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Welcome to CHEM BIO 3OA3! Bio-organic Chemistry [OLD CHEM 3FF3]

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Biology Chemistry. Chemistry. Explains events of biology: ... Bases in nucleic acids ch. 25. Also see Dobson, ch.9. Topics in Current Chemistry, v 259, p 29-68 ... – PowerPoint PPT presentation

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Title: Welcome to CHEM BIO 3OA3! Bio-organic Chemistry [OLD CHEM 3FF3]


1
Welcome to CHEM BIO 3OA3! Bio-organic
Chemistry OLD CHEM 3FF3
  • Sept. 11, 2009

2
  • Instructor Paul Harrison
  • ABB 418, ext. 27290
  • Email pharriso_at_mcmaster.ca
  • Course website http//www.elm.mcmaster.ca/
  • Lectures MW 0830, F 1030 (ABB/106)
  • Office Hours M 1230-230 or by appointment
  • Labs
  • 230-530 R or F (ABB 217)
  • Every week
  • Labs start next Fri. Sept. 17, 2009

3
Web site update
  • ELM page
  • Lectures 1 includes everything for today, and
    approx. 1 week of material intro and bases
  • Course outline
  • Detailed course description lecture-by-lecture
  • Calendar

4
  • For Thursday 11th Friday 12th
  • Check-in, meet TA, safety and Lab 1 (Isolation of
    Caffeine from Tea)
  • Lab manuals Available on web MUST bring printed
    copy
  • BEFORE the lab, read lab manual intro, safety and
    exp. 1
  • Also need
  • Duplicate lab book (20B3 book is ok)
  • Goggles (mandatory)
  • Lab coats (recommended)
  • No shorts or sandals
  • Obey safety rules marks will be deducted for
    poor safety
  • Work at own pacesome labs are 2 or 3 wk labs.
    In some cases more than 1 exp. can be worked in a
    lab periodyour TA will provide instruction

5
  • Evaluation
  • Assignments 2 x 5 10
  • Labs -write up 15
  • - practical mark 5
  • Midterm 20
  • Final 50
  • Midterm test
  • Fri. Oct. 30, 2009 at 700 pm
  • Assignments Oct. 9 Oct. 19
  • Nov. 13 Nov. 23
  • Note academic dishonesty statement on outline-NO
    copying on assignments or labs (exception when
    sharing results)

6
  • Texts
  • Dobson Foundations of Chemical Biology,
    (Optional- bookstore)
  • Background Refreshers
  • An organic chemistry textbook (e.g. Solomons)
  • A biochemistry textbook (e.g. Garrett)
  • 2OA3/2OB3 old exam on web
  • This course has selected examples from a variety
    of sources, including Dobson
  • Buckberry Essentials of Biological Chemistry
  • Dugas, H. "Bio-organic Chemistry"
  • Waldman, H. Janning, P. Chemical Biology
  • Also see my slides on the website

7
  • What is bio-organic chemistry? Biological chem?
    Chemical bio?
  • Chemical Biology
  • Development use of chemistry techniques for
    the study of biological phenomena (Stuart
    Schreiber)
  • Biological Chemistry
  • Understanding how biological processes are
    controlled by underlying chemical principles
    (Buckberry Teasdale)
  • Bio-organic Chemistry
  • Application of the tools of chemistry to the
    understanding of biochemical processes (Dugas)
  • Whats the difference between these???
  • Deal with interface of biology chemistry

8
Simple organics eg HCN, H2CO (mono-functional) C
f 20A3/B3
BIOLOGY
CHEMISTRY
Life large macromolecules cellscontain 100,
000 different compounds interacting
Biologically relevant organics polyfunctional
1 Metabolism present in all cells (focus of
3OA3) 2 Metabolism specific species, eg.
Caffeine (focus of 4DD3)
How different are they?
CHEMISTRY Round-bottom flask
BIOLOGY cell
9
  • Exchange of ideas
  • Biology Chemistry
  • Chemistry
  • Explains events of biology mechanisms,
    rationalization
  • Biology
  • Provides challenges to chemistry synthesis,
    structure determination
  • Inspires chemists biomimetics ? improved
    chemistry by understanding of biology (e.g.
    enzymes)

