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Chapter 3

Chapter 3 Amino acids.doc

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CHY 204
Mario Estable

Chapter 3 Amino acids, peptides & proteins -All proteins are constructed from the same 20 aa that are covalently linked in characteristic linear sequences b/c of their side chains, each has distinct chemical properties; think of the 20 aa as the alphabet for pro structure. From these building blocks, various combinations give rise to enzymes, hormones, antibodies, transporters, muscle fibers, lens pro of the eye, feathers, spider webs, rhinoceros horn, milk pro, antibiotics, etc. Enzymes are the most varied & specialized; virtually all cellular rxns are catalyzed by enzymes 3.1 Amino acids -pro are polymers of aa w/ each aa residue (residue means the loss of elements of H2O when an aa acid is joined to another) joined to its neighbour by a specific type of covalent bond. First aa discovered was aspargine (found in asparagus) & the last was threonine; names are derived from where the aa were first isolate, eg. glutamate in wheat gluten, tyrosine in cheese & glycine due to sweet taste Amino acids share common structural features -The 20 common aa are all alpha-aa; have a carboxyl group & amino group bonded to the sam C but aa differ in their side chains/R groups which vary is size, structure & electric charge—these factors influence solubility of aa in water. Table 3-1 shows aa of pro that have been assigned 3 letter abbrev & 1 letter symbols, to indicate aa composition & sequence polymerized in pro. -all common aa have the alpha C bonded to 4 diff groups (carboxyl group, amino group, R group & H atom) except glycine (R group is another H atom). This means the alpha-C is a chiral center so in total there 19 chiral C, one for each aa except glycine. The 4 diff groups can occupy 2 spatial arrangements thus aa have 2 possible stereoisomers, L & D & since they are nonsuperimposable images of one another, they can be classified as enantiomers. All molecules w/ a chiral center are also optically active, ie. Rotates in plane-polarized light. -There are 2 conventions used to identify Cs in an aa: The additional C in an R group are commonly designated as β,γ,δ,ε (3,4,5,6) etc proceeding out from the α C. The carboxyl C of an aa would be C-1 & then α C would be C-2, etc. In some cases, aa w/ heterocyclic R groups, eg. Histidine, the numbering system is preferred. For branched aa side chains, C are given numbers after the Greek letters, eg. Leucine has δ1 &δ2 C. -Special nomenclature has been developed for absolute configuration of the 4 substituents of chiral C atoms. Absolute configs for simple sugars &aa are specified by the D, L system based on absolute config of the 3C glyceraldehyde; system was proposed by Emil Fischer 1891. For all chiral compounds, stereoisomers having a config related to L-glyceraldehyde are designated L & same goes for D. L & D refer only to absolute configurations of the 4 substituents around the chiral C not the optical properties of the molecule. -Eg.(Fig3-4) Func groups of L-alanine are matched w/ L-glyeraldehyde by aligning those that can be interconverted by simple, one-step rxns in this case conversion of carboxyl group via one-step oxidation. L-aa are those w/ amino group on the left of the α C & D-aa are those w/ amino group group on the right. *levrorotatory (rotating plane-polarized light to the left) & dextrorotatory (rotating plane- polarized light to the right. Not all L-aa are levrorotatory -Another system of specifying configuration is the RS system which describes more precisely the configuration of molecules w/ more than 1 chiral center. * All pro have only L-stereoisomer aa Practice drawing aa (refer to table 3-1 & fig 3-5 Amino acid residues -aa residues in pro are exclusively L-stereoisomers. In ordinary chemical rxnbs, the result is a racemic mix of D & L stereoisomers but to a living system, both are as different as a right hand is from a left hand. Cells are able to specifically synthesize L isomers of aa b/c of the active sites of enzymes are asymmetric causing rxns they catalyze to be stereospecific AA can be classified by R groups -aa can be grouped together into 5 main classes based on the properties of their R groups, particularly in terms of polarity; varies widely from nonpolar & hydrophobic (H2O insoluble) to polar & hydrophilic (H2O soluble) 1. Nonpolar, aliphatic R groups: nonpolar & hydrophobic. Side chains of ala, val, leu & ile tend to cluster together w/ pro stabilizing pro via hydrophobic interactions. Gly has the simplest structure but its very small side chain makes no real contribution to hydrophobic interactions. Met, 1 of 2 sulfur-containing aa has nonopolar thioether group in its