Chirality of Biochemical Molecules

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Chirality of Biochemical Molecules
Group 8 The Chiral Crew
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Focuses of our Project

• Enzyme-Substrate Relationships
• Effects on Tastes and Odors
• Pharmaceutical Applications
• As Seen in Living Organisms

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Introduction What is Chirality?
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Introduction What is Chirality?

• The geometric property of a molecule being
  non-superimposable on its mirror image
  non-superimposable is not being able to place
  over or something.
• When an atom has four non-equivalent atoms or
  groups attached to it, this is termed as the
  chirality center.

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Introduction What is Chirality?

• Two Stereoisomers that differ only in their
  chirality the arrangement of four different
  atoms or groups attached to a center atom
  typically a carbon, are called enantiomers.
• Enantiomers are designated as R or S to signify
  whether they have a right-handed (R) or
  left-handed (S) configuration.
• Active Learning How do you determine if this
  molecule is the R-enantiomer or the S-enantiomer?

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Introduction What is Chirality?

• Molecules that portray chirality or handedness
  may also be referred to as
• Levorotary (Lcounterclockwise) or
• Dextrorotary (Dclockwise).
• The L-configuration corresponds to the
  S-enantiomer while the D-configuration
  corresponds to the R-enantiomer.
• This notation is often used to denote the
  chirality of many common biochemical molecules
  such as D-Fructose or L-Glyceraldehyde.

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Introduction
When is a Molecule Achiral?

• A molecule is achiral (non-chiral) if and only if
  it has an axis of improper rotation, that is, an
  n-fold rotation (rotation by 360/n) followed by
  a reflection in the plane perpendicular to this
  axis maps the molecule on to itself.

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IntroductionGuidelines for Chirality

• You can determine if a molecule is chiral or
  achiral based on symmetry.
• On the above model, you had a chiral reactant
  binding to a chiral reactant site where
  everything fits into place.
• On the next model however, the enantiomer of the
  reactant below will not bind to the enzyme, so it
  will not react.
• This leads to substrate specificity.

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Enzyme-Substrate Relationships
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Enzyme-Substrate Relationships

• Enzymes
• Macromolecules, mostly of protein nature, that
  function as (bio) catalysts by increasing the
  reaction rates. In general, an enzyme catalyses
  only one reaction type (reaction specificity) and
  operates on only one type of substrate.

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Enzyme-Substrate Relationships

• Substrate
• In an enzymatic reaction a substrate is the
  specific biochemical molecule that is acted upon
  by the enzyme to yield a specific product.

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Enzyme-Substrate Relationships

• Substrate Specificity
• A characteristic feature of enzyme activity in
  relation to the kind of substrate on which the
  enzyme or catalytic molecule reacts.

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Effects on Tastes and Odors

• CHIRALITY AND ODOR

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Effects on Tastes and Odors

• WHAT ACCOUNTS A DIFFERENCE IN ODOR PERCEPTION?

• The affect of chirality on bioactivity? results
  in a variation in odor.
• Each enantiomer has a different 3-D fit on odor
  receptors in the nose.
• This phenomenon of specificity is not unlike that
  of enzyme- substrate relations.
• The influence of this characteristic not only
  effects the specific odor, but also intensity of
  odor.
• ?Note Bioactivity is defined as The effect of a
  given agent, such as a vaccine, upon a living
  organism or on living tissue.

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Effects on Tastes and Odors

• Why Do Lemons and Oranges Smell Differently?

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Effects on Tastes and Odors

• Why Do Lemons and Oranges Smell Differently?

• Found in both orange and lemon peels,
  Limonene is the molecule that is responsible
  for their characteristic odors.
• Oranges contain the left-handed molecule, and
  lemons, the right-handed.
• The same way your left foot fits only your left
  shoe, these molecules fit only into the
  appropriate left or right-handed receptors in
  your nose.
• This is how the same molecule can cause the
  orange
• and the lemon to have different smells.

