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Introduction to Biochemistry Andy Howard Biochemistry, Fall 2007 IIT What is biochemistry? By the end of biology 402 you should be able to construct your own definition; but for now: Biochemistry is the study of chemical reactions in living tissue. Plans What is biochemistry? Organic and biochemistry Concepts from organic chemistry to remember Small molecules and macromolecules Classes of small molecules Classes of macromolecules Water Catalysis Energetics Regulation Molecular biology Evolution What will we study? Biochemistry is the study of chemical reactions in living tissue, both within cells and in intercellular media. As such, it concerns itself with a variety of specific topics: Topics in biochemistry What reactions occur; The equilibrium energetics and kinetics of those reactions; How the reactions are controlled, at the chemical and cellular or organellar levels; How the reactions are organized to enable biological function. Organic and biological chemistry Most molecules in living things (other than H2O and O2) contain C-C or C-H bonds, so biochemistry depends heavily on organic chemistry But the range of organic reactions that occur in biological systems is fairly limited compared to the full range of organic reactions: Why we use only a subset of organic chemistry in biochem Biochemical reactions are almost always aqueous. They occur within a narrow temperature and pressure range. They occur within narrowly buffered pH ranges. Many of the complex reaction mechanisms discovered and exploited by organic chemists since the 1860's have no counterparts in the biochemical universe. Concepts from organic chemistry There are some elements of organic chemistry that you should have clear in your minds. All of these are concepts with significance outside of biochemistry, but they do play important roles in biochemistry. If any of these concepts is less than thoroughly familiar, please review it: Organic concepts I Covalent bond: A strong attractive interaction between neighboring atoms in which a pair of electrons is roughly equally shared between the two atoms. – Covalent bonds may be single bonds, in which one pair of electrons is shared; double bonds, which involve two pairs of electrons; or triple bonds, which involve three pairs. – Single bonds do not restrict the rotation of other substituents around the bond; double and triple bonds do. Organic concepts II Ionic bond: a strong attractive interaction between atoms in which one atom or group is positively charged, and another is negatively charged. Organic concepts III Hydrogen bond: A weak attractive interaction between neighboring atoms in which a hydrogen atom carrying a slight, partial positive charge shares that positive charge with a neighboring electronegative atom. – The non-hydrogen atom to which the hydrogen is covalently bonded is called the hydrogen-bond donor; – the neighboring atom that takes on a bit of the charge is called the hydrogen-bond acceptor. Van der Waals interaction: A weak attractive interaction between nonpolar atoms, arising from transient induced dipoles in the two atoms. Organic Concepts IV Chirality: The property of a molecule under which it cannot be superimposed upon its mirror image. Tautomerization: The interconversion of two covalently different forms of a molecule via a unimolecular reaction that proceeds with a low activation energy. The two forms of the molecule are known as tautomers: because of the low activation barrier between the two forms, we will typically find both species present. Organic Concepts V Nucleophilic substitution: a reaction in which an electron-rich (nucleophilic) molecule attacks an electron-poor (electrophilic) molecule and replaces group or atom within the attacked species. – The displaced group is known as a leaving group. – This is one of several types of substitution reactions, and it occurs constantly in biological systems. Organic Concepts VI Polymerization: creation of large molecules by sequential addition of simple building blocks – often by dehydration, i.e., the elimination of water from two species to form a larger one: R1-O-H + HO-R2-X-H R1-X-R2-OH + H2O – The product here can then react with HO-R3-X-H to form R1-X-R2-X-R3-OH, and so on. Organic Concepts VII Equilibrium: in the context of a chemical reaction, the state in which the concentrations of reactants and products are no longer changing with time because the rate of reaction in one direction is equal to the rate in the opposite direction. Kinetics: the study of the rates at which reactions proceed. Organic Concepts VIII Catalysis: the lowering of the energetic barrier between substrates and products in a reaction by the participation of a substance that ultimately is unchanged by the reaction – It is crucial to recognize that catalysts (chemical agents that perform catalysis) do not change the equilibrium position of the reactions in which they participate: – they only change the rates (the kinetics) of the reactions they catalyze. Zwitterion: a compound containing both a positive and a negative charge Classes of small molecules Small molecules other than water make up a small percentage of a cell's mass, but small molecules have significant roles in the cell, both on their own and as building blocks of macromolecules. The classes of small molecules that play significant roles in biology are listed below. In this list, "soluble" means "water-soluble". Biological small molecules I Water: Hydrogen hydroxide. In liquid form in biological systems. See below. Lipids: Hydrophobic molecules, containing either alkyl chains or fused-ring structures. A biological lipid usually contains at least one highly hydrophobic moeity. Biological small molecules II Carbohydrates: Polyhydroxylated compounds for which the building blocks are highly soluble. – The typical molecular formula for the monomeric forms of these compounds is (CH2O)n, where 3 < n < 9, – but usually n = 5 or 6. Biological small molecules III Amino acids: Compounds containing an amine (NH3+) group and a carboxyl (COO-) group. The most important biological amino acids are a-amino acids, in which the amine group and the carboxyl group are separated by one carbon, and that intervening carbon has a hydrogen attached to it. Thus the general formula for an a-amino acid is H3N+ - CHR - COO- Biological small molecules IV Nucleic acids: Soluble compounds that include a nitrogen-containing ring system. – The ring systems are derived either from purine or pyrimidine. – The most important