The Chemistry of Amino Acids

 

Introduction

Amino acids play central roles both as building blocks of proteins and as intermediates in metabolism. The 20 amino acids that are found within proteins convey a vast array of chemical versatility. Tertiary Structure of a proteinThe precise amino acid content, and the sequence of those amino acids, of a specific protein, is determined by the sequence of the bases in the gene that encodes that protein. The chemical properties of the amino acids of proteins determine the biological activity of the protein. Proteins not only catalyze all (or most) of the reactions in living cells, they control virtually all cellular process. In addition, proteins contain within their amino acid sequences the necessary information to determine how that protein will fold into a three dimensional structure, and the stability of the resulting structure. The field of protein folding and stability has been a critically important area of research for years, and remains today one of the great unsolved mysteries. It is, however, being actively investigated, and progress is being made every day.

As we learn about amino acids, it is important to keep in mind that one of the more important reasons to understand amino acid structure and properties is to be able to understand protein structure and properties. We will see that the vastly complex characteristics of even a small, relatively simple, protein are a composite of the properties of the amino acids which comprise the protein. 


Essential amino acids

Humans can produce 10 of the 20 amino acids. The others must be supplied in the food. Failure to obtain enough of even 1 of the 10 essential amino acids, those that we cannot make, results in degradation of the body's proteins—muscle and so forth—to obtain the one amino acid that is needed. Unlike fat and starch, the human body does not store excess amino acids for later use—the amino acids must be in the food every day.

The 10 amino acids that we can produce are alanine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine and tyrosine. Tyrosine is produced from phenylalanine, so if the diet is deficient in phenylalanine, tyrosine will be required as well. The essential amino acids are arginine (required for the young, but not for adults), histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. These amino acids are required in the diet. Plants, of course, must be able to make all the amino acids. Humans, on the other hand, do not have all the the enzymes required for the biosynthesis of all of the amino acids.

Why learn these structures and properties?
It is critical that all students of the life sciences know well the structure and chemistry of the amino acids and other building blocks of biological molecules. Otherwise, it is impossible to think or talk sensibly about proteins and enzymes, or the nucleic acids.

 

 

 


Amino Acids


   Alanine
   Arginine
   Asparagine
   Aspartic acid
   Cysteine
   Glutamic acid
   Glutamine
   Glycine
   Histidine
   Isoleucine
   Leucine
   Lysine
   Methionine
   Phenylalanine
   Proline
   Serine
   Threonine
   Tryptophan
   Tyrosine
   Valine

 

Atoms in Amino Acids
Legend describing the atoms of hydrogen, carbon, nitrogen, oxygen and sulfur found in amino acids

Amino Acids
   

Alanine A (Ala)

Chemical Properties:
    Aliphatic
(Aliphatic R-group)
Physical Properties:
    Nonpolar

 

Alanine is a hydrophobic molecule. It is ambivalent, meaning that it can be inside or outside of the protein molecule. The α carbon of alanine is optically active; in proteins, only the L-isomer is found.

Note that alanine is the α-amino acid analog of the α-keto acid pyruvate, an intermediate in sugar metabolism. Alanine and pyruvate are interchangeable by a transamination reaction.

Molecualar Structure of Alanine CH3-CH(NH3)-COO-

Chemical structure of Alanine
 

Interchangeable with Pyruvate

Molecular Structure for Pyruvate CH3-C(O)-COO-

Chemical structure of Pyruvate

 


  

Arginine R (Arg)

Chemical Properties:
    Basic
(Basic R-group)
Physical Properties:
    Polar (positively charged)
  

Arginine,
an essential amino acid, has a positively charged guanidino group. Arginine is well designed to bind the phosphate anion, and is often found in the active centers of proteins that bind phosphorylated substrates. As a cation, arginine, as well as lysine, plays a role in maintaining the overall charge balance of a protein.

Arginine also plays an important role in nitrogen metabolism.Chemical structure of Urea H2N -C(O)-NH2 In the urea cycle, the enzyme arginase cleaves (hydrolyzes) the guanidinium group to yield urea and the L-amino acid ornithine. Ornithine is lysine with one fewer methylene groups in the side chain. L-ornithine is not normally found in proteins.

There are 6 codons in the genetic code for arginine, yet, although this large a number of codons is normally associated with a high frequency of the particular amino acid in proteins, arginine is one of the least frequent amino acids. The discrepancy between the frequency of the amino acid in proteins and the number of codons is greater for arginine than for any other amino acid.