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Effects on Tastes and OdorsEnantiomers of
Limonene
S-Limonene
R-Limonene
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Effects on Tastes and Odors
Caraway
Spearmint
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Effects on Tastes and Odors
Carvone

• Carvone is a ketone that can be found in caraway,
  dill, and spearmint oils.
• These oils are used for flavoring liqueurs and
  in perfumes and soaps.
• (S)-carvone is a molecule with a caraway-like
  odor, while its mirror image molecule,
  (R)-carvone has a spearmint odor.

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Effects on Tastes and OdorsEnantiomers of
Carvone
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Effects on Tastes and OdorsChirality and Food
Flavor
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Effects on Tastes and Odors

• WHAT ACCOUNTS FOR FOOD FLAVOR?
• The major components of the food we eat, amino
  acids, proteins, carbohydrates, triacylglycerols
  and some vitamins, are all chiral.
• This has a major impact on the perceived taste.
• Chiral compounds can even be used to determine a
  products age, storage and handling procedures,
  and whether or not the food is of natural or
  synthetic origin.

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Effects on Tastes and Odors
Aspartame Molecule
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Effects on Tastes and Odors

• Aspartame is a sugar substitute composed of
  aspartic acid and phenylalanine.
• Found in Equal and Nutrasweet,
• aspartame is very low in
• calories compared to
• sucrose (table sugar).
• Although it is
• 100-200x sweeter
• than sugar, its
• stereoisomer is bitter.

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Effects on Tastes and Odors

• FAST FACTS
• There are more than 285 enantiomeric pairs (570
  enantiomers) that are known to demonstrate odor
  differences or odor intensity differences.
• Until the mid-1970s to 1980s, the idea that
  optical enantiomers could have different odors
  was not generally accepted by academics.
• 8-10 of the population cannot distinguish
  between R-carvone and S-carvone.
• In 1848, French scientist, Louis Pasteur,
  discovered the chirality in the spin of molecules
  while examining salt of tartaric acid.

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Pharmaceutical Applications

• Chirality and Pharmaceutical Drugs
• Most drugs derived from natural sources are
  chiral and are almost always obtained as a single
  enantiomer whereas approximately 80 of
  synthesized drugs are composed of a 5050 racemic
  mixture.
• Receptors and enzymes in the body are very stereo
  selective and only react with one of the
  enantiomers of a chiral molecule in a process
  called chiral recognition
• As a result, one enantiomer has the desired
  effect on the body, while the other may have no
  effect or an adverse effect.

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Pharmaceutical Applications

• In Vivo Effect of Enantiomers
• Both enantiomers exhibit similar therapeutic
  properties (e.g. Promet-hazine, Flecainide)
• Only one isomer shows pharmacological activity
  (S-propranolol is a beta blocker) while the other
  one is inactive (R-propranolol)
• One type of isomer may show one type of
  pharmacological activity (S-penicillamine) and
  the other one shows toxicity (R-penicillamine)
• One type of isomer may show one type of
  pharmacological activity (R- methylphenylpropyl
  barbituric acid anesthetic) and the other type
  shows a convulsant effect

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Pharmaceutical Applications
Thalidomide - C13H10N2O4
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Pharmaceutical Applications

• Thalidomide
• Drug that was used in Europe during the period
  1959 1962 to combat morning sickness in
  pregnant women.
• ( R ) thalidomide contained the properties that
  made it useful as a sedative and antinausea drug.
• ( S ) thalidomide was responsible for many
  birth defects such as phocomelia.
• Even if thalidomide were purified to only the
  R- isomer, the pH of blood would cause rapid
  racemization into roughly equal amounts of both
  isomers.

