Amino Acids and Peptides
Chapter 3
Biomedical Importance
• L-α-AA are the monomers of proteins.
• Derivatives participate in nerve transmission and synthesis of
nucleotides and hormones.
• Peptides are used as hormones or neurotransmitters.
• Humans cannot synthesize ten (10) of the amino acids present in
proteins which should be obtained from diet.
• Essential – His, Iso, Leu, Lys, Met, Phe, Thr, Trp and Val (PVT TIM HALL**)
• Conditional – Arg, Cys, Glu, Tyr, Gly, Pro, Ser
• Kidney can filter over 50g of AA but is totally absorbed hence, only
traces are found in the urine.
Biomedical Importance
• Some microbes form D-AA and of therapeutic value such as
antibiotics bacitracin and gramicidin and the antitumor bleomycin.
• There are also toxic peptides such as microcystin and nodularin from
cyanobacteria which can cause gastroenteritis and liver disease.
Properties of Amino Acids
• More than 300 AA are almost exclusively synthesize from 20 AA encoded
by codons.
• The genetic code is redundant since several AA have more than 1 codon.
• The side groups (R) can be hydrophilic or hydrophobic which affects its
location in proteins.
• Some proteins undergo posttranslational modifications of AA such as
hydroxylation of proline to 4-hydroxyproline in collagen.
• These modifications increase the diversity of proteins by altering stability,
solubility, catalytic activity and interaction with other proteins.
Selenocysteine, the 21 st AA
• Present in all life forms.
• Directly translated rather than a modification of cysteine.
• Found in peroxidases, reductases and deiodinase.
• Selenocysteine is specified by a complex gene for the unusual tRNASec
which uses UGA which is normally as stop codon.
• The codon with a stem-loop structure, selenocysteine insertion
element, is recognized by synthetic mechanisms.
Stereochemistry of AA
• Except glycine, the α-carbon of all other AA is chiral meaning the
mirror image cannot be superimposed.
• The L-glyceraldehyde portion is shared among all amino acids.
• Almost all proteins are in S configuration except cysteine. – however
the books states otherwise.
• The stereochemistry is important since only L-isomers are recognized
by enzymes
Posttranslational Modifications confer
Additional Properties
• These modifications generate new R groups that impart additional
properties.
• Carboxylation of glutamate residues in coagulation proteins allow
chelation of calcium ions.
• Histones undergo acetylation and methylation of lysine or
deamination of arginine to modify gene activity.
• Modifications can also be done in the laboratory to form unnatural
AAs in proteins, gene recombination and study protein structure-
function relationships.
Extraterrestrial Amino Acids Detected in
Meteorites
• In 2013, a meteorite that exploded over West Siberia yielded amino
acids.
• The first such event was reported in 1969 at Australia.
• These AAs contain racemic mixtures of D- and L-isomers and other
AAs without an equivalent on Earth.
• Nucleobases, phosphates and molecules related to sugars have been
detected.
L-α-AA Serve Additional Metabolic Roles
• Hormones (thyroxine)
• Neurotransmitters (epinephrine)
• Metabolic intermediates (ornithine and citrulline in urea synthesis)
Certain Plant L-α-AA Adversely Impact Health
• Nonprotein AA found in Lathyrus cause neurolathyrism characterized
by irreversible spastic paralysis of the legs.
• L-homoarginine
• β-N-oxalyl-L-α, β-diaminoproprionic acid (β-ODAP).
• γ-glutamyl-β-aminoproprionitrile (BAPN).
• α,γ-diaminobutyric acid
• The disease is more prevalent during famines where the seeds of the
plant are widely consumed.
• Cycad seeds contain L-β-methylaminoalanine is a neurotoxin that can
cause Amyotrophic Lateral Sclerosis (ALS)-Parkinson Dementia
Complex.
D-AA
• D-Ser and D-Asp in brain
• D-Ala and D-Glu in Gram (+) cell walls
• Peptides in bacteria, fungi, reptiles and amphibians.
AAs May Have Positive, Negative or Zero Net
Charge
• The –COOH and –NH3 exist in dynamic protonic equilibrium.
• Both are acids but –COOH is stronger and forms -COO- at physiologic
pH while amino groups are –NH3+.
• Histidine and Arginine distributes the positive charge with its two or
three nitrogens, respectively.