Molecular Structure of Arginine HN=C(NH2)-NH-(CH2)3-CH(NH3)-COO

 

Chemical structure of arginine

 


 

Asparagine N (Asn)

Chemical Properties:
    Neutral
(Amides of acidic amino acids R-group)
Physical Properties:
   Polar (uncharged)
   
Asparagine is the amide of aspartic acid. The amide group does not carry a formal charge under any biologically relevant pH conditions. The amide is rather easily hydrolyzed, converting asparagine to aspartic acid. This process is thought to be one of the factors related to the molecular basis of aging.

Asparagine has a high propensity to hydrogen bond, since the amide group can accept two and donate two hydrogen bonds. It is found on the surface as well as buried within proteins.

Asparagine is a common site for attachment of carbohydrates in glycoproteins.

molecular structure of asparagine H2N-CO-CH2-CH(NH3)-COO

Chemical structure for asparagine

 


   

Aspartic Acid D (Asp)

Chemical Properties: Physical Properties:

  

Acidic

(Acidic R-group and their amides)

Polar (charged)

Aspartic acid is one of two acidic amino acids. Aspartic acid and glutamic acid play important roles as general acids in enzyme active centers, as well as in maintaining the solubility and ionic character of proteins.

Proteins in the serum are critical to maintaining the pH balance in the body; it is largely the charged amino acids that are involved in the buffering properties of proteins. Aspartic acid is alanine with one of the β hydrogens replaced by a carboxylic acid group. The pKa of the β carboxyl group of aspartic acid in a polypeptide is about 4.0

Note that aspartic acid has an α-keto homolog, oxaloacetate, just as pyruvate is the α-keto homolog of alanine. Aspartic acid and oxaloacetate are interconvertable by a simple transamination reaction, just as alanine and pyruvate are interconvertible.

Oxaloacetate is one of the intermediates of the Krebs cycle.

molecular structure  HOOC-CH3-CH(NH3)-COO

Chemical structure for aspartic acid
 

Aspartic acid and oxaloacetate are interconvertable by a simple transamination reaction

Molecular Structure of oxaloacetate COO-­CH2­CO­COO-

Chemical structure of oxaloacetate

 


   

Cysteine C (Cys)

Chemical Properties:
    Sulfur-containing

(Sulfur containing group)
 

Physical Properties:
    Polar (uncharged)
 

Cysteine
is one of two sulfur-containing amino acids; the other is methionine. Cysteine differs from serine in a single atom-- the sulfur of the thiol replaces the oxygen of the alcohol. The amino acids are, however, much more different in their physical and chemical properties than their similarity might suggest.

Consider, for example, the differences between H2O and H2S. The hydrogen bonding propensity of water is well known and is responsible for many of its remarkable features. Under similar conditions of temperature and pressure, however, H2S is a gas as a consequence of its weak H-bonding propensity. Furthermore, the proton of the thiol of cysteine is much more acid than the hydroxylic proton of serine, making the nucleophilic thiol(ate) much more reactive than the hydroxyl of serine.

Cysteine also plays a key role in stabilizing extracellular proteins. Cysteine can react with itself to form an oxidized dimer by formation of a disulfide bond. The environment within a cell is too strongly reducing for disulfides to form, but in the extracellular environment, disulfides can form and play a key role in stabilizing many such proteins, such as the digestive enzymes of the small intestine.

Cysteine and methionine are the only sulfur-containing amino acids.

molecular structure for  HS-CH2-CH(NH3)-COO

Chemical structure for cysteine

 


   

Glutamic Acid E (Glu)

Chemical Properties:

Acidic

(AcidicR-group and  their  amides)

Physical Properties:

Polar (charged)

   Interconvertible with α-ketoglutarate
   Involved in the biosynthesis of Proline

Glutamic acid has one additional methylene group in its side chain than does aspartic acid. The side chain carboxyl of aspartic acid is referred to as the β carboxyl group, while that of glutamic acid is referred to as the γ carboxyl group.

The pKa of the γ carboxyl group for glutamic acid in a polypeptide is about 4.3, significantly higher than that of aspartic acid. This is due to the inductive effect of the additional methylene group. In some proteins, due to a vitamin K dependent carboxylase, some glutamic acids will be dicarboxylic acids, referred to as γ carboxyglutamic acid, that form tight binding sites for calcium ion.

