundations

Evolutionary foundations

1.1 Cellular Foundations

Cells

Structural & functional units of living organisms Structure of cells

Plasma membrane Structural barrier from the surroundings Barrier of molecular transport Composed of lipids and proteins

Cytoplasm Cytosol: concentrated aqueous solution

– Enzymes, coenzymes, RNA, building blocks, metabolites, inorganic ions, proteasomes

Particles and organelles– Ribosome, ER, mitochondria, lysosomes, chloroplasts

(plants)

Nucleus (eukaryotes) or nucleoid (prokaryotes) Storage of genome and replication

Universal Features of Living Cells

Cellular Dimensions

Cell sizesBacteria: 1 ~ 2 mAnimal cells : 5 ~100 m

Limitations of cell sizeLower limit

Minimum number of biomolecules required by the cell

– Micoplasma: 300 nm– c.f. ribosome : 20 nm

Upper limitOxygen diffusionBacteria: small size high surface/volume ratio

Classification of Life

Three domains (kingdoms) Eukaryotes Prokaryotes

Eubacteria Archaebacteria

Classification of Life

Classification of prokaryotes depending of the habitats Aerobic : O2 as electron acceptor Anaerobic : nitrate( N2), sulfate (H2S), CO2 (CH4) as e-

acceptors Classification according to carbon & energy sources

Structure of E. coli

Most-studied bacterium

15,000 ribosomes ~1,000 enzymes Circular DNA Plasmids

Gram Staining

Cell Envelopes of Prokaryotes

Animal Cell

Plant Cell

Subcellular Fractionation of Tissue

Organization of Cytoplasm

Cytoskeleton Actin filaments, microtubules, intermediate filaments

Highly dynamic structureAssembly and disassembly of subunits

FunctionsStructural organization of cytoplasmMolecular & organellar transport

Types of Cytoskeleton

Actin filaments Microfilaments, 8-9 nm in diameter

Determine cell shape with membrane-binding proteins

Intermediate filaments 10 nm

Support nuclear membrane

Tissue formation through cell-cell, cell-matrix interactions

Microtubules Hollow tube-like structure, 24 nm

Organization of certain subcellular structures

Vasicular transport

Cells Build Supramolecular Structures

Macromolecules

Linkage of monomeric subunits by covalent bonds Amino acids (e.g. ala: 0.5 nm) Assembled into proteins (e.g.

hemoglobin, 5.5 nm in diameter) by ribosome (20 nm in diameter)

Interactions of macromolecules

Noncovalent interactions Hydrogen bonds Ionic interactions Hydrophobic interactions Van der Waals interactions

Cells Build Supramolecular Structures

In vitro studies vs. in vivo reality Gel-like cytosol High concentration, limited diffusion, uneven distribution

1.2 Chemical Foundations

Elements Essential to Life

Bulk elements : structural components of cells H, O, N, C

Most abundant elements : > 99% of cell mass

P,S, Na, Cl, K, Ca Trace elements

Fe, Cu, Zn etc.

Carbon in Biomolecules

Carbon Major component of biomolecules

Most biomolecules are derivatives of hydrocarbons

Bonding versatility Single or double bonds Bonding with diverse functional groups

Small Molecules

Primary metabolites (Mr ~100 to ~500)

Evolutionarily conserved in all types of cellsAmino acids, nucleotides, sugars, mono-,

di-, and tricarboxylic acids Secondary metabolites

Specific to cell typese.g. morphine in plant, antibiotics in bacteria

Metabolome

Macromolecules are the Major Constituents of Cells

Proteins Enzyme, structural function,

transport, signal transduction etc.