AAs May Have Positive, Negative or Zero Net
Charge
• Molecules with equal positive and negative charges are called
zwitterions.
pKa Values Express Strengths of Weak Acids
• The net charge of an AA depends on the pKa values of its functional
groups and pH of the medium.
• Altering the pH can alter the charge of the AA and derivatives which
can facilitate separation.
At Isoelectric pH (pI), AA Bears No Charge
• Zwitterions are isoelectric species.
• The isoelectric pH is midway between pKa values for the ionization on
either side of the isoelectric species.
• Alanine only has two dissociating groups hence:
At Isoelectric pH (pI), AA Bears No Charge
• For polyprotic AA such as Asp, pI is also the pH midway between pKa
of the isoionic species.
• Knowing pI will aid in separation of different species through
electrophoresis or chromatography.
pKa Vary with the Environment
• A nonpolar environment which has less capacity of stabilizing species
raises the pKa of a carboxyl group while lowering the pKa of an amino
group.
• An adjacent opposite charge can stabilize or destabilize the charge of
a side group.
Solubility of AAs Reflects their Ionic Character
• Charges of the functional groups ensure
that AAs are soluble in water but not in
non-polar solvents.
• AAs do not absorb visible light.
• Tyr, Phe and Trp absorb UV at 250-290 nm
with Trp having the major absorption.
α-R groups Determine the Properties of AAs.
• Each R group exhibits all its chemical reactions.
• Carboxylic acids can form esters, amides and anhydrides.
• Amino groups can form acylation, amidation and esterification.
• For –OH and –SH, these form oxidation and esterification reactions.
• Glycine is usually found in areas of bending due to its small size.
• Hydrophobic and aromatic AAs are found in the interior of proteins.
• Charge groups of basic and acidic AAs stabilize protein conformations
via ionic interactions or salt bridges.
α-R groups Determine the Properties of AAs.
• Histidine is unique since its imidazole ring allows the AA to function at
neutral pH as either an acid or base.
• Serine and cysteine are excellent nucleophiles due to –SH and
selenocysteine is even better at lower pH of 5.2
• Ser, Tyr and Thr have –OH groups for phosphorylation during protein
function regulation.
AA sequence Determines Primary Structure
• AAs form peptide bonds.
• Suffixes –ate or –ine are replaced by –yl when referred to in
the sequence.
• The carboxyl terminal residue is the basis of the name of the
peptide.
• Lys-Leu-Tyr-Gln is lysyl-leucyl-tyrosyl-glutamine.
• When using the single letter abbreviations, lines are omitted
hence the sequence above is KLYQ.
• Prefixes like tri- or octa- denote the number of residues
• The amino terminal is at the beginning while the carboxyl is
at the end. This is also the sequence of synthesis.
Peptide Structures are Easy to Draw
• Zigzag
• α-nitrogen, α-carbon, α-nitrogen, α-carbon
• Add hydrogen to nitrogen and carbon atoms.
• Add oxygen to the carbonyl carbon.
• Add R groups.
Some Peptides have Unusual AA
• Usually, hormones contain the 20 codon specified AAs.
• An example of atypical AA include the terminal Glu of glutathione
which is linked to cysteine by a non-α peptide bond.
α-carbon
α-carbon
α-carbon
Some Peptides have Unusual AA
• The amino terminal Glu of thyrotropin-releasing hormone (TRH) is
cyclized to pyroglutamic acid.
• Carboxy terminal carboxyl group of proline is amidated in TRH
• D-Phe and ornithine are present in antibiotics tyrocidine and
gramicidin.
• Heptatpeptides dermorphin and deltophorin contain D-Tyr and D-Ala.
The Peptide Bond has a Partial Double-Bond
property
• The bonds connecting the
carboxyl carbon and nitrogen
cannot rotate.
• The O, C, N and H atoms are
coplanar meaning there is
rigidity.
Noncovalent Forces Constrain Peptide
Conformations
• Folding occurs with biosynthesis.
• The active conformation reflects the collective contributions of the
AA sequence, noncovalent interactions and minimization of steric
hindrance.
Peptides are Polyelectrolytes
• The peptide bond is uncharged at a pH of physiologic interest.
• Formation of a peptide bond is accompanied by a loss of one positive
and one negative charge.
• However, peptides are charge due to the carboxyl and amino groups
of every AA as well as the presence of acidic or basic R groups in
some AA.
• For AA, the net charge depends on the pH of the medium and the pKa
values of other dissociable groups.
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