section
2.2
Classification
23
Acidic Amino Acids
Aspartic Acid
The /3-carboxylic acid group of aspartic acid has a pK'
of 3.86 and is ionized at pH 7.0 (the anionic form is called
aspartate).
The anionic carboxylate groups tend to occur
on the surface of water-soluble proteins, where they inter-
act with water. Such surface interactions stabilize protein
folding.
COO'
I
+ H3N—aC— H
I
/?CH2
Aspartate
Glutamic Acid
The y-carboxylic acid group of glutamic acid has a pK'
of 4.25 and is ionized at physiological pH. The anionic
groups of glutamate (like those of aspartate) tend to oc-
cur on the surfaces of proteins in aqueous environments.
Glutamate is the primary excitatory neurotransmitter in the
brain. Its levels are regulated by clearance that is mediated
by glutamate transfer protein in critical motor control areas
in the CNS. In
amyotrophic lateral sclerosis
(ALS) gluta-
mate levels are elevated in serum, spinal fluid, and brain;
glutamate excitotoxicity is implicated in the progression of
the disease. ALS is a progressive disorder affecting motor
neurons in the spinal cord, brain stem, and cortex. The pre-
cise molecular basis of the disease is unknown; however,
factors involved are glutamate excitotoxicity, genetics, ox-
idative stress, and diminished neurotrophic factors.
Two
drugs
that
provide
neuroprotection
against
glutamate excitotoxicity are riluzole and gabapentin.
Gabapentin is an amino acid structurally related to the
neurotransmitter
y-aminobutyrate
(GABA).
GABA,
an inhibitory neurotransmitter in the CNS, is produced
by the decarboxylation of glutamate by glutamate de-
carboxylase, a pyridoxal phosphate dependent enzyme.
GABA, when bound to its receptors, causes an increase
in permeability to chloride ions in neuronal cells. A
group of tranquilizing drugs known as benzodiazopines
enhance the membrane permeability of chloride ions
by GABA. In some proteins, the y -carbon of glutamic
acid contains an additional carboxyl group. Residues of
y -carboxyglutamic acid
(Gla) bear two negative charges
and can strongly bind calcium ions, y-Carboxylation of
glutamic acid residues is a posttranslational modification
and requires
vitamin K
as a cofactor, y -Carboxyglutamate
residues are present in a number of blood coagulation
proteins (factors II, VII, IX, and X) and anticoagulant
proteins C and S (Chapter 36). Osteocalcin, a protein
present in the bone, also contains y-carboxyglutamate
residues (Chapter 37).
A cyclic, internal amide derivative of glutamic acid
is pyrrolidone carboxylic acid (also known as pyroglu-
tamic acid or 2-oxoproline). Some proteins (e.g., heavy
chains of immunoglobulins; Chapter 35) and peptides
(e.g., thyrotropin-releasing hormone; Chapter 33) have py-
roglutamic acid as their N-terminal amino acid residue.
cocr
+ H3N— aC— H
C O O '
1
1
ßCH2
HN-----------C— H
1
1
-
0
-
X
ro
0 = c
CH2
o ^ S , -
Glutamate
H2
Pyrrolidone carboxylate
(pyroglutamate)
C O O '
i
nh
2
+ H3N— C— H
1
1
CH2
CH2
1
1
CH2
CH
I
CH2
o = c r
^ c = o
O '
O '
1
C O O '
y-amino butyrate
(GABA)
y-Carboxy glutamate
Basic Amino Acids
Lysine
Lysine is an essential amino acid. The long side chain of
lysine has a reactive amino group attached to the e-carbon.
The e-NH
2
(pK' = 10.53) is protonated at physiological
pH. The lysyl side chain forms ionic bonds with negatively
charged groups of acidic amino acids. The e-NTL groups
of lysyl residues are covalently linked to biotin (a vitamin),
lipoic acid, and retinal, a derivative of vitamin A and a
constituent of visual pigment.
In collagen and in some glycoproteins, 5-carbons of
some lysyl residues are hydroxylated (Figure 2-6), and
sugar moieties are attached at these sites. In elastin and
collagen, some s-carbons of lysyl residues are oxidized
to reactive aldehyde (-CHO) groups, with elimination of
NH
3
. These aldehyde groups then react with other
e-
NH
2
groups to form covalent cross-links between polypep-
tides, thereby providing tensile strength and insolubility to
