Lecture 3: Amino Acids Bonus seminar today at 3PM 148 Baker (bonus point assignment due on Wed. in class or electronically by email) Quiz next Wed. (9/7)

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Lecture 3: Amino Acids Bonus seminar today at 3PM 148 Baker (bonus point assignment due on Wed. in class or electronically by email) Quiz next Wed. (9/7) Introduction to amino acid structure Amino acid chemistry

Uncharged polar side chains COO- H3N + CH2 OH Tyrosine Tyr Y CH2 C H COO- H3N + Serine Ser S OH C H COO- H3N + Threonine Thr T CH3 OH H C COO- H3N + Glycine Gly G Polar Aas are imortant since they provide chemical groups for interaction with water. Thus, the hydrogen bonding character of polar Amino acids is key in forming structures. Whie the ionic bonding character of charged polar Aas is also important for protein structures. They also provide chemically reactive groups in proteins. Serine has a OH group that does not normally ionize so it is not charged in proteins (it is neutral). It is the smallest of the polar amino acids and very polar. The hydroxyl group on Ser provides enzymes a very giooid nucleophilic group for doing chemistry., It is also important to form esters with phosphate making phosphester proteins. Phosphyorylation of proteins and enzymes is very important in regulation of activity. Thr adds a carbon on to Ser, which makes the hydroxyl group less accessible than in Ser. Thr is more oftten in a structural role in proteins and is not as chemically active as Ser. Thr can form esters with phosphoric acid and phospho-Threionine is often found in proteins. Tyr is a hydrophobic aromatic alcohol but has some polar character. The hydroxyl of Tyr is like the hydroxyl group on phenol, so if the pH is high (basic) it can ionize. Tyr can also form phosphoesters like Ser and Thr. It is important in proteins and in enzymes for regulation of the cell cycle.

Uncharged polar side chains COO- H3N + C H R-SH R-S- + H+ CH2 SH R-OH R-O- + H+ Cysteine Cys C Cys is essentially a thiol-Ala. The thiol (-SH) group of Cys can ionize at about pH 8 so they are usually protonated at biological pH. Hydroxyl groups have a pK of about 15 and do not ionize normally. Asn is a small and polar amino acid. Amides are neutral and do not ionize nor do they accept protons. Gln is larger than Asn because of the longer side chain. Both of the amides are neutral derivatives of acidic amino acids (Asp and Glu).

Formation of cystine The formation of Cystine can take place between 2 polypeptide chains to make a cross link between them. Extracellular proteins often contain Cys-Cys bonds, while cellular proteins rarely have them in the m since the environment in the cell is reducing. In the presence of oxygen or oxidizing conditions, the 2 thils react to form a disulfide bond between them. Since this is a redox reaction, the hydride ion released by each thil is usually coupled to an electonacceptor reaction or in simple oxidation with oxygen, hydrogen peroxide is usually formed with further reduction to water.

Uncharged polar side chains COO- H3N + CH2 Glutamine Gln Q O NH2 C H COO- H3N + Asparagine Asn N CH2 O NH2 Asn is a small and polar amino acid. Amides are neutral and do not ionize nor do they accept protons. Gln is larger than Asn because of the longer side chain. Both of the amides are neutral derivatives of acidic amino acids (Asp and Glu).

Amino acids Polar, uncharged amino acids Contain R-groups that can form hydrogen bonds with water Includes amino acids with alcohols in R-groups (Ser, Thr, Tyr) Amide groups: Asn and Gln Usually more soluble in water Exception is Tyr (most insoluble at 0.453 g/L at 25 C) Sulfhydryl group: Cys Cys can form a disulfide bond (2 cysteines can make one cystine)

Charged polar (acidic) side chains COO- H3N + C H COO- H3N + CH2 CH2 CH2 C C O O- O O- Aspartic acid Asp D Glutamic acid Glu E

Amino acids Acidic amino acids Amino acids in which R-group contains a carboxyl group Asp and Glu Have a net negative charge at pH 7 (negatively charged pH > 3) Negative charges play important roles Metal-binding sites Carboxyl groups may act as nucleophiles in enzymatic interactions Electrostatic bonding interactions

