bio-organic chemistry dr. supartono, m.s. harjono, s.pd. m.si
TRANSCRIPT
Bio-organic Chemistry
Dr. Supartono, M.S.
Harjono, S.Pd. M.Si.
Part #1
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)
What’s the difference between these???
Deal with interface of biology & chemistry
BIOLOGY CHEMISTRY
Simple organics
eg HCN, H2C=O
(mono-functional)
Biologically relevant organics: polyfunctional
Lifelarge macromolecules; cells—contain ~ 100, 000 different compounds interacting
1 ° Metabolism – present in all cell
2 ° Metabolism – specific species, eg. Caffeine
CHEMISTRY:
Round-bottom flaskBIOLOGY:
cell
How different are they?
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)
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 3 parts:
1) How do chemists synthesize these structures?
2) How are they made in vivo?
3) Improved chemistry through understanding the biology: biomimetic synthesis
Properties of Biological Molecules that Inspire Chemists
1) Large → challenges: for synthesisfor structural prediction (e.g. protein folding)
2) Size → multiple FG’s (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
5) Regulated → switchable, allows control of cell → activation/inhibiton
6) Catalysis → groups work in concert
7) Replication → turnover
e.g. an enzyme has many turnovers, nucleic acids replicates
Evolution of Life• Life did not suddenly crop up in its element 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: HCN + NH3 bases
H2C=O sugars
nucleosides
phosphate
nucleotides
RNA
"RNA world"
catalysismore RNA, other molecules
modern "protein" world
CH4, NH3
H2Oamino acids
proteinsRNA
(ribozyme)
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
DNA
transcriptionRNA protein
translation
requiresprotein
requires RNA+ protein
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 vivo – how is the cell CONTROLLED?
c) in chemical models – can we design better chemistry through understanding biochemical mechanisms?
Relevance of Labs to the CourseLabs illustrate:
1) Biologically relevant small molecules (e.g. caffeine )
2) Structural principles & characterization(e.g. anomers of glucose, anomeric effect, diastereomers, NMR)
3) Cofactor chemistry – pyridinium ions (e.g. NADH)
4) Biomimetic chemistry (e.g. simplified model of NADH)
5) Chemical mechanisms relevant to catalysis (e.g. NADH)
6) Application of biology to stereoselective chemical synthesis (e.g. yeast)
7) Synthesis of small molecules (e.g. drugs, dilantin, tylenol)
8) Chemical catalysis (e.g. protection & activation strategies relevant to peptide synthesis in vivo and in vitro)
All of these demonstrate inter-disciplinary area between chemistry & biology
Two Views of DNA
1) Biochemist’s view: shows overall shape, ignores atoms & bonds
2) chemist’s view: atom-by-atomstructure, functional groups
Biochemist’s View of the DNA Double Helix
Major groove
Minor groove
N
NH
O
O
O
H
OH
H
OH
HH
OP OOO
HH
OP
O
OO
2o alcohol(FG's)
alkene
bonds
resonance
Ringconformationax/eq
H-bonds
nucleophilic
electrophilic
substitution rxn
chirality
+
diastereotopic
Chemist’s View
BASES
N N
pyridine pyrrole
• Aromatic structures: – all sp2 hybridized atoms (6 p orbitals, 6 π e-)– planar (like benzene)
• N has lone pair in both pyridine & pyrrole basic (H+ acceptor or e- donor)
ArN: H+ ArNH+
pKa?
N H
N
H
H
+
+
6 π 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!)
• Pyridine’s 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
• 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 suffice
N HO
H:
e- donor e- acceptor
H-bond acceptor
H-bonddonor
acidbase
Contrast with Nucleic Acid Bases (A, T, C, G, U) – Specific!
N N
NN
NH2
H
N N
NN
O
NH2
H
N
NH
O
O
H
N
NH
O
O
HN
N
O
NH2
HThymine (T)
Guanine (G)Adenine (A)
Uracil (U)Cytosine (C)
* *
*
*
*
Pyrimidines (like pyridine):
Purines
(DNA only) (RNA only)
* link to sugar
• Evidence for specificity?• Why are these interactions specific? e.g. G-C & A-T
• 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!
NH N
NN
O
N
H
H
HNHN
O
N
H
H
G C
2 lone pairs inplane at 120o toC=O bond
e.g. Guanine-Cytosine:
• Why?– In G-C duplex, 3 complementary H-bonds can form: donors &
acceptors = molecular recognition
• Can use NMR to do a titration curve:
• Favorable reaction because ΔH for complex formation = -3 x H-bond energy
• ΔS is unfavorable → complex is organized 3 H-bonds overcome the entropy of complex formation
• **Note: In synthetic DNAs other interactions can occur
G + CKa
G C
get equilibrium constant,
G = -RT ln K = H-TS
• Molecular recognition not limited to natural bases:
Create new architecture by thinking about biology i.e., biologically inspired chemistry!
Forms supramolecular structure: 6 molecules in a ring
Synthesis of Bases (Nucleic)
• Thousands of methods in heterocyclic chemistry– we’ll do 1 example:– 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
NH N
NN
NH2
NH3 + HCN
Adenine
Polymerization of HCN
Mechanism?CN NH
H+
NHN
H
NH
NN
H
H NH
C N
N
H
HNH
NH
N
H+
NH
N
N NH
N
H
NH H+
NN
NN
H
NH2
NH3
H+
NN
NN
NH2
H
H
HH
+
NN
NH
N
NH2
H
H+
tautomerization
N
NH3
N N
N H
HC
G, U, T and C
(cyanogen)
(cyanoacetylene)
Other Bases?
** Try these mechanisms!
Properties of Pyridine • We’ve seen it as an acid & an H-bond acceptor• Lone pair can act as a nucleophile:
N R X N+
R
NX
O
N
O
+SN2
+ +
N
O
NH2
PhN
O
NH2
PhN
O
NH2
Ph
HH
++
aromatic, but +ve charge
electron acceptor:electrophile
"H-"
reduction
(like NaBH4)
e.g. exp 3: benzyl dihydronicotinamide
• Balance between aromaticity & charged vs non-aromatic & neutral!
• can undergo REDOX reaction reversibly:
NAD-H NAD+ + "H-"
reductant oxidant
• Interestingly, nicotinamide may have been present in the pre-biotic world:
• NAD or related structure may have controlled redox chemistry long before enzymes involved!
NH
CN
NH
CN
N
NH2
O
Diels-Alder
[O],hydrolysis of CN
1% yield
electical discharge
CH4 + N2 + H2
Another example of N-Alkylation of Pyridines
NHN
NNH
O
O NN
NNH
O
O
CH3
Caffeine
This is an SN2 reaction with stereospecificity
R
NH
RCH3
S+
Met
Ad R
N
R
CH3 SMet
Ad+ +
s-adenosyl methionine
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