Lecture 5. Amino acids

Monday 12 September 2016

General framework of α-amino acids. The collection of 20 "standard" amino acids Assignment of configuration to chiral centers: Relative and also absolute. Chiral next chains. Part notable functions of selected amino acids. Histidine: an "ambidextrous" amino mountain residue. PKa values. Intrinsic vs. Perturbed pKas. Amino mountain modifications and derivatives. Glutathione.

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Reading: VVP4e - Ch.4, pp.76-90.



The general structural formula because that an α-amino acid, displayed at right, has the amino and carboxyl functional teams as substituents that a solitary carbon atom designated together C-alpha (Cα). These groups are shown in their intended ionization state in ~ a physiological pH of about 7. The other two substituents of Cα room the alpha hydrogen (Hα) and a variable substituent denoted as R. Once the latter is not hydrogen (nor amino or carboxyl), Cα is a chiral center. Therefore the number represents an l configuration, according to the loved one configuration assignment convention. This matches the chiral configuration of the naturally-occurring α-amino acids, return exceptions space not unknown. We ususally think that the natural α-amino acids as making up a set of 20 that room encoded by nucleotide triplets and also incorporated into ribosomally-synthesized polypeptides and also proteins. Again, we now recognize of some minor, however interesting, exceptions. The figure below shows the structure formulas for each member that the collection of 20 "standard" amino acids, presented using the bond-line format. The setup of the frameworks in the number reflects details similarities. The 2 amino acids at the optimal left, serine (S) and threonine (T), both contain the hydroxyl useful group. Glycine (G) and also proline (P) are distinctive in terms of chirality (Gly is achiral) and the conformational adaptability they confer ~ above the polypeptide chain the incorporates them. Proline could be thought about to have actually a nonpolar character, so it is shown surrounding to the other amino acids with nonpolar hydrocarbon R groups - alanine (A), isoleucine (I), valine (V), leucine (L). Cysteine (C) and methionine (M) room the 2 sulfur-containing amino acids; phenylalanine (F), tyrosine (Y) and tryptophan (W) room aromatic; histidine (H), lysine (K) and arginine (R) are an easy and presented in stimulate of increasing basicity. The acidic amino mountain aspartate (D) and also glutamate (E), are displayed together, along with their amides, asparagine (N) and also glutamine (Q).


by convention, a polypeptide sequence deserve to be stood for by the solitary letter symbol for an amino acid, v the an initial letter listed the amino end or in ~ the N-terminus and the critical letter noted the carboxy end or C-terminus.


Glycine (Gly, G) is the easiest of the 20 naturally-occurring amino acids. As listed above, because R is simply a hydrogen, glycine is the only organic amino acid that is no chiral at the alpha carbon. Although in some group schemes, glycine is taken into consideration nonpolar, hydrogen is so little that that contributes negligibly come nonpolar surface area. That is lot more significant that the smallness of its hydrogen R group offers fairly little steric hindrance come bond rotations in ~ Cα and also thus the visibility of Gly confers greater conformational adaptability in the paper definition of a polypeptide chain.


Histidine (His, H) is one of the most amazing amino acids since of the range of duties it have the right to play in protein function, particularly as a crucial residue in numerous enzyme active sites. Of all the ionizable side chains, the usual pKa of the imidazole ring that His is closest come a neutral pH. Research studies of version compounds have established a selection of 6.0 - 7.0 because that the intrinsic pKa the the histidine next chain.


The neutral kind of the imidazole ring have the right to exist in two different tautomeric forms: through hydrogen top top the δ1 nitrogen or v hydrogen ~ above the ε2 nitrogen. The pKa that the ε2 nitrogen has been shown in 13-C NMR researches of a design compound come be around 0.6 pH units higher than the of the δ1 nitrogen, therefore in the absence of countervailing eco-friendly effects, the type on the best will tend to predominate.


Neutral imidazole is a particularly great nucleophile, and also histidine is among the much more reactive residual water in proteins. Through a pKa near 7, the imidazole side chain is just one of the strongest bases that can exist in ~ neutral pH. In the neutral form, the imidazole side chain has an "ambidextrous" nature, due to the fact that the nitrogen there is no a hydrogen is nucleophilic and also can act together a hydrogen link acceptor, while the nitrogen with the hydrogen bond is electrophilic and can act as a H-bond donor.


Protonation the a histidine residue inactivates it as a nucleophile. The protonated kind of the imidazole ring is stabilized through resonance, whereby the optimistic charge is common by both nitrogen atoms of the ring.

A prominent instance of histidine as a vital catalytic component in one enzyme mechanisms found in the serine proteases. Histidine is the main residue in a catalytic triad that is characteristic of this form of enzyme. A neutral imidazole acts together a basic to enhance the power of serine together a nucleophile to strike the acyl carbon that a peptide bond to kind a tetrahedral intermediate. The protonated His residue subsequently acts as a proton donor (general acid) to promote the loss of a leaving team from a tetrahedral intermediate.