side chain. Proline has a an aliphatic side chain w/ a distinctive cyclic structure; the 2ndary amino/imino group of proline residues is held in a rigid conformation that reduces structural flexibility of polypeptide regions containing proline 2. Aromatic R groups: phe, tyr & trp, w/ their aromatic side chains are relatively nonpolar but can all participate in hydrophobic interactions. The OH gorup of tyr can form H bonds & an important func group in enzymes. Tyr & trp are way more polar than phe b/c of the OH group in tyr & N of trp indole ring. Tyr, trp & much lesser extent, phe absorb UV light accounting for the characteristic absorbance of light by most pro @ 280nm. 3. Polar, uncharged R groups: R groups are more soluble in H2O, more hydrophilic than those of nonpolar aa b/c they have func groups that can H bond w/ H2O. Incl ser, thr, cys, asn & gln. Polarity of ser & thr is due to their OH groups; cysteine by it sulfhydryl goroups & asn & gln by their amide groups. Asn & gln are amides of other aa found in pro, aspartate & glutamate in which they are easily hydrolyzed by acid/bas. Cys is readily oxidized to form covalently liked dimeric aa called cystine (2 cys are joined by a disulfide bond which are strongly hydrophobic & play a special role in pro structures by forming covalent links b/w parts of a polypeptide molecule/chains. 4. Posndively charged (Basic) R groups: Rthroups have sig + charge at pH 7 incl lys (has a 2 primary amino group at the ε/6 position on its aliphatic chain), arg (has a + charged guanidinium group) & his (has an aromatic imidazole group). His is the only common aa that have an ionizable side cahin w/ pKa near neutrality this it may be + charged or neutral at pH 7; His residues facilitate many enzyme catalyzed rxns by serving as proton donors/acceptors 5. Negatively charged (Acidic) R groupnd has a net neg charge at pH 7 incl aspartate & glutamate both of which has a 2 carboxyl group. *Most hydrophilic R groups are those that are + & - charged. Uncommon aa also have important functions -created by modification of common residues already incorporated into a polypeptide. Addition of phosphoryl, methyl, acetyl, adenyl, ADP-ribosyl, etc to particular aa residues can inc/dec a pro’s activity. Basically, there are many non-standard AA in pro that are derived from standard AA; over 300 types of AA exist in cells but not all are pro. Ornithin & citrulline are special b/c they are key intermediates in biosynthesis of arginine & urea cycle. AA can act as acids & bases -amino & carboxyl groups of aa & the ionisable R groups function as weak acids/bases. When an aa lacking an ionisable R group is dissolved in H2O at a neutral pH, it exists in soln as a dipolar ion, aka Zwitterion (hybrid ion; net charge: +1 0 -1) which can act as either acid (proton donor)/base (proton acceptor) Substances w/ these dual natures are amphoteric & are often called ampholytes, eg. alanine is a diprotic acid when fully protonated, it has a --COOH & --NH3+ that can yield protons. AA have characteristic titration curves -Fig 3-10: Glycine: mono-amino, mono-carboxylic & diprotic. The plot has 2 stages corresponding to deprotonation of 2 diff groups of glycine, resembles titration curve of a monoprotic acid thus can be analyzed the same way. The titration curve of 0.1 M glycine at 25°C shows that at very low pH, predominant ionic species of glycine is the fully protonated form, st (+H3N—CH2—COOH)at the midpt (pK1=2.34) in the 1 stage of titration, --COOH loses its proton, equimolar [ ] of proton donor (+H3N—CH2—COOH) & proton acceptor are present (+H3N—CH2—COO-). At the midpt of any titration, point of inflection is reached where pH=pKa of the protonated group being titrated. As titration proceeds, another point of inflection st nd (5.97) is reached at which the removal of the 1 proton is complete & remondl of 2 just started; at this pH glycine is present as a Zwitterion (+H3N—CH2—COO-). 2 stage corresponds top removal of proton from the –NH3+ group of glycine & the pH at the midpt of this stage is equal to the pK2 for the –NH3+; titration is complete at ~pH12 in which predominant form of glycine is H2N—CH2—COO- Summary: fully protonatedpK1pIunprotonated (in vivo: not a good buffer since blood has pH of 7.4) -This titration curve gives a quantitative measure of pKa of each of the 2 ionizing groups: 2.34 for –COOH & 9.60 for --NH3+. -Fig 3.11: The pKa values for ionisable groups in glycine are lower than those for simple CH3 substitued amino & --COOH groups. These downward perturbations of pKa are due to intramolecular interactions (repulsion b/w departing pro & nearby + charge amino group on α C); similar effects can be caused by chemical groups that happen to be positioned nearby, eg. Active site of an enzyme. pKa