Lecture 3: Chemistry of LifeLecture 3: Chemistry of LifePart 3 of 2Part 3 of 2

Same songSecond verse

A little bit louder And a whole lot worse

Lecture 3: Chemistry of LifeLecture 3: Chemistry of LifePart 3 of 2Part 3 of 2Goals:• Finish with biochemistry• Understand: 1.)What protein is, 2.)What protein

does, and 3.) how make one• Relate concepts of protein structure and function

to real events and issues

Key Terms: Amino acid, R-group, polypeptide, protein types, Key Terms: Amino acid, R-group, polypeptide, protein types, protein structure (1protein structure (1°°,2,2°°,3,3°°,4,4°°), peptide bond, lipoprotein, ), peptide bond, lipoprotein, glycoprotein, diffusion, permeability, transport, gradientglycoprotein, diffusion, permeability, transport, gradient

Assingment:Assingment:For Tuesday, read Ch 12 and 13For Tuesday, read Ch 12 and 13For Thursday, read Ch 8 and 14For Thursday, read Ch 8 and 14

Amino Acid StructureAmino Acid Structure

aminogroup

carboxylgroup

R group

Properties of Amino Acids

• Determined by the “R group”

• Amino acids may be:

– Non-polar

– Uncharged, polar

– Positively charged, polar

– Negatively charged, polar

Amino acidsAmino acids

NH2

CH

O

CH2

CH2

CH2

NH

NHNH2

OH

NH2

CH

O

CH3

OH NH2

CH

O

CH2

O

NH2

OH

NH2

CH

O

CH2

O

OH

OH

NH2

CH

O

CH2SH

CH3

Alanine Arginine Asparagine Aspartic Acid

Cysteine

NH2

CH

O

CH2

CH2

ONH2

OH

NH2

CH

O

CH2

CH2

OOH

OH

NH2

CH2

O

OH

Glutamine Glutamic Acid Glycine

NH2

CH

O

CH2

N

CH

CH

NH

OH

NH2

CH

CHCH2

O

CH3

CH3

OH

Histidine

Isoleucine

NH2

CH

CH2

CH

O

CH3

CH3

OH

NH2

CH

O

CH2

CH2

CH2

CH2

NH2

OHLysine

Leucine

NH2

CH

O

CH2

CH2

SCH3

OH

NH2

CH

CH2

O

CH

CH

CHCH

CH

OH

NH

CH

CH2

CH2C

H2

O

OH

NH2

CH

CH2

OH

O

OH

Methionine Phenylalanine Proline Serine

CH

CH

NH2

CH3OH

O

OH NH2

CH

CH2

OCH

NH

CH

CH

CH

CH

OH

NH2

CH

CH2

OCH

CH

CH

CHOH

OH

NH2

CH

CHCH3

O

CH3

OH

Threonine Tryptophan Tyrosine Valine

If you memorize the single and three letter

abreviations, the chemical structure, the

pKa and the relative hydrophobicity for each amino acid, then you are

a student of biochemistry and do not

belong in this class.

•The R-groups are different

•R-groups help to determine the intramolecular arrangement of a protein

Protein Synthesis

• Protein is a chain of amino acids

linked by peptide bonds

• Peptide bond

– Type of covalent bond

– Links amino group of one amino acid

with carboxyl group of next

– Forms through condensation reaction

Protein = chain of amino acids

Condensation of Amino Acids is the formation of a peptide bond

Chemical ReactionChemical Reaction

Forming Peptide Bonds

We need a vocabulary for We need a vocabulary for describing proteins describing proteins

1. General shape

2. Level of detail we are talking about

Identity

Homology

3D Structure

1. General function of the protein

Protein ShapesProtein Shapes

• Fibrous proteins

– Polypeptide chains arranged as strands or

sheets

• Globular proteins

– Polypeptide chains folded into compact,

rounded shapes

Protein StructureProtein Structure

• Primary- just the sequence (1D)

• Secondary- interactions on the chain (2D)

• Tertiary- interactions between parts of the

chain the chain. (3D)

• Quaternary- interactions with other chains

Primary StructurePrimary Structure• Sequence of amino acids

• Unique for each protein

• Three or more = polypeptide

• Backbone of polypeptide has nitrogen atoms (not just a hydrocarbon):– -N-C-C-N-C-C-N-C-C-N-

Secondary StructureSecondary Structure

• Hydrogen bonds form between different parts of polypeptide chain

• These bonds give rise to coiled or extended pattern

• Helix or pleated sheet

Examples of Secondary Examples of Secondary StructureStructure

-helix-helix

-sheet-sheet

Tertiary StructureTertiary Structure

Folding as a result

of interactions

between R groups

heme group

coiled and twisted polypeptide chain of one globin molecule

Quaternary StructureQuaternary Structure

Some proteins

are made up of

more than one

polypeptide

chain

Hemoglobin

Polypeptides With Attached Polypeptides With Attached Organic CompoundsOrganic Compounds

Nothing new! Just more combinations of

Tuesday’s vocabulary

• Lipoproteins

– Proteins combined with cholesterol, triglycerides,

phospholipids

• Glycoproteins – Proteins combined with oligosaccharides

DenaturationDenaturation

• Disruption of three-dimensional shape

• Breakage of weak bonds

• Causes of denaturation:– pH

– Temperature

• Destroying protein shape disrupts function

Protein Restoration

Renaturing proteins

Refolding ?

A Permanent WaveA Permanent Wave

hair wrapped around cuticles

differentbridges form

bridgesbroken

hair’scuticle

keratinmacrofibril

one hair cell microfibril (threechains coiled into one strand)

coiled keratinpolypeptidechain

A brief survey of some protein types

• Structural

• Muscle

• Binding

• Signaling

• Storage protein

• Defensive protein

• Transportation

• Enzymes

StructuralFunction: Hold togetherGive shape

Examples:Hair

Tendons

Ligaments

Structural

Function: Attachment

CollagenA triple helix

Collagenous fiber

Macrofibril

Microfibril

Collagen molecule

Polypeptide chain

Structural Proteins

Crystallins Lens Fibers

Keratin Actin

Types of protein

• Structural

• Muscle

• Binding

• Signaling

• Storage protein

• Defensive protein

• Transportation

• Enzymes

MuscleFunction: Contraction

Muscle Flagella

Image courtesy of Dr. Fatih Uckun, Parker Hughes Institute, St. Paul, MN

Movement in the CellActin and Myosin VATP Dependent Reaction

Nature Reviews Molecular Cell Biology 2, 387-392 (2001)

Types of protein

• Structural

• Muscle

• Signaling

• Storage protein

• Defensive protein

• Transportation

• Enzymes

Insulin

Function: Messengers

Receptors

Signaling

Insulin

In

Action

Types of protein

• Structural

• Muscle

• Signaling

• Storage protein

• Defensive protein

• Transportation

• Enzymes

Function: Store What?

Expensive molecules for later useChemical energy

Ovalbumin- globular glycoprotein

Storage

Types of protein

• Enzymes

• Structural

• Muscle

• Signaling

• Storage protein

• Defensive protein

• Transportation

Protein for Defense• Example: Antibodies

• Key component of immune system

• Label invading microbes as intruders

Types of protein

• Structural

• Muscle

• Signaling

• Storage protein

• Defensive protein

• Transportation

• Enzymes

Function: Moving molecules:

In side the organismBetween cellsInside Cells

Example: Getting O2 to where it’s needed

Hemoglobin: gives blood cells their red color…

Transportation

Concepts in TransportationThe Basic Terms

• Permeability• Diffusion - Gradients• Membrane transport

– Active – Passive– Bulk

Cell Membranes And Selective Permeability

(Think Grapefruit!)

O2, CO2, H2O,and small non-polar molecules

Sugar, and other large,

polar molecules

Iions such as H+, Na+, CI-, Ca++

X

Gradients- Unequal distributionsGradients- Unequal distributionsMembranes are required for gradientsMembranes are required for gradients

Mechanisms ofCrossing Over

(the membrane)

1. Diffusion across lipid bilayer

2. Passive transport

3. Active transport

4. Bulk Transport

Endocytosis

Exocytosis

• Span the lipid bilayer• Interior is able to

open to both sides• Change shape when

they interact with solute

• Play roles in active and passive transport

Transport ProteinsGeneral Characteristics

Passive Transport

• Going down the gradient(That whole water runs down hill thing)

• Selective- only some things fit• Not directional- two way door• Its FREE! Does not require

any energy input

Active Transport

• Movement of target is against the concentration gradient (Think about Water flowing up hill)

• Transport protein requires energy(Not free, someone pays)

• ATP is often the source of chemical energy

Bulk Transport

Exocytosis

Endocytosis

Types of protein

• Structural

• Muscle

• Binding

• Signaling

• Storage protein

• Defensive protein

• Transportation

• Enzymes

Enzyme Structure and Function

Enzymes are catalytic molecules

They speed the rate at which reactions approach equilibrium

Features of Enzymes

Enzymes make unlikely reactions happen and happen faster

Enzymes aren’t usually reactants or products and usually aren’t used up orseverely altered

The same enzyme usually works for both the forward and reverse reactions

Each type of enzyme recognizes and binds to only certain molecules.(Substrate Specificity)

Enzymes make, break and Enzymes make, break and rearrange chemical bondsrearrange chemical bonds

Activation Energy

• For a reaction to occur, an energy barrier must be surmounted

• Enzymes make the energy barrier smaller

activation energywithout enzyme

activation energywith enzyme

energyreleased

by thereaction

products

starting substance

Induced-Fit Model

two substrate

molecules

active sight

substratescontactingactive siteof enzyme

TRANSITIONSTATE(tightestbinding butleast stable)

endproduct

enzymeunchangedby thereaction

• Substrate molecules are brought together

• Substrates are oriented in ways that favor reaction

• Active sites may promote acid-base reactions

• Active sites may shut out water

Receptor

Inhibitor

Metabolic pathway

Enzyme

Hydrophobic and Hydrophillic

Sterols

Transport protein

Pulling it all together

Why is CholesterolImportant?

Sales of Lipitor grew 25% in 2001 to $4.4 billion. Pfizer spent $50 million on Lipitor ads last year.

                                                                                                                                 

High cholesteroldoesn’t care who

you are

Observational studies provideoverwhelming evidence thatHDL-C is an independent riskfactor for coronary heart disease

Disclaimer

1. I am a PhD not an MD

2. Genuine exchange of scientific information vs. medical advice

3. I’m un-sponsored

Basic Cholesterol Metabolism• We make all the cholesterol we need and it is absolutely

essential• Major sources of circulating cholesterol

– Peripheral cholesterol synthesis– Hepatic cholesterol synthesis– Intestinal cholesterol absorption

• Once synthesized or absorbed it is packaged into lipoprotein complex so that it can be transported

• The problem is getting cholesterol back to the liver– High Density Lipoprotein – Low Density Lipoprotein

• Transport through the cell membrane is receptor mediated

Basic Cholesterol Metabolism• Delivery of cholesterol from other tissues to the

liver results in the formation of Low Density Lipoprotein (LDL) complexes.

• Problem: Big and sticky and form plaques on artery walls– Atherosclerosis- Clogged arteries

• when plaques break loose the plug up arteries

Cholesterol and Health

• Diet?

• Exercise ?

• Genetics?

• Age?

• Pharmaceuticals ?

Statins• Originally intended to be antibiotics

– Bacteria need cholesterol too– Found a small molecule in a Penicillum

• Mechanism of Action– Bind a receptor that is just on liver cells– Once inside, get stuck in an enzyme’s active site. Compete

with substrate– HMG-CoA Reductase– Liver cells want more cholesterol to package so they make

more receptors for LDL

• Less synthesis and more adsorption results in lower cholesterol levels.

StatinsWhat is a good drug?1. Good enzyme inhibitor- a little bit goes a long

way (IC50)

2. Specific tissue action- only works where you want it

3. Pharmacokinetics- goes in fast and stays there a long time.

4. Doesn’t interact with other drugs

Cholesterol Synthesis

Metabolic Pathway• Linear, branched or

cyclic?• What else do we

need HMG-CoA Reductase for?

• Does it only affect liver cells?

Statins on the Market• Atorvastatin, Lipitor, Pfizer• Fluvastatin, Lescol, Novartis• Lovastatin, Mevacor, Merck• Prevastatin, Pravachol, Bristol-Myers Squibb • Simvastatin, Zocor, Merck• Cerivastatin, Baycol, Bayer

Too Much of a Good Thing

Rhabdomyolysis

•Rapid muscle tissue breakdown. (Quite painful, like a permanent cramp)

•Heme protein-induced renal tubular cytotoxicity, intraluminal cast formation, leading to tubular obstruction (kidney plugs up and you can’t make urine, very bad)

Lecture 3: Chemistry of LifeLecture 3: Chemistry of LifePart 3 of 2Part 3 of 2Goals:• Finish with biochemistry• Understand: 1.)What protein is, 2.)What protein

does, and 3.) how make one• Relate concepts of protein structure and function

to real events and issues

Key Terms: Amino acid, R-group, polypeptide, protein types, Key Terms: Amino acid, R-group, polypeptide, protein types, protein structure, peptide bond, lipoprotein, glycoprotein, protein structure, peptide bond, lipoprotein, glycoprotein,