Molecular structure of glutamic acid  HOOC-(CH2)2-CH(NH3)-COO
 

Chemical structure for glutamic acid

 


Glutamic acid is interconvertible by transamination withα-ketoglutarate
Glutamic acid and α-ketoglutarate, an intermediate in the Krebs cycle, are interconvertible by transamination. Glutamic acid can therefore enter the Krebs cycle for energy metabolism, and be converted by the enzyme glutamine synthetase into glutamine, which is one of the key players in nitrogen metabolism.


Molecular Structure of alpha-ketoglutarate COO-­CH2­Ch2­CO­COO-

Chemical structure of alpha-ketoglutarate

Biosynthesis of Proline
Note also that glutamic acid is easily converted into proline. First, the γ carboxyl group is reduced to the aldehyde, yielding glutamate semialdehyde. The aldehyde then reacts with the α-amino group, eliminating water as it forms the Schiff base. In a second reduction step, the Schiff base is reduced, yielding proline.

Glutamic acid to Glutamate Semialdehyde to pyrroline 5-carboxylate to Proline

 


   

Glutamine Q (Gln)

Chemical Properties:
    Neutral
(Amides of acidic amino acids R-group)
Physical Properties:
   Polar (uncharged)
 

Glutamine
is the amide of glutamic acid, and is uncharged under all biological conditions.

The additional single methylene group in the side chain relative to asparagine allows glutamine in the free form or as the N-terminus of proteins to spontaneously cyclize and deamidate yielding the six-membered ring structure pyrrolidone carboxylic acid, which is found at the N-terminus of many immunoglobulin polypeptides. This causes obvious difficulties with amino acid sequence determination.

Molecule Structure of Glutamine H2N-CO-(CH2)2-CH(NH3)-COO

      Chemical structure for glutamine

 


 

Glycine G (Gly)

Chemical Properties:
    Aliphatic
(Aliphatic R-group)

 

Physical Properties:     
Nonpolar
   
Glycine is the smallest of the amino acids. It is ambivalent, meaning that it can be inside or outside of the protein molecule. In aqueous solution at or near neutral pH, glycine will exist predominantly as the zwitterion

The isoelectric point or isoelectric pH of glycine will be centered between the pKas of the two ionizable groups, the amino group and the carboxylic acid group.

In estimating the pKa of a functional group, it is important to consider the molecule as a whole. For example, glycine is a derivative of acetic acid, and the pKa of acetic acid is well known. Alternatively, glycine could be considered a derivative of aminoethane.

Molecular Structure of Glycine NH2-CH2-COOH

Chemical structure for glycine

 


 

Histidine H (His)

Chemical Properties:
    Basic
(Basic group)
Physical Properties:
    Polar (positively charged)
   

Histidine,
an essential amino acid, has as a positively charged imidazole functional group.

The imidazole makes it a common participant in enzyme catalyzed reactions. The unprotonated imidazole is nucleophilic and can serve as a general base, while the protonated form can serve as a general acid. The residue can also serve a role in stabilizing the folded structures of proteins.

molecular structure for histidine NH-CH=N-CH=C-CH2-CH(NH3)-COO

Chemical structure of histidine

 


   

Isoleucine I (Ile)

Chemical Properties:
    Aliphatic
(Aliphatic R-group)
Physical Properties:
    Nonpolar 
  

Isoleucine,
an essential amino acid, is one of the three amino acids having branched hydrocarbon side chains. It is usually interchangeable with leucine and occasionally with valine in proteins.

The side chains of these amino acids are not reactive and therefore not involved in any covalent chemistry in enzyme active centers.

However, these residues are critically important for ligand binding to proteins, and play central roles in protein stability. Note also that the β carbon of isoleucine is optically active, just as the β carbon of threonine. These two amino acids, isoleucine and threonine, have in common the fact that they have two chiral centers.

Molecular Structure of Isoleucine CH3-CH2-CH(CH3)-CH(NH3)-COO


 

Chemcial structure for Isoleucine

 


   

Leucine L (Leu)

Chemical Properties:
    Aliphatic
(Aliphatic R-group)
Physical Properties:
    Nonpolar
 

Leucine
, an essential amino acid, is one of the three amino acid with a branched hydrocarbon side chain. It has one additional methylene group in its side chain compared with valine.

Like valine, leucine is hydrophobic and generally buried in folded proteins.

Molecular Structure for Leucine (CH3)2-CH-CH2-CH(NH3)-COO

Chemical structure for leucine

 


 

Lysine K (Lys)

Chemical Properties:
    Basic
(Basic R-group)
Physical Properties:
    Polar (positively charged)
 

Lysine.
an essential amino acid, has a positively charged ε-amino group (a primary amine).