Cysteine (Cys, C), one of two sulfur-containing amino acids, bear the many reactive side chain, a thiol (-SH, likewise called sulfhydryl) group attached to the beta carbon. The thiol is weakly acidic (intrinsic pKa 9.0-9.5), the the dissociation leaves the thiolate anion. Both of these, specifically thiolate, are an excellent nucleophiles, for this reason the cysteine side chain can engage in numerous substitution reactions. Various other reactions involve the oxidation that the thiol group.

The nucleophilic thiol group can be alkylated by reaction with alkyl halides or iodoacetate. An additional common reaction, specifically important one because that cysteine"s biological role in protein function, is the development of a thioester link (formally a carboxylic mountain derivative).

A disulfide bond is a covalent chemistry bond between two sulfur atoms that have the right to arise native the oxidative linking of two sulfhydryl (thiol) groups. This is a common theme for cysteine residual water in proteins, particularly those in oxidizing settings such as prevailing extracellular conditions. The formation of disulfide bonds within proteins in vivo is a usual example of a posttranslational modification.

displayed at best are two cysteine residues in polypeptide chain(s). The thiol groups are in their reduced forms (in red in figure). Removal of 2 hydrogens (H+ + e−) from each thiol (by an oxidizing agent, not consisted of in the figure, which represents an oxidation half-reaction), and concomitant formation of a new covalent shortcut - the disulfide bond - between the 2 sulfur atoms yields the lower structure in ~ right. A disulfide-linked pair of cysteine residual water is termed a cystine residue. The switch of two sulfhydryl groups to a disulfide linkage is an oxidation reaction. Conversely, de defiders bonds deserve to be diminished to yield 2 thiols, which is the reverse of the half-reaction presented at right. Reagents used to rest disulfides notably incorporate other thiol-containing species, such as β-mercaptoethanol (mercaptan is yet an additional name because that the thiol group) and also glutathione. The lessened thiols undergo a de defiders exchange reaction with disulfide-linked species.

Perturbed or "anomalous" pKa values

As has currently been suggested, the intrinsic pKa values for ionizable groups are no guarantee that a certain residue in a specific protein will be in a particular ionization state at a pH continuous with that is physiologically appropriate structure and function. Part pKa values room perturbed significantly from your intrinsic values, and also these "anomalous" values are additionally demonstrably vital for the proper role of a protein in part cases.

To highlight the idea, think about an aspartate residue in a neutral (pH 7) aqueous environment with a "normal" pKa. The residue will be overwhelmingly ionized. By plugging in values for the pKa that the residue, the pH that the medium, the Henderson-Hasselbalch equation can be supplied to calculation the relationship of ionized to unionized develops of the residue. The top fifty percent of the figure listed below illustrates the situation.


Now take into consideration the influence of a nearby negative charge ~ above the ionization the our hypothetical residue. The presence of the an unfavorable charge provides the ionization much much less favorable, changing the equilibrium come the left. The greater the change in the equilibrium, the much more the pKa is increased from that intrinsic value. In the extreme case illustrated, the quantities of both develops of the residue space equal, and also the pKa has actually been perturbed increase by 3 units.

An instance of this impact where the residue through an anomalous pKa is directly affiliated in the protein"s duty is listed by lysozyme. Lysozyme is an enzyme produced by a range of organisms the hydrolyzes the polysaccharide ingredient of the peptidoglycan cell walls of many varieties of bacteria. The mechanism of lysozyme relies on 2 acidic residues, Asp52 and also Glu35. Asp52 has actually a normal pKa. Its an unfavorable charge stabilizes a developing positive charge as the reaction proceeds through a oxonium ion intermediate. However, Glu35 has actually an anomalously high pKa (its pKa is believed to be around 6.5), maintaining it an ext in the protonated form. The unionized kind of Glu35 donates a hydrogen ion to the oxygen the the glycosidic linkage, assisting the breaking of the bond in between sugar residues. Glu35 would certainly not it is in so reliable in this role if that is pKa was normal.

Amino mountain derivatives

Tyrosine can be readily derived from phenylalanine by hydroxylation the the latter. Thus, when phenylalanine is an essential amino acid, tyrosine is not. More hydroxylation of tyrosine, combined with that decarboxylation leads to the catecholamine neurotransmitter dopamine, which in can be additional derivatized to norepinephrine and also epinephrine.

Posttranslational modifications of amino acid residues

Phosphorylation and glycosylation are an extremely common posttranslational modifications. The most frequently phosphorylated residual water in proteins space serine, threonine, and tyrosine. There are an extremely many types of posttranslational modifications. Some various other notable instances are the hydroxylation of proline, i m sorry is vital in collagen, and also the carboxylation that glutamate to form γ-carboxyglutamate, particularly adept in ~ chelating Ca2+, which is vital to the cascade that protein aspect activation in blood clotting.

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A specifically dramatic (and colorful!) example of posttranslational alteration is the green fluorescent protein (GFP), a bioluminescent jellyfish protein. GFP experience a voluntary reaction the converts a three-residue sequence, Ser-Tyr-Gly, right into a fluorophore.