AMINO ACID AMINO ACID CLASSIFICATION

• Building block of proteins BASED ON STRUCTURE

• 300 naturally occurring – 20 common
• Short polymers = peptides
• Can contain D or L a-amino acids
• Most are L a-amino acids; D amino-microorganisms
• All amino acids follow levorotatory (L-configuration
or L-glyceraldehyde)
• Most amino acids are a-amino acids (except proline-
imino acid)
o Means amino group is attached to same carbon
atom to which carboxyl group is attached
• Selenocysteine
o -L a-amino acids peroxidises and reductases –
catalysis of electron transport reactions
o -Se atom replaces sulfur of its structural analog,
cysteine
o -not spec. with a 3-letter codon
ALIPHATIC
• Mono amino mono carboxylic acids
o Simple – glycine, alanine
o Branched chain – valine, leucine, isoleucine
o Hydroxylic – serine, threonine
o Sulfur containing – cysteine, methionine
o Amino acid with carboxamide group –
asparagine, glutamine
• Mono amino dicarboxylic (acidic)
o Aspartic acid (Aspartate), glutamic acid
(glutamate)
• Diamino monocarboxylic (basic) – lysine, arginine,
histidine

AMINO ACID STRUCTURE

• Carbon (the alpha carbon)

• Hydrogen atom (H)
• Carboxyl group (-COOH)
• Amino group (-NH2)
• A “variable” group or “R” group (side chain)

• Proline
o R with three-carbon chain that joins the
nitrogrn to the alpha-carbon iin a five-
membered ring-IMINO ACID
 IMINO ACID
• Proline (Pro [P])
• Not an a-amino acid

SPECIAL GROUPS IN SIDE CHAINS OF AMINO ACID

• Arginine – guanidinium
• Phenylalanine – benzene
• Tyrosine – phenol
• Tryptophan – indole
• Histidine – imidazole
• Proline – pyrrolidine

BASED ON SIDE CHAIN CHARACTERS

• Hydrophobic vs hydrophilic
• Properties that affect their location in a protein’s
mature folded conformation

AMINO ACIDS WITH NON-POLAR SIDE CHAINS

• Electrons are equally shared between carbon and
hydrogen atoms in side chains, so cannot form
hydrogen
• Hydrophobic in nature
• Amino acids:
o Alanine
o Valine
o Leucine
AROMATIC AMINO ACID o Isoleucine
• Histidine (His [H]) o Methionine
• Phenylalanine (Phe [F]) o Proline
• Tyrosine (Tyr [Y]) o Phenylalanine
• Tryptophan (Trp [W]) o Tryptophan
o Glycine

AMINO ACIDS WITH UNCHARGED OR NON-IONIC

POLAR SIDE CHAIN
• Hydrophilic in nature
• Amino acids:
o Serine
o Threonine
o Tyrosine
o Cysteine
o Glutamine
o Asparagine
• Amide group in asparagine and glutamine and
hydroxyl group in serine, tyrosine, and threonine can BASED ON NUTRITIONAL REQUIREMENT
form hydrogen bond
• Sulfur in cysteine can form disulfide bond leading to ESSENTIAL AMINO ACIDS
formation of cystine • M, I, L, K, V, F, T, W
• Their carbon skeleton cannot be synthesized by
AMINO ACIDS WITH CHARGE OR IONIC POLAR SIDE human and are performed and are taken in food
CHAIN
• Acidic – with negative charge in the R-group; aspartic SEMI-ESSENTIAL
acid, