Aspartic acid ionization

The most significant amino acids for modification and conjugation purposes are the ones containing ionizable side chains aspartic acid, glutamic acid, lysine, arginine, cysteine, histidine, and tyrosine (Figure 1.6). In their unprotonated state, each of these side chains can be potent nucleophiles to engage in addition reactions (see the discussion on nucleophilicity below). 

The mechanism schematized above is a summary of the current knowledge. The role of Asp102 has long been controversial [10], Indeed, the catalytic triad has been depicted as a charge-relay system, meaning that the activation of the serine residue involves a concerted transfer of two protons, i.e., from serine to histidine and then to aspartic acid. More recent studies have shown that aspartic acid remains ionized and serves to stabilize the ionic transition state [6] [14-16],... 

Some amino acids have additional ionizable groups in their side-chains. These may be acidic or potentially acidic (aspartic acid, glutamic acid, tyrosine, cysteine), or basic (lysine, arginine, histidine). We use the term potentially acidic to describe the phenol and thiol groups of tyrosine and cysteine respectively under physiological conditions, these groups are unlikely to be ionized. It is relatively easy to calculate the amount of ionization at a particular pH, and to justify that latter statement. 

Similar calculations as above for the basic side-chain groups of arginine pK 12.48) and lysine pK 10.52), and the acidic side-chains of aspartic acid (pATa 3.65) and glutamic acid (pAfa 4.25) show essentially complete ionization at pH 7.0. However, for cysteine (pATa of the thiol group 10.29) and for tyrosine (pAfa of the phenol group 10.06) there will be negligible ionization at pH 7.0. 

When the R group contains another ionizable group, the amino acid will have more than two dissociation constants. The carboxylic acid gronps of aspartic acid and glutamic acid, the amine of lysine, and the guanidino group of arginine will all... 

The amino acids in question are the basic amino acids lysine, arginine, and histidine, and the acidic amino acids aspartic acid and glutamic acid. The side-chain functions of these amino acids, ionized at pH 7 (see Box 4.7), act as acids or bases. In a reverse sequence, protons may be acquired or donated to regenerate the conjugate acids and conjugate bases. 

Cardoso et al. [115] using the phase transfer technique studied the driving forces involved in the selective solubilization of three different amino acids having same pi, namely aspartic acid (hydrophilic), phenylalanine (slightly hydrophobic), and tryptophan (hydrophobic) in cationic TOMAC-RMs. The main driving forces involved were found to be hydrophobic and electrostatic interactions. Few other researchers have also identified that the major driving forces involved in the amino acid solubilization were hydrophobic interactions [ 114,159] and amino acid structure as well as its ionization state [160,161]. 

A more strongly acidic solution is needed to repress this ionization. Aspartic acid s isoelectric point is strongly acidic (pH = 2.7). (d) Cystine is a diaminodicarboxylic acid and behaves like a monoaminomonocarboxylic acid. The isoelectric point is slightly acid (pH = 4.6). (e) Tyrosine is a monoaminomonocarboxylic acid containing a phenolic OH, which however is too weakly acidic to ionize to any significant extent. The isoelectric point is slightly acidic (pH = S.6). 

Another good example of the use of affinity labels involves pepsin, and is illustrated in Chapter 16, equations 16.28 and 16.29. The enzyme has two catalyt-ically important aspartic acid residues, one ionized and the other un-ionized. The ionized carboxylate is trapped with an epoxide, which, of course, requires the reaction of a nucleophilic group. The un-ionized carboxyl is trapped with a diazoacetyl derivative of an amino acid ester ... 

An additional point should be noted from table 3.3. Whereas the amino acid side chains (R groups) that are normally charged at physiological pH are restricted to five amino acids (aspartic acid, glutamic acid, lysine, arginine, and sometimes histidine), a number of potentially ionizable R groups are part of other amino acids. These include cysteine, serine, threonine, and tyrosine. The ionization reac-... 

When amino acid ester prodrugs of acetaminophen were prepared (Kovach et al., 1975 Pitman, 1976), the hydrobromide salt of the glycine ester showed enhanced solubility in water, but the hydrochloride salt of th -aspartic acid ester exhibited a solubility lower than that of the parent compound. The enhanced solubility resulted from the formation of a salt, while the parent drug is a weakly acidic phenol and behaves as essentially a neutral molecule in solution. The reduced solubility in the case of th0-aspartic acid ester resulted from ionization of the terminal carboxylic acid, which, with the protonated amine, gives a zwitterionic compound. The zwitterion also behaved as a molecule with an overall neutral character, as is commonly observed with zwitterion behavior in aqueous media, but its larger size resulted in a further reduced solubility. 

Write the equations for the ionization equilibria of aspartic acid. Indicate the net charge carried on each species. 

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