Lysine is basically alanine with a propylamine substituent on theβcarbon. The ε-amino group has a significantly higher pKa (about 10.5 in polypeptides) than does the α-amino group.

The amino group is highly reactive and often participates in a reactions at the active centers of enzymes. Proteins only have one α amino group, but numerous ε amino groups. However, the higher pKa renders the lysyl side chains effectively less nucleophilic. Specific environmental effects in enzyme active centers can lower the pKa of the lysyl side chain such that it becomes reactive.

Note that the side chain has three methylene groups, so that even though the terminal amino group will be charged under physiological conditions, the side chain does have significant hydrophobic character. Lysines are often found buried with only theεamino group exposed to solvent.

Molecular structure of Lysine H2N-(CH2)4-CH(NH3)-COO

Chemcial structure for lysine

 


   

Methionine M (Met)

Chemical Properties:
    Sulfur-containing

(Sulfur containing group)
 

Physical Properties:
 Non polar (hydrophobic)
 

Methionine
, an essential amino acid, is one of the two sulfur-containing amino acids. The side chain is quite hydrophobic and methionine is usually found buried within proteins. Unlike cysteine, the sulfur of methionine is not highly nucleophilic, although it will react with some electrophilic centers. It is generally not a participant in the covalent chemistry that occurs in the active centers of enzymes.

The chemical linkage of the sulfur in methionine is a thiol ether. Compare this terminology with that of the oxygen containing ethers. The sulfur of methionine, as with that of cysteine, is prone to oxidation. The first step, yielding methionine sulfoxide, can be reversed by standard thiol containing reducing agents. The second step yields methionine sulfone, and is effectively irreversible. It is thought that oxidation of the sulfur in a specific methionine of the elastase inhibitor in human lung tissue by agents in cigarette smoke is one of the causes of smoking-induced emphysema.

Methionine as the free amino acid plays several important roles in metabolism. It can react to form S-Adenosyl-L-Methionine (SAM) which servers at a methyl donor in reactions.

Methionine and cysteine are the only sulfur-containing amino acids.
 

Molecular structure of methionine CH3-S-(CH2)2-CH(NH3)-COO

Chemical structure for methionine

 


   

Phenylalanine F (Phe)

Chemical Properties:
    Aromatic
(Aromatic R-group)
Physical Properties:
    Nonpolar

  

 

 

As the name suggests, phenylalanine, an essential amino acid, is a derivative of alanine with a phenyl substituent on the β carbon. Phenylalanine is quite hydrophobic and even the free amino acid is not very soluble in water.

It is an interesting point of history that Marshall Nirenberg and Phil Leder in their earliest experiments were studying the translation of the synthetic message polyU, which encodes polyphenylalanine. It was a happy coincidence that the product was insoluble. At the time, they did not know that UUU encodes Phe, but soon after the precipitate formed in their translation mix, they did, and they were on the way to unraveling the genetic code, and the Nobel prize.

Due to its hydrophobicity, phenylalanine is nearly always found buried within a protein. The π electrons of the phenyl ring can stack with other aromatic systems and often do within folded proteins, adding to the stability of the structure.

Molecular structure of phenylalaline

Chemical structure for phenylalanine

 


Proline P (Pro)

Chemical Properties: Physical Properties:

  

Cyclic

   Biosynthesis of Proline

Nonpolar

Proline shares many properties with the aliphatic group.

Proline is formally NOT an amino acid, but an imino acid. Nonetheless, it is called an amino acid. The primary amine on the α carbon of glutamate semialdehyde forms a Schiff base with the aldehyde which is then reduced, yielding proline.

When proline is in a peptide bond, it does not have a hydrogen on the α amino group, so it cannot donate a hydrogen bond to stabilize an α helix or a β sheet. It is often said, inaccurately, that proline cannot exist in an α helix. When proline is found in an α helix, the helix will have a slight bend due to the lack of the hydrogen bond.

Proline is often found at the end of α helix or in turns or loops. Unlike other amino acids which exist almost exclusively in the trans- form in polypeptides, proline can exist in the cis-configuration in peptides. The cis and trans forms are nearly isoenergetic. The cis/trans isomerization can play an important role in the folding of proteins and will be discussed more in that context.

Proline is the only cyclic amino acid.