Charged polar (basic) side chains COO- H3N + COO- C H COO- H3N + H3N + C H CH2 CH2 CH2 CH2 CH2 CH2 CH2 HC C CH2 NH H+N NH LYSINE has a protonated alky amino group Argining has a guanidinium Histidine has an imidazolium ionized group C NH3+ CH NH2+ NH2 Lysine Lys K Histidine His H Arginine Arg R

Amino acids Basic amino acids Amino acids in which R-group have net positive charges at pH 7 His, Lys, and Arg Lys and Arg are fully protonated at pH 7 Participate in electrostatic interactions His has a side chain pKa of 6.0 and is only 10% protonated at pH 7 Because His has a pKa near neutral, it plays important roles as a proton donor or acceptor in many enzymes. His containing peptides are important biological buffers

Nonstandard amino acids 20 common amino acids programmed by genetic code Nature often needs more variation Nonstandard amino acids play a variety of roles: structural, antibiotics, signals, hormones, neurotransmitters, intermediates in metabolic cycles, etc. Nonstandard amino acids are usually the result of modification of a standard amino acid after a polypeptide has been synthesized. If you see the structure, could you tell where these nonstandard amino acids were derived from?

Nonstandard amino acids These are amino acids derivatives found in proteins 4-hydroxyproline and 5-hydroxylysine are structural components of collagen a structural protein N-formyl methionine is the N-terminal residue of all prokaryotic proteins but is usually removed as the protein matures Gamma-carbocyglutamate is part of proteins involved in blood clotting Methylated and acetylated amino acids are important parts of ribosomal proteins and chromosomal proteins called histones (important for chromatin formation in eukaryotes)

Nonstandard amino acids Amino acids with specialized roles GABA is a glutamate decarboxylation product, dopamine and glycine are neurotransmitters Histamine is a mediator of allergic reactions Thyroxine is an iodine-containing hormone that stimulates metabolism Some amino acids are important intermediates in metabolic processes Citrulline and ornithine are important in urea biosynthesis Homocysteine is an intermediate in amino acid metabolism S-adnosylmethionine is methylating agent (adds methyl groups to other compounds) Azaserine is an antibiotic Beta-cyanoalanine is an intermediate in cyanide production in plants.

Peptide bonds + + H2O H C R1 H3N + O OH N H C R2 O- O H C N R1 H3N + O Proteins are sometimes called polypeptides since they contain many peptide bonds H C R1 H3N + O OH N H C R2 O- O + H C N R1 H3N + O R2 O- + H2O

Structural character of amide groups Understanding the chemical character of the amide is important since the peptide bond is an amide bond. These characteristics are true for the amide containing amino acids as well (Asn, Gln) Amides will not ionize: O O R C NH2 R C NH2

Acid-base properties of amino acids The dissociation of first proton from the -carboxyl group is The dissociation of the second proton from the -amino group Gly+ + H2O Gly0 + H3O+ Gly0 + H2O Gly- + H3O+ [Gly0][H3O+] [Gly-][H3O+] K1= K2= [Gly+] [Gly0] The pKa’s of these two groups are far enough apart that they can be approximated by Henderson-Hasselbalch [Gly0] [Gly-] pK1 + log pH = pK2 + log pH = [Gly+] [Gly0]

Titration curve of glycine H C COO- H3N + Neutral form At low pH values both acid-base groups of glycine are fully protonated. The pK values of glycine’s two ionizable groups are different enough that the Henderson-Hasselbalch equation closely approximates each phase of the titration. pI = 1/2(pKi +pKj) Where Ki and Kj are the dissociation constants of the two ionizations involving the neutral species. The pH at which the molecule carries no net electric charge is the isoelectric point.

Titration of Gly pK1 pK2 pH 2.3 pH 9.6 COOH COO- + H2N H3N C H From the pK values we can calculate the pI (isoelectric point) where the amino acid is neutral. pI ≈ average of (pK below neutral+ pK above neutral) So, for Gly, pI = (pK1 + pK2)/2 = (2.3 + 9.6)/2 ≈ 6

General rules for amino acid ionization Alpha carboxylic acids ionize at acidic pH and have pKs less than 6; So in titrating a fully protonated amino acid, alpha carboxylic acids lose the proton first. Alpha amino groups ionize at basic pH and have pKs greater than 8; So after acids lose their protons, amino groups lose their proton. Most of the 20 amino acids are similar to Gly in their ionization properties because their side chains do not ionize at biological pHs. However, there are 5 exceptions worth noting (the amino acids with polar charged side chains) Glu, Asp, Lys, Arg, His Each has 3 ionizible groups and thus, 3 pKs.

