Each functional group of an amino acid exhibits all of its characteristic chemical reactions. For carboxylic acid groups, these reactions include the formation of esters, amides, and acid anhydrides; for amino groups, acylation, amidation, and esterification; and for —OH and —SH groups, oxidation and esterification. Since glycine, the smallest amino acid, can be accommodated in places inaccessible to other amino acids, it often occurs where peptides bend sharply. The hydrophobic R groups of alanine, valine, leucine, and isoleucine and the aromatic R groups of phenylalanine, tyrosine, and tryptophan occur primarily in the interior of cytosolic proteins. The charged R groups of basic and acidic amino acids stabilize specific protein conformations via ionic interactions, or salt bridges. These interactions also function in “charge relay” systems during enzymatic catalysis and electron transport in respiring mitochondria. Histidine plays unique roles in enzymatic catalysis. The pKa of its imidazole proton permits histidine to function at neutral pH as either a base or an acid catalyst without the need for any environmentally induced shift. The primary thioalcohol (—SH) group of cysteine, whose pKa is 8.3, is an excellent nucleophile and often functions as such during enzymatic catalysis. For selenocysteine, its pK3 of 5.2 is 3 pH units lower than that of cysteine. At a distinctly acidic pH, selenocysteine thus should be the better nucleophile. The primary alcohol of serine functions as the active site nucleophile in trypsin and other serine proteases. However, the secondary alcohol group of threonine is not known to serve this role in catalysis. The —OH groups of serine, tyrosine, and threonine frequently serve as the points of covalent attachment for phosphoryl groups that regulate protein function.

Amino Acid Sequence Determines Primary Structure

Amino acids are linked together by peptide bonds.

The number and order of the amino acid residues in a polypeptide constitute its primary structure. Amino acids present in peptides, called aminoacyl residues, are referred to by replacing the ate or ine suffixes of free amino acids with yl (eg, alanyl, aspartyl, tyrosyl). Peptides are then named as derivatives of the carboxy terminal aminoacyl residue. For example, Lys-Leu-Tyr-Gln is called lysyl-leucyl-tyrosyl-glutamine. Theineending on the carboxy-terminal residue (eg, glutamine) indicates that its α-carboxyl group is not involved in a peptide bond. Three-letter abbreviations linked by straight lines represent an unambiguous primary structure. Lines are omitted when using single-letter abbreviations.

Prefixes like tri- or octa- denote peptides with three or eight residues, respectively. By convention, peptides are written with the residue that bears the free α-amino group at the left. This convention was adopted long before it was discovered that peptides are synthesized in vivo starting from the amino terminal residue.

Peptide Structures Are Easy to Draw

To draw a peptide, use a zigzag to represent the main chain or backbone. Add the main chain atoms, which occur in the repeating order: α-nitrogen, α-carbon, carbonyl carbon. Now add a hydrogen atom to each α-carbon and to each peptide nitrogen, then add an oxygen to the carbonyl car bon. Finally, add the appropriate R groups (shaded) to each α-carbon atom.

Some Peptides Contain Unusual Amino Acids

In mammals, peptide hormones typically contain only the 20 codon-specified α-amino acids linked by standard pep tide bonds. Other peptides may, however, contain nonprotein amino acids, derivatives of the protein amino acids, or amino acids linked by an atypical peptide bond. For example, the amino terminal glutamate of glutathione, a tripeptide that participates in the metabolism of xenobiotics and the reduction of disulfide bonds, is linked to cysteine by a non-α peptide bond that utilizes the side chain, rather than the α-, carboxylic acid group (Figure 1). The amino terminal glutamate of thyrotropin-releasing hormone (TRH) is cyclized to pyroglutamic acid, and the carboxyl group of the carboxyl terminal prolyl residue is amidated. The nonprotein amino acids d-phenylalanine and ornithine are present in the cyclic peptide antibiotics tyrocidine and gramicidin S, while the heptapeptide opioids dermorphin and deltophorin in the skin of South American tree frogs contain d-tyrosine and d-alanine.

Fig1. Glutathione (γ-glutamyl-cysteinyl-glycine). Note the non–α peptide bond that links Glu to Cys.

The Peptide Bond Has Partial Double-Bond Character

Although peptide structures are written as if a single bond linked the α-carboxyl and α-nitrogen atoms, this bond in fact exhibits partial double-bond character:

The bond that connects a carbonyl carbon to the α-nitrogen therefore cannot rotate, as this would require breaking the partial double bond. Consequently, the O, C, N, and H atoms of a peptide bond are coplanar. The imposed semirigidity of the peptide bond has important consequences for the manner in which peptides and proteins fold to generate higher orders of structure. In Figure 2, encircling brown arrows indicate free rotation about the remaining bonds of the polypeptide backbone.

Fig2. Dimensions of a fully extended polypeptide chain. The four atoms of the peptide bond are coplanar. Free rotation can occur about the bonds that connect the α-carbon with the α-nitrogen and with the α-carbonyl carbon (brown arrows). The extended polypeptide chain is thus a semirigid structure with two thirds of the atoms of the backbone held in a fixed planar relationship to one another. The distance between adjacent α-carbon atoms is 0.36 nm (3.6 Å). The interatomic distances and bond angles, which are not equivalent, are also shown. (Reproduced with permission from Pauling L, Corey LP, Branson HR: The structure of proteins: two hydrogen-bonded helical configurations of the polypeptide chain. Proc Natl Acad Sci USA. 1951;37(4):205-211.)

Noncovalent Forces Constrain Peptide Conformations

 Folding of a peptide probably begins coincident with its bio synthesis. The mature, physiologically active conformation reflects the collective contributions of the amino acid sequence, noncovalent interactions (eg, hydrogen bonding, hydrophobic interactions), and the minimization of steric hindrance between residues. Common repeating conformations include α-helices and β-pleated sheets.

Peptides Are Polyelectrolytes

The peptide bond is uncharged at any pH of physiologic interest. Formation of peptides from amino acids is therefore accompanied by a net loss of one positive and one negative charge per peptide bond formed at physiologic pH. Peptides nevertheless are charged owing to their terminal carboxyl and amino groups and, where present, their acidic or basic R groups. As for amino acids, the net charge on a peptide depends on the pH of its environment and on the pKa values of its dissociating groups.

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