Nucleic acids : DNA, RNA Storage and transmission of

genetic information Structural and catalytic role

(RNA) Polysaccharides

Energy storage Extracellular structural element

for cellular signaling Lipids

Constitution of membrane Energy storage

3D Structure

Stereoisomers

Same chemical bonds but different configuration

Geometric (cis-, trans-) isomers Double bonds

Enantiomers or diastereomers Compounds with chiral centers

Interactions Between Biomolecules are Stereospecific

Usually one chiral formAmino acids : L isomersGlucose : D isomer

Biological reactions and interactions are stereospecific

Binding of argininamide to HIV RNA genome

1.3 Physical Foundations

Energy is a central theme in biochemistry. 1. No equilibrium 2. Dynamic steady state 3. Exchange energy and matter 4. Energy conservation 5. Enzymes promote sequences of chemical reactions. 6. Metabolism in balance and economy

Thermodynamics of Living Organism

Dynamic steady state Maintaining cellular constituents by balancing the

rate of production and consumption Open system

Exchanging energy and matter with its surroundings First law of thermodynamics: Energy conservation

Energy transduction in cells Flow of electrons along the electrochemical

potential gradient Sunlight energy transfer of e- from H2O to CO2

Production of energy-rich products (e.g glucose) 6CO2 + 6 H2O + light C6H12O6 + 6O2

Oxidation of energy-rich products transfer of e- to O2 to form H2O Production of energy

C6H12O6 + O2 6CO2 + 6 H2O + energy

Thermodynamics of Living Organism

Energy transduction in cells

Flow of electrons along the electrochemical potential gradient Sunlight energy transfer of e- from

H2O to CO2 Production of energy-rich products (e.g glucose)

6CO2 + 6 H2O + light C6H12O6 + 6O2

Oxidation of energy-rich products transfer of e- to O2 to form H2O Production of energy

C6H12O6 + O2 6CO2 + 6 H2O + energy

Free Energy Change for Biological Reactions

G = H –TS G: free-energy change H: enthalpy S: entropy

Coupling of energy-requiring (endergonic) reaction with reactions liberating free energy (exergonic) to make negative G Polymerization reaction: G1 is positive (endergonic) Hydrolysis of ATP: G2 is negative (exergonic) G1 + G2 is negative (exergonic)

Energy Coupling in Mechanical & Chemical processes

Measurement of Reactions Tendency to Proceed Spontaneously

aA + bB cC + dD

Equilibrium constant [Ceq]c [Deq]d

[Aeq]a [Beq]b

Go : standard free energy change (joules/mole)

[Ci]c [Di]d

[Ai]a [Bi]b

At equilibrium, G=0

Go = -RT ln Keq

Spontaneous reaction Keq >>1 Go : large and negative

Keq =

G = Go + RT ln

Enzymes

Functions of enzymes

Increasing reaction rate (kinetics) without affecting thermodynamics

Decreasing activation energy G‡

Better fit for transition state Binding of reactants with proper stereospecific orientations

Metabolism

Catabolism

Degrading pathways

Free-energy-yielding reactions Anabolism

Synthetic pathways

Energy-consuming reactions ATP is the major connecting link Tight regulation to achieve

balance and economy

e.g. feed back inhibition

1.4 Genetic Foundations

Inheritance of Genetic Information

DNA contains encoded genetic information DNA replication Expression of genetic information

DNA RNA protein

1.5 Evolutionary Foundations

Evolution

Mutation

Provides opportunity for evolution

Survival of the fittest under selective pressure

Chemical evolution

Generation of organic compounds under primitive atmospheric conditions

RNA world scenario RNA as initial self-replicating and

catalytic molecule

Miler and Urey, 1953

Biological Evolution

Chemoheterotroph Photosynthetic

bacteria Aerobic bacteria Eukaryotic cells

Endosymbiosis of aerobic or photosynthetic bacteria

Muticellular eukaryotes

Endosymbiosis

Molecular Anatomy Reveals Evolutionary Relationships

Homologs

Genes with sequence similarity Paralogs

Homologs in the same species

Gene duplication Orthologs

Homologs in different species

Information from Genome Sequences

Genome annotation Deduction of the function of each genes by

sequence comparison with known genes Construction of evolutionary phylogeny

Based on sequence homology Functional genomics

Allocations of genes to specific cellular processes Complex organisms has higher portion of genes

involved in regulation Human biology and medicine

Identification of human-specific genes Use genetic information to diagnosis and treatment

of diseases