Charged polar (acidic) side chains 2.1 2.0 C H COOH H3N + CH2 Glutamic acid Glu E O OH 9.5 9.8 C H COOH H3N + Aspartic acid Asp D CH2 O OH 3.9 4.1

How to calculate the pI of a compound with more than 2 pKs Find the amino acid form with no net charge (total charge = 0). Take the pK of the amino acid form going towards +1 form as the lower pK. Next find the amino acid form going towards the -1 form. Finally, average these two pKs to get the pI.

Titration curve of aspartic acid At low pH values both acid-base groups of glycine are fully protonated. The pK values of glycine’s two ionizable groups are different enough that the Henderson-Hasselbalch equation closely approximates each phase of the titration. pI = 1/2(pKi +pKj) Where Ki and Kj are the dissociation constants of the two ionizations involving the neutral species. The pH at which the molecule carries no net electric charge is the isoelectric point. The neutral form of Asp is close to pH 2.8 Take the pKs for +1 and -1 from this point and average to get approximate pI, pI = (pK3 + pK1)/2 = (2.0 + 3.9)/2 = 2.95

Charged polar (basic) side chains 2.2 1.8 C H COOH H3N + 1.8 COOH 9.2 C H COOH H3N + H3N + C 9.3 H 9.0 CH2 CH2 CH2 CH2 CH2 CH2 CH2 C 6.0 HC CH2 NH H+N NH C NH3+ CH NH2+ NH2 Lysine Lys K 10.8 Histidine His H Arginine Arg R 12.5

Titration curve of arginine At low pH values both acid-base groups of glycine are fully protonated. The pK values of glycine’s two ionizable groups are different enough that the Henderson-Hasselbalch equation closely approximates each phase of the titration. pI = 1/2(pKi +pKj) Where Ki and Kj are the dissociation constants of the two iionizations involving the neutral species. The pH at which the molecule carries no net electric charge is the isoelectric point. The neutral form of Asp is close to pH 10.8 Take the pKs for +1 and -1 from this point and average to get approximate pI, pI = (pK2 + pK3)/2 = (9.0 + 13.0)/2 = 11.0

Acid-base properties of amino acids -COOH pKa -NH3+ pKa R-group pKa Gly 2.3 9.6 - Ala 2.4 9.7 Val Leu Iso Met 9.2 Pro 2.1 10.6 Phe 1.8 9.1 Trp 9.4 Ser 2.2 13 Thr 2.6 10.4 Tyr 10.1 Cys 1.7 10.8 8.3 Asn 2.0 8.8 Gln Asp 9.8 3.9 Glu 4.3 Lys 9.0 10.5 Arg 12.5 His 6.0

More rules for amino acid ionization Carboxylic acid groups near an amino group in a molecule have a more acidic pK than isolated carboxylic groups. Amino groups near a carboxylic acid group also have a more acidic pK than isolated amines. Aromatic amines like His have a pK about pH 6. When titrating an amino acid that is fully protonated (ie starting at pH = 1), the alpha carboxylic acids lose their proton first (all free amino acids have this group), then side chain carboxylic acids, then aromatic amine side chains (His), then alpha amino groups, then side chain amino groups. These rules apply to small peptides too.

Amino acids are optically active All amino acids are optically active (exception Gly). Optically active molecules have asymmetry; not superimposable (mirror images) Central atoms are chiral centers or asymmetric centers. Enantiomers -molecules that are nonsuperimposable mirror images Enantiomers of fluorochlorobormomethane

Asymmetry Molecules are classified as Dextrorotatory (right handed), D or Levrotatory (left handed) L depending on whether they rotate the plane of plane-polarized light clockwise or counterclockwise determined by a polarimeter

Asymmetry Fischer projections are a shorthand way to write molecules with chiral centers In Fisxher projections all horizontal bonds point above the page and all vertical bonds below the page.

Asymmetry For -amino acids the arrangement of the amino, carboxyl, R, and H groups about the C atom is related to glyceraldehyde Thus L glyceraldehyde and L-alpha amino acids are said to have the same relative configurations.