10
Key Processes of 1 Metabolism
  • Bases sugars ? nucleosides
    nucleic acids
  • Sugars (monosaccharides)
    polysaccharides
  • Amino acids
    proteins
  • Polymerization reactions cell also needs the
    reverse process
  • We will look at each of these processes, forwards
    and backwards, in 4 parts, comparing and
    contrasting the reactions
  • How do chemists synthesize these structures?
  • How might these structures have formed in the
    pre-biotic world, and have led to life on earth?
  • How are they made in vivo?
  • Can we design improved chemistry by understanding
    the biology biomimetic synthesis?

11
Properties of Biological Molecules that Inspire
Chemists
  • Large ? challenges for synthesis
  • for structural prediction (e.g. protein
    folding)
  • 2) Size ? multiple FGs (active site) ALIGNED to
    achieve a goal
  • (e.g. enzyme active site, bases in NAs)
  • 3) Multiple non-covalent weak interactions ? sum
    to strong, stable binding non-covalent complexes
  • (e.g. substrate, inhibitor, DNA)
  • 4) Specificity ? specific interactions between 2
    molecules in an ensemble within the cell

12
  • 5) Regulated ? switchable, allows control of cell
    ? activation/inhibition
  • 6) Catalysis ? groups work in concert
  • 7) Replication ? turnover
  • e.g. an enzyme has many turnovers, nucleic
    acids replicate

13
Evolution of Life
  • Life did not suddenly crop up in its current form
    of complex structures (DNA, proteins) in one
    sudden reaction from mono-functional simple
    molecules
  • In this course, we
  • will follow some of the
  • ideas of how life may
  • have evolved

14
RNA World
  • Catalysis by ribozymes occurred before protein
    catalysis
  • Explains current central dogma
  • Which came first nucleic acids or protein?
  • RNA world hypothesis suggests RNA was first
    molecule to act as both template catalyst
  • catalysis replication

15
  • How did these reactions occur in the pre-RNA
    world? In the RNA world? in modern organisms?
  • CATALYSIS SPECIFICITY
  • How are these achieved? (Role of NON-COVALENT
    forces BINDING)
  • a) in chemical synthesis
  • b) in the pre-biotic world
  • c) in vivo how is the cell CONTROLLED?
  • d) in chemical models can we design better
    chemistry through understanding biochemical
    mechanisms?

16
Relevance of Labs to the Course
  • Labs illustrate
  • Biologically relevant small molecules (e.g.
    caffeine Exp 1, related to bases)
  • Cofactor chemistry pyridinium ions (e.g. NADH,
    Exp 2 4)
  • Biomimetic chemistry (e.g. simplified model of
    NADH, Exp 2)
  • Chemical mechanisms relevant to catalysis (e.g.
    NADH, Exp 2)
  • Structural principles characterization (e.g.
    sugars anomers of glucose, anomeric effect,
    diastereomers, NMR, Exp 3)

17
  • Application of biology to stereoselective
    chemical synthesis (e.g. yeast, Exp 4)
  • Synthesis of small molecules (e.g. peptides,
    drugs, dilantin, esters, Exp 5,6,7)
  • Chemical catalysis (e.g. protection activation
    strategies relevant to peptide synthesis in vivo
    and in vitro, Exp 5)
  • Comparison of organic and biological reactions
    (Exp. 6)
  • Enzyme mechanisms and active sites (Exp. 7)
  • All of these demonstrate inter-disciplinary area
    between chemistry biology

18
  • Two Views of DNA
  • Biochemists view shows overall shape,
    ignores atoms bonds
  • Chemists view atom-by-atom structure,
    functional groups illustrates concepts from
    2OA3/2OB3
  • GOAL to think as both a chemist and a
    biochemist i.e. a chemical biologist!