Assingment:Assingment:For Tuesday, read Ch 12 and 13For Tuesday, read Ch 12 and 13For Thursday, read Ch 8 and 14For Thursday, read Ch 8 and 14

Nucleic acids = Macromolecules

Gene = Basic unit of inheritance =

DNA = •Deoxyribonucleic acid

•PolynucleotideNucleotide =Building block of nucleic acids

or the Information Molecules of Life

“Passing the torch”

• Sugar

– Ribose or deoxyribose

• At least one phosphate group

• Base

– Nitrogen-containing

– Single or double ring structure

Nucleotide StructureNucleotide Structure

= Nucleotide

+ Sugar

OO

H

H

H

H

H

C C

C C

C

OH

+ Base

Purine

-Adenine (A)

-Guanine (G)

Pyrimidine

-Thymine (T)

-Cytosine (C)

Phosphate

O

O

O

O P

DNA

(Deoxyribose)

= Nucleotide

+ Sugar

OO

H

OH

H

H

H

C C

C C

C

OH

+ Base

Purine

-Adenine (A)

-Guanine (G)

Pyrimidine

-Thymine (T)

-Cytosine (C)

Phosphate

O

O

O

O P

RNA= messenger (m), ribosomal (r), transfer (t) e.g. mRNA, rRNA & tRNA

Uracil (U)

(Ribose)

Two views of the DNA molecule

DNA is a helix

Pairs of nucleotides make up the “rungs” of the “ladder”

Nucleotide FunctionsNucleotide Functions

• Energy carriers

• Coenzymes

• Chemical messengers

• Building blocks for

nucleic acids

Careful: Nucleotide isn’t just DNA or RNACareful: Nucleotide isn’t just DNA or RNA

• Composed of nucleotides

• Single- or double-stranded

• Sugar-phosphate backbone

Nucleic AcidsNucleic AcidsAdenineCytosine

GUANINE CYTOSINE

NucleotidesNucleotides

Fig. 3.19, p. 46

ADENINE THYMINE

3 phosphate groupsBase

Sugar

DNADNA

• Double-stranded • Consists of four

types of nucleotides

• A bound to T• C bound to G

RNARNA

• Usually single strands

• Four types of nucleotides

• Unlike DNA, contains the base uracil in place of thymine

• Three types are key players in protein synthesis

• Normal metabolic products of one

species that can harm or kill a

different species

• Natural pesticides

– Compounds from tobacco

– Compounds from chrysanthemum

Natural ToxinsNatural Toxins

Synthetic Toxins

Atrazine DDTMalathion

Atmospheric Carbon Dioxide

• Researchers have studied concentration of CO2 in air since the 1950s

• Concentration shifts with season– Declines in spring and summer when

producers take up CO2 for photosynthesis

CO2 and Global Warming

• Seasonal swings in CO2 increasing

• Spring decline starting earlier

• Temperatures in lower atmosphere increasing

• Warming may be promoting increased photosynthesis

Humans and Global Warming

• Fossil fuels are rich in carbon

• Use of fossil fuels releases CO2 into atmosphere

• Increased CO2 may contribute to global warming

Producers Capture Carbon

Using photosynthesis, plants and other producers turn carbon dioxide and

water into carbon-based compounds

Bioremediation

Use of living organisms to withdraw harmful substances

from the environment

Negative Effects of Pesticides

• May be toxic to predators that help fight pests

• May be active for weeks to years

• Can be accidentally inhaled, ingested, or absorbed by humans

• Can cause rashes, headaches, allergic reactions

•Omega-6 fatty acids are the predominant polyunsaturated fatty acids (PUFAs) in the Western diet.

•The omega-6 and omega-3 fatty acids are metabolically distinct and have opposing physiologic functions.

•The increased omega-6/omega-3 ratio in Western diets most likely contributes to an increased incidence of heart disease and inflammatory disorders.

•Omega-3 PUFAs suppress cell mediated immune responses and reduce inflammation

Omega-3

Omega-6

PolyunsaturatedPolyunsaturated Fatty Acids Fatty Acids

•Bioactive Lipids•Made in all cells•Short range signaling•Eicosanoids?

•Prostaglandins•Inflammation and Pain Perception•Kidney Function•Bone Development•Reproductive Process

•Commercially Important•$4 BILLION/ Year spend on drugs to inhibit prostaglandin synthesis•Vioxx, Celebrex, Ibuprofen, Asprin

Lipids in Cell Signaling

PGE2