biological nucleic acids are those in which the ring system is covalently attached to a five-carbon sugar, ribose, usually with a phosphate group attached to the same ribose ring. Small molecules V Inorganic ions: Ionic species containing no carbon but containing one or more atoms and at least one net charge. – Ions of biological significance include Cl-, Na+, K+, Mg+2, Mn+2, I-, Ca+2, PO4-3, SO4-2, NO3-, NO2-, and NH4+. – Phosphate (PO4-3) is often found in partially protonated forms HPO4-2 and H2PO4 – Ammonium ions occasionally appear as neutral ammonia (NH3) Biological Small Molecules VI Cofactors: This is a catchall category for organic small molecules that serve in some functional role in biological organisms. Many are vitamins or are derived from vitamins; a vitamin is defined as an organic molecule that is necessary for metabolism but cannot be synthesized by the organism. Thus the same compound may be a vitamin for one organism and not for another. Ascorbate (vitamin C) is a vitamin for humans and guinea pigs but not for most other mammals. Cofactors often end up as prosthetic groups, covalently or noncovalently attached to proteins and involved in those proteins' functions. Biological macromolecules Most big biological molecules are polymers, i.e. molecules made up of large numbers of relatively simple building blocks. Cobalamin is the biggest nonpolymeric biomolecule I can think of (MW 1356 Da) Categories of biological polymers Proteins Nucleic acids Polysaccharides Lipids (sort of): – 2-3 chains of aliphatics attached to a polar head group, often built on glycerol – Aliphatic chains are usually 11-23 C’s Polymers and oligomers These are distinguished only by the number of building-blocks contained within the multimer Oligomers: typically < 50 building blocks Polymers 50 building blocks. Categories of biopolymers Category Protein # monomers 20 <mol wt/ # mono- Branchmonomer> mers ing? 110 65-5000 no RNA 4-10 220-400 50-15K no DNA 4 200-400 50-106 no Polysaccharide ~10 180 2-105 Sometimes Water: a complex substance Oxygen atom is covalently bonded to two hydrogens Single bond character of these bonds means the H-O-H bond angle is close to 109.5º = acos(-1/3) This contrasts with O=C=O (angle=180º) or urea ((NH2)2-C=O) (angles=120º) Two lone pairs available per oxygen: these are available as H-bond acceptors Water is polar Charge is somewhat unequally shared Small positive charge on H’s (d+); small negative charge on O (2d-) A water molecule will orient itself to align partial negative charge on one molecule close to partial positive charges on another. Hydrogen bonds are involved in this. Liquid water is mobile The hydrogen-bond networks created among water molecules change constantly on a subpicosecond time scale At any moment the H-bonds look like those in crystalline ice Solutes disrupt the H-bond networks Water in reactions Water is a medium within which reactions occur; But it also participates in reactions Enzymes often function by making water oxygen atoms better nucleophiles or water H’s better electrophiles Therefore water is a direct participant in reactions that wouldn’t work in a nonenzymatic lab setting! Water’s physical properties High heat capacity: stabilizes temperature in living things High surface tension Nearly incompressible (density almost independent of pressure) Density max at 3.98ºC Catalysis Catalysis is the lowering of the activation energy barrier between reactants and products How? – Physical surface on which reactants can be exposed to one another – Providing moieties that can temporarily participate in the reaction and be restored to their original state at the end Biological catalysts 1890’s: Fischer realized that there had to be catalysts in biological systems 1920’s: Sumner said they were proteins It took another 10 years for the whole community to accept that It’s now known that RNA can be catalytic too: – Can catalyze modifications in itself – Catalyzes the key step in protein synthesis in the ribosome Energy in biological systems We distinguish between thermodynamics and kinetics: Thermodynamics characterizes the energy associated with equilibrium conditions in reactions Kinetics describes the rate at which a reaction moves toward equilibrium Thermodynamics Equilibrium constant is a measure of the ratio of product concentrations to reactant concentrations at equilibrium Free energy is a measure of the available energy in the products and reactants They’re related by DGo = -RT ln Keq Kinetics Rate of reaction is dependent on Kelvin temperature T and on activation barrier DG‡ preventing conversion from one site to the other Rate = Qexp(-DG‡/RT) Job of an enzyme is to reduce DG‡ Regulation Biological reactions are regulated in the sense that they’re catalyzed by enzymes, so the presence or absence of the enzyme determines whether the reaction will proceed The enzymes themselves are subject to extensive regulation so that the right reactions occur in the right places and times Typical enzymatic regulation Suppose enzymes are involved in converting A to B, B to C, C to D, and D to F. E is the enzyme that converts A to B: (E) ABCDF In many instance F will inhibit (interfere) with the reaction that converts A to B by binding to a site on enzyme E so that it can’t bind A. This feedback inhibition helps to prevent overproduction of F—homeostasis. Molecular biology This phrase means something much more specific than biochemistry: It’s the chemistry of replication, transcription, and translation, i.e., the ways that genes are reproduced and expressed. Most of you have taken biology 214 or its equivalent; we’ll review some of the contents of that course here. The molecules of molecular bio Deoxyribonucleic acid: polymer; backbone is deoxyribose-phosphate; side chains are nitrogenous ring compounds RNA: polymer; backbone is ribosephosphate; side chains as above Protein: polymer: backbone is NH-(CHR)-CO; side chains are 20 ribosomally encoded styles Steps in molecular biology DNA replication (makes accurate copy of existing double-stranded DNA prior to mitosis) Transcription (RNA version of DNA message is created) Translation (mRNA copy of gene serves as template for making protein: 3 bases of RNA per amino acid of synthesized rotein) Evolution and Taxonomy Traditional studies of interrelatedness of organisms focused on functional similarities This enables production of phylogenetic trees Molecular biology provides an alternative, possibly more quantitative, approach to phylogenetic tree-building More rigorous hypothesis-testing possible