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Bio-organic Chemistry Dr. Supartono, M.S. Harjono, S.Pd. M.Si.
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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
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BIOLOGYCHEMISTRY Simple organics eg HCN, H 2 C=O (mono-functional) Biologically relevant organics: polyfunctional Life large macromolecules; cells—contain ~ 100, 000 different compounds interacting 1 ° Metabolism – present in all cell 2 ° Metabolism – specific species, eg. Caffeine CHEMISTRY: Round-bottom flask BIOLOGY: cell How different are they?
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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)
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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
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Properties of Biological Molecules that Inspire Chemists 1)Large → challenges: for synthesis for 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
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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
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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:
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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
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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?
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Relevance of Labs to the Course Labs 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)
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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
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Two Views of DNA 1)Biochemist’s view: shows overall shape, ignores atoms & bonds 2)chemist’s view: atom-by-atom structure, functional groups
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Biochemist’s View of the DNA Double Helix Major groove Minor groove
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Chemist’s View
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BASES Aromatic structures: –all sp 2 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)
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6 π electrons, stable cation weaker acid, higher pKa (~ 5) & strong conj. base sp 3 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
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The lone pair also makes pyridine a H-bond acceptor e.g. benzene is insoluble in H 2 O but pyridine is soluble: This is a NON-specific interaction, i.e., any H-bond donor will suffice
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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
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Evidence? –If mix G & C together → exothermic reaction occurs; change in 1 H 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
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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
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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
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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
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Mechanism?
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Other Bases? ** Try these mechanisms!
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Properties of Pyridine We’ve seen it as an acid & an H-bond acceptor Lone pair can act as a nucleophile:
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Balance between aromaticity & charged vs non-aromatic & neutral! can undergo REDOX reaction reversibly:
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Interestingly, nicotinamide may have been present in the pre-biotic world: NAD or related structure may have controlled redox chemistry long before enzymes involved! electical discharge CH 4 + N 2 + H 2
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Another example of N-Alkylation of Pyridines This is an S N 2 reaction with stereospecificity
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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
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