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Pharmaceutical Applications
Birth Defects Caused by Thalidomide
Thalidomide Babies
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Pharmaceutical Applications

• Enantiomers of Thalidomide

'S' Optical isomer
'R' Optical Isomer
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Pharmaceutical Applications

• Advantages of using the more
• active isomer of a drug
• It leads to opportunities for racemic switching
• Increase in production capacity
• Less waste
• Dose will be halved
• Less likelihood of side effects

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As seen in living organisms

• The Chirality of biochemical molecules greatly
  affects their functions in living organisms.
• Many Organisms can use only the D-configuration
  or the L-configuration of a specific molecule.
• A specific enantiomer may be produced by one
  organism and passed on to another for further
  use.
• Many major biochemical molecules present even in
  our own bodies are chiral.
• Typically in nature

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As seen in living organisms

• Monosaccharide are found in the D-configuration

D-Galactose
D-Glucose
In what foods would you find these monosaccharide?
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As seen in living organisms

• D-Galactose is commonly referred to as milk sugar
  because it is found in dairy products such as
  milk, cheese and yogurt.
• D-Glucose is found in a wide variety of foods
  from vegetables to baked goods.
• D-Glucose molecules are synthesized by plants to
  store energy collected from the sun through the
  reactions of photosynthesis.
• The D-Glucose we consume is oxidized within our
  cells to release this stored energy as heat and
  ATP.

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As seen in living organisms

• While Amino Acids are found in the L-Conformation

L-Cysteine
L-Serine
What Amino Acid is Achiral?
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As seen in living organisms

• The Amino Acid
• Glycine is Achiral
• because it has
• 2 Hydrogen atoms
• attached to its
• central Carbon
• Atom.

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As seen in living organisms

• A major exception to the generalization that
  amino acids in nature exist in the
  L-Configuration is found in the cell walls of
  bacteria
• Bacterial cell walls are consist of a
  Peptidoglycan layer.
• The Peptidoglycan layer is made up of chains of
  the sugar units NAM (N-acetylmuramic acid) and
  NAG (N-acetylglucosamine).
• Amino acids are attached to the NAM units and are
  cross linked together between the sugar unit
  chains.

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As seen in living organisms

• Diagram of Gram-Negative Bacterial Cell Wall

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As seen in living organisms

• In Gram-Positive Bacteria the Peptidoglycan layer
  is very thick.
• The 4th Amino Acid in each chain is cross-linked
  to the 3rd Amino Acid in the adjacent chain
  directly or by a bridge of multiple amino acids.
• The amino acids attached to the NAM units in the
  NAG-NAM chains are 1) L-Alanine
• 2) D-Glutamic Acid
• 3) L-Lysine
• 4) D-Alanine

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As seen in living organisms

• Amino Acid Bridge in Cell Wall of Gram Positive
  Bacteria

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As seen in living organisms

• In Gram-Negative Bacteria the Peptidoglycan layer
  is not as thick, but an outer membrane is present
  to help protect the cell.
• The cell walls of Gram-Negative Bacteria differ
  in their amino acid chains in the 3rd position
  there is Meso-Diaminopimelic acid (DAP) instead
  of the L-Lysine found in Gram-Positive.
• The Peptidoglycan layers of Gram Negative
  Bacteria also lack interpeptide bridges their
  amino acid chains are connected by direct bonding
  between the 3rd and 4th amino acids only.

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As seen in living organisms
Direct Amino Acid linkages in Gram-Negative
Bacteria
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Conclusion Active Learning

• 3. (1996 F 4) Vitamin E is a fat soluble vitamin
• essential for muscle development. Two Chemistry
  32
• students take Vitamin E Fred gets his vitamin
  from a
• discount drug store Sara believes in "natural
  foods
• and so she buys her Vitamin E from a health food
• store. Freds Vitamin E is made in a factory
  Saras
• Vitamin E is derived from soybeans. Fred and Sara
• compared their Vitamin E samples by taking a
  melting
• point and measuring the 1H NMR spectrum of each.
• The melting points are different!!

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Conclusion Active Learning
A. What is the difference between Fred and Sara's
samples? B. What additional experiment would
clarify the difference between Fred and Sara's
Vitamin E? C. Would the NMR spectra of the two
samples be the same? D. What do you advise Fred
and Sara about taking the synthetic versus
natural Vitamin E?