Molecular Structure of proline, NH2-(CH2)3-CH-COO
 


Chemical structure of Proline

Biosynthesis of Proline
Glutamic acid is easily converted into proline. First, the γcarboxyl group is reduced to the aldehyde, yielding glutamate semialdehyde. The aldehyde then reacts with the α-amino group, eliminating water as it forms the Schiff base. In a second reduction step, the Schiff base is reduced, yielding proline.

Glutamic acid to Glutamate Semialdehyde to pyrroline 5-carboxylate to Proline
 

 


   

Serine S (Ser)

Chemical Properties:
    Non-aromatic
hydroxyl

(Hydroxyl group)

Physical Properties:
    Polar (uncharged)
 

Serine
differs from alanine in that one of the methylenic hydrogens is replaced by a hydroxyl group.

Serine is one of two hydroxyl amino acids. Both are commonly considered to by hydrophilic due to the hydrogen bonding capacity of the hydroxyl group.
 

Molecular Structure of Serine HO-CH2-CH(NH3)-COO

Chemical structure for serine

 


  

Threonine T (Thr)

Chemical Properties:
    Non-aromatic
hydroxyl

(Hydroxyl group)
 

Physical Properties:
    Polar (uncharged) 

 

Threonine, an essential amino acid, is a hydrophilic molecule.

Threonine is an other hydroxyl-containing amino acid. It differs from serine by having a methyl substituent in place of one of the hydrogens on the β carbon and it differs from valine by replacement of a methyl substituent with a hydroxyl group.

Note that both the α and β carbons of threonine are optically active.

molecular structure for threonine CH3-CH(OH)-CH(NH3)-COO

Chemical structure for threonine
 

Differs from serine

Molecular structure of Serine HO-CH2-CH(NH3)-COO

Chemical structure of Serine

Differs from valine

Molecular Structure of Valine (CH3)2-CH-CH(NH3)-COO

Chemical structure of valine

 


   

Tryptophan W (Trp)

Chemical Properties:
    Aromatic
(Aromatic R-group)
Physical Properties:
    Nonpolar

  


Tryptophan
, an essential amino acid, is the largest of the amino acids. It is also a derivative of alanine, having an indole substituent on the β carbon. The indole functional group absorbs strongly in the near ultraviolet part of the spectrum. The indole nitrogen can hydrogen bond donate, and as a result, tryptophan, or at least the nitrogen, is often in contact with solvent in folded proteins.

molecular structure for tryptophan Ph-NH-CH=C-CH2-CH(NH3)-COO

Chemical structure for tryptophan

 


   

Tyrosine Y (Tyr)

Chemical Properties:
    Aromatic
(Aromatic group & Hydroxyl group)
Physical Properties:
    Nonpolar

  


Tyrosine,
an essential amino acid, is also an aromatic amino acid and is derived from phenylalanine by hydroxylation in the para position. While tyrosine is hydrophobic, it is significantly more soluble that is phenylalanine. The phenolic hydroxyl of tyrosine is significantly more acidic than are the aliphatic hydroxyls of either serine or threonine, having a pKa of about 9.8 in polypeptides. As with all ionizable groups, the precise pKa will depend to a major degree upon the environment within the protein. Tyrosines that are on the surface of a protein will generally have a lower pKa than those that are buried within a protein; ionization yielding the phenolate anion would be exceedingly unstable in the hydrophobic interior of a protein.

Tyrosine absorbs ultraviolet radiation and contributes to the absorbance spectra of proteins. The absorbance spectrum of tyrosine will be shown later; the extinction of tyrosine is only about 1/5 that of tryptophan at 280 nm, which is the primary contributor to the UV absorbance of proteins depending upon the number of residues of each in the protein.

molecular structure for tyrosine

Chemical structure of tyrosine

 


   

Valine V (Val)

Chemical Properties:
    Aliphatic
(Aliphatic R-group)

 

Physical Properties:
   Nonpolar
 
Valine, an essential amino acid, is hydrophobic, and as expected, is usually found in the interior of proteins.

Valine differs from threonine by replacement of the hydroxyl group with a methyl substituent. Valine is often referred to as one of the amino acids with hydrocarbon side chains, or as a branched chain amino acid.

Note that valine and threonine are of roughly the same shape and volume. It is difficult even in a high resolution structure of a protein to distinguish valine from threonine.   

Molecular Structure of Valine (CH3)2-CH-CH(NH3)-COO

    

Chemical structure for valine

 

 

Differs from threonine

Molecular structure of Threonine CH3-CH(OH)-CH(NH3)-COO

Chemical Structure of threonine