of any functional group is greatly affected by its chemical environment. -The titration curve of glycine also indicates that this aa has 2 regions of buffering power; w/ the buffering ranges of glycine, the Henderson-Hassleback equan can be used to calc proportions of proton-donor/proton-acceptor species of glycine req to make a buffer at a given pH. Opposite charges on the Zwitterion are stabilizing *Note that pKa is the measure of tendency of a group to give up a proton w/ that tendency decreasing 10x as pKa inc by 1 unit. Titration curves predict the electric charge of aa -titration curves of aa show the relationship b/w its net charge & pH of the soln. The characteristic pH at which net electric charge is 0 is the isoelectric pt (pI)/isoelectric pH. pI= ½ (pK1 + pK2) = ½ (2.34+9.60)=5.97 -as noted, glycine has a net electric charge & will thus move toward the anode (+), At pH below its pI, it will have a + charge & will move toward cathode (-). The further the pH of glycine or any aa from its pI, the greater the net electric charge of the popn of glycine molecules. AA differ in their acid-base properties -AA w/ single α amino group, single α carboxyl group & an R group that doesn’t ionize will resemble titration curves like glycine; these aa have very similar pKa values. The diff in pKa values reflect the effects of the R groups. -AA w/ an ionizable R groups have more complex titration curves w/ 3 stages, the 3 possible ionization steps; the additional stage for the ionizable R group merges to some extent w/ the other 2, eg. Glutamate & histidine. Summary: -There are 20 common AA; all are α AA & in total have 19 chiral C that are all stereoisomers & all L-α-aa in proteins. Only 1 AA, glycine is achiral, ie. Doesn’t have a chiral center. AA can be classified into 5 groups according to the polarity of their R groups. Zwitterions occur in aq solns being able to act as both acid & base. Understand titration curves w/ pKa & importance of pI. 3.2 Peptides & proteins Peptides are chains of aa -aa molecules are covalently joined by a peptide bond which is formed via condensation (removal of the elements of H2O) from the α-carboxyl group of on aa & the α-amino group of the other. To make the rxn thermodynamically favourable, carboxyl group must be chemically modified/activated so that the OH group can be readily eliminated. Dipeptide (2AA), tripeptide (3AA), oligopeptides (several AA—4, 5, 6…), polypeptides (many AA; generally have MW<10000). Polypeptides are interchangeably used w/ pro but pro has MW>10000. -In a peptide, the aa residue at the end w/ a free α-amino group is the amino terminal (N-terminal) residue; the residue at the other end, which has a free carboxyl group, is the carboxyl-terminal (C- terminal) residue. *key convention: when an aa seq of peptide, polypep or pro is displayed, the N terminal is placed on the left & the C terminal on the right; sequence is read left to right beginning w/ the N terminal. -Hydrolysis of peptide bond is exergonic but occurs slowly b/c of the high a.e. that’s why peptide bonds in pro are quite stable w/ ave half life of ~7yrs. *AA groups are good nucleophiles but hydroxyl group is a poor LG thus can’t be readily displaced. Peptides can be distinguished by their ionization behaviour - The α-amino &α-carbonyl groups of all nonterminal aa are covalently joined in the peptide bonds, which don’t ionize & thus don’t contribute to the total acid-base behaviour of peptides BUT R groups can ionize & thus contribute to overall acid-base properties of the molecule, ie. Acid-base behaviour of a peptide can be predicted from its free α-amino &α-carbonyl groups as well as nature & # of ionizable R groups. -Peptides also have characteristic titration curves & pI at which they don’t move in an electric field which is useful when trying to separate peptides & pro. pKa value for an ionizable R group can somewhat change when AA becomes a residue in a peptide due to loss of charge in the α- COOH & α-amino groups, interactions w/ other peptide R groups & other environmental factors. Biologically active peptides & polypeptides occur in a vast range of sizes & compositions - peptides can have very important biological activites, eg. Of small active peptides -oxytocin (9AA)=stimulates uterine contractions -bradykinin (9AA)=inhibits tissue inflammation -many antibiotics -nutrasweet (aspartame)=aspartate—phenylalanine -insulin=2 polypeptides of <30 AA each -glucagon=29 AA (opp effects to insulin) -Vast majority of naturally occurring pro are much smaller containing <2000 aa residues. Multisubunit pro have 2/more polypeptide chains assoc’d noncovalently; subunits can be identical/diff. If at leas 2 are identical, the pro is said to be
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