Asymmetry All -amino acids from proteins have the L-stereochemical configuration The designation of the relative configuration of chirl centers is the same as the absolute configuration. We can use the CORN crib mnemonic. We look at the alpha carbon from its H atom the other substituents should read CO-R-N in the clockwise direction.

Diastereomers Stereoisomers or optical isomers are molecules with different configurations about at least one of their chiral centers but are otherwise identical Since each asymmetric center in a chiral molecule can have two possible configurations, a molecule with n chiral centers has 2n different possible stereoisomers and 2n-1 enantiomeric pairs Ex. Threonine and Isoleucine both have two chiral centers, and thus 4 possible stereoisomers.

Diastereomers * * The mirror images on the top of this figure are the L and D forms. The two other optical isomers are the Diastereomers or allo forms of the L and D forms. The D-allo and L-allo forms are mirror images of one another just like the D and L forms Neither allo form is symmetrically related to either of the D or L forms Diastereomers are physically and chemically distinct. We see differences in melting points, spectra, and chemical reactivity. VERY Different from one another.

Diastereomers Special case: 2 asymmetric centers are chemically identical (2 asymmetric centers are mirror images of one another) A molecule that is superimposable on its mirror image is optically inactive (meso form) D and L isomers are mirror images of one another but the meso has internal mirror symmetry and therefore lacks optical activity.

Cahn-Ingold-Prelog or (RS) System The 4 groups surrounding a chiral center a ranked as follows: Atoms of higher atomic number bonded to a chiral center are ranked above those of lower atomic number. Priorities of some common functional groups SH > OH > NH2 > COOH > CHO > CH2OH > C6H5 > CH3 > 2H > 1H Prioritized groups are assigned letters W, X, Y, Z, so that W > X > Y > Z Z group has the lowest priority (usually H) and is used to establish the chiral center. If the order of the groups W X Y is clockwise, as viewed from the direction of Z, the configuration is (R from the latin rectus, right) If the order of the groups W X Y is counterclockwise, as viewed from the direction of Z, the configuration is (S from the latin sinister, left) The Fischer scheme can be ambiguous so an absolute nomenclature system was developed in 1956 by Cahn, Ingold and Prelog.

Cahn-Ingold-Prelog or (RS) System So L-Glyceraldehyde is S-glyceraldehyde by the RS system representation. The chiral C atom is represented by the large circle and H atom is located behind the plane of the screen.

Cahn-Ingold-Prelog or (RS) System The Fischer scheme can be ambiguous so an absolute nomenclature system wad developed in 1956 by Cahn, Ingold and Prelog.

Cahn-Ingold-Prelog or (RS) System Newman projection diagrams of the stereoisomer of threonine and isoleucine derived from proteins. Here the C alpha - C beta bond is viewed end on.

Prochiral centers have distinguishable substituents Prochiral molecules can be converted from an achiral to chrial molecule by a single substitution Molecules can be assigned a right side and left side for two chemically identical substituents. True for tetrahedral centered molecules Example is ethanol The Fischer scheme can be ambiguous so an absolute nomenclature system wad developed in 1956 by Cahn, Ingold and Prelog.

Prochiral centers The two H atoms are prochiral. If assigned a and b then Hb is pro-R because in sighting from C1 towards Ha the order is clockwise whereas Hb is pro-S because substitutents decrease in a counterclockwise direction Planar objects with no rotational symmetry are also prochiral.

Planar objects can also be prochiral Stereospecific additions in enzymatic reactions If a trigonal carbon is facing the viewer so that the substituents decrease in a clockwise manner it is the re face If a trigonal carbon is facing the viewer so that the substituents decrease in a counterclockwise manner it is the si face Acetaldehyde example A represents the re face and b is the si face. We are mostly going to use the DL convention of naming but the RS system is necessary for describing prochirality and stereospecific reactions.

Nomenclature Glx can be Glu or Gln Asx can be Asp or Asn Polypeptide chains are always described from the N-terminus to the C-terminus Amino acid residues in polypeptides are named by dropping of the suffix -ine and replacying it by -yl The C- terminus is given the name of the parent amino acid. So this compound is called alanyltyrosylaspartylglycine. We can replace this by Ala-Tyr-Asp-Gly or AYDG

Nomenclature Nonhydrogen atoms of the amino acid side chain are named in sequence with the Greek alphabet Greek letter used to identify the atoms in the glutamyl and lysyl R groups