19
Biochemists View of the DNA Double Helix
Minor groove
Major groove
20
Chemists View
21
BASES
  • Aromatic structures
  • all sp2 hybridized atoms (6 p orbitals, 6 p e-)
  • planar (like benzene)
  • N has lone pair in both pyridine pyrrole ?
    basic (H acceptor or e- donor)

22
6 p electrons, stable cation ? weaker acid,
higher pKa ( 5) strong conj. base
sp3 hybridized N, NOT aromatic ? strong acid, low
pKa ( -4) weak conj. base
  • Pyrrole uses lone pair in aromatic sextet ?
    protonation means loss of aromaticity
    (BAD!)
  • Pyridines N has free lone pair to accept H
  • ? pyridine is often used as a base in organic
    chemistry, since it is soluble in many common
    organic solvents

23
  • The lone pair also makes pyridine a H-bond
    acceptor e.g. benzene is insoluble in H2O but
    pyridine is soluble
  • This is a NON-specific interaction, i.e., any
    H-bond donor will work

24
What about pyrrole?
  • Is it soluble in water?

25
Other groups form H-bonds
  • Electronegative atoms, e.g. carbonyl group
  • Acetone is soluble in water, but propane is not
  • Again, non-specific interactions

26
Bifunctional compounds
27
Bifunctional compounds
28
Contrast with Nucleic Acid Bases (A, T, C, G, U)
Specific!
  • Evidence for specificity?
  • Why are these interactions specific? e.g. G-C
    A-T

29
  • Evidence?
  • If mix G C together ? exothermic reaction
    occurs change in 1H chemical shift in NMR other
    changes ? reaction occurring
  • Also occurs with A T
  • Other combinations ? no change!

e.g. Guanine-Cytosine
  • Why?
  • In G-C duplex, 3 complementary H-bonds can form
    donors acceptors molecular recognition

30
  • Can use NMR to do a titration curve
  • Favorable reaction because ?H for complex
    formation -3 x H-bond energy
  • ?S is unfavorable ? complex is organized ?
    3 H-bonds overcome the entropy of complex
    formation
  • Note In synthetic DNAs other interactions can
    occur

31
  • Molecular recognition not limited to natural
    bases

Forms supramolecular structure 6 molecules in a
ring
? Create new architecture by thinking about
biology i.e., biologically inspired chemistry!
32
Synthesis of the Bases in Nucleic Acids
  • Thousands of methods in heterocyclic chemistry
    well do 1 example
  • Juan Or (1961)
  • May be the first step in the origin of life
  • Interesting because H-CN/CN- is probably the
    simplest molecule that can be both a nucleophile
    electrophile, and also form C-C bonds

32
33
Mechanism?
33
34
Other Bases?
All these species are found in interstellar
space observed by e.g. absorption of IR
radiation a natural example of IR
spectroscopy! Try these mechanisms!
34
35
Properties of Pyridine
  • Weve seen it as an acid an H-bond acceptor
  • Lone pair can act as a nucleophile

35
36
  • Balance between aromaticity charged vs
    non-aromatic neutral!
  • ? can undergo REDOX reaction reversibly

36
37
  • Interestingly, nicotinamide may have been present
    in the pre-biotic world
  • NAD or related structure may have controlled
    redox chemistry long before enzymes involved!

37
38
Another example of N-Alkylation of Pyridines
This is an SN2 reaction stereospecific with
INVERSION
38
39
References
  • Solomons
  • Amines basicity ch.20
  • Pyridine pyrrole pp 644-5
  • NAD/NADH pp 645-6, 537-8, 544-6
  • Bases in nucleic acids ch. 25
  • Also see Dobson, ch.9
  • Topics in Current Chemistry, v 259, p 29-68

39
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