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Conclusion Active Learning

A. What is the difference between Fred and Sara's
samples? Natural compounds, such as Sara's
sample, occur as one enantiomer. Vitamin E has 3
chiral centers, so there are 238 possible
stereoisomers, many of which are probably
contained in the synthetic analog that Fred
bought.
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Conclusion Active Learning
B. What additional experiment would clarify the
difference between Fred and Sara's Vitamin
E? Because Fred's sample is a mixture of
diastereomers and Sara's sample is one pure
enantiomer, the samples will have different
physical and light-rotating properties.
Chromatography or solubility experiments could
clarify the differences in physical properties.
NMR might elucidate how the structures differ. In
addition, the optical activity of the samples
could be checked. (Fred's sample is probably
racemic.)

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Conclusion Active Learning

C. Would the NMR spectra of the two samples be
the same? They would be different. Fred's NMR
would be complex because he has a mixture of
diastereomers, which would be present in
unpredictable ratios Sara's would be simpler.
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Conclusion Active Learning
D. What do you advise Fred and Sara about taking
the synthetic versus natural Vitamin
E? Biological receptors are often stereospecific,
so only the proper enantiomer would be effective.
Fred's Vitamin E probably has only 1/8 of the
proper compound and probably contains other
diastereomers that may be harmful. Sara's Vitamin
E is a pure sample of the proper, natural
compound and would be well received in the body.

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For More Information see(References)

• Carey, Francis A. Organic Chemistry. 5th ed. New
  York McGraw-Hill, 2000
• Dr. Gilmers Chapter 19 lecture
• EXPERIMENT 3 Essential Oils (EO). EO-1.
  MASSACHUSETTS INSTITUTE OF TECHNOLOGY Department
  of Chemistry. 5.310 Laboratory Chemistry.
  EXPERIMENT 3 ESSENTIAL OILS.
• http//web.mit.edu/5.310/www/Essential_oils.pdf
• http//en.wikipedia.org/wiki/ImageD-glucose.png
• http//en.wikipedia.org/wiki/ImageD-galactose_Fis
  cher.png
• http//orion.math.iastate.edu/mathnight/activities
  /modules/Mirror/leftpanel.pdf
• http//web.mit.edu/5.310/www/Essential_oils.pdf

51
For More Information see(References)

• http//www.alislam.org/library/books/revelation/pa
  rt_5_section_6.html
• http//www.answersingenesis.org/docs/3991.asp
• http//www.arches.uga.edu/kristenc/cellwall.html
• http//www.chemie.fu-berlin.de/chemistry/bio/amino
  acid/cystein_en.html
• http//www.chemie.fu-berlin.de/chemistry/bio/amino
  acid/serin_en.html
• http//www.chm.bris.ac.uk/motm/thalidomide/start.h
  tml
• http//www.chm.bris.ac.uk/motm/thalidomide/optical
  2iso.html
• http//www.factsandcomparisons.com/assets/advinpha
  rm/AIP_1-3_242-252.PDF
• http//www.geocities.com/pribond/bioinfo/glossary/
  pharmabio.htm

52
For More Information see(References)

• http//www.google.com/search?qcacheyNHjdf5_NpMJ
  www.dissolutiontech.com/DTresour/0803art/DT0803art
  2.pdfchiralityinpharmacydrugshlen
• http//www.leffingwell.com/download/chirality-pham
  acology.pdf
• http//www.leffingwell.com/chirality/chirality.htm
  
• http//www.roycastle.co.uk/gal_6/devon-foods.jpg
• http//www.scri.sari.ac.uk/SCRI/Web/Site/home/Rese
  archAreas/Theme2GenestoProducts/QHN/External/Chir
  ality.asp
• http//www.tock.com/chem32/ste1/
• Ghuysen, J.-M., Kakenbeck, R. New Comprehensive
  Biochemistry Bacterial Cell Wall (Volume 27).
  New York, 1994. ElsevierScience B.V.

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For More Information see(References)

• Inouye, Masayori. Bacterial Outer Membranes
  Biogenesis and Functions. New York, 1979. John
  Wiley Sons, Inc.
• What is chirality?. http//chirality.ouvaton.or
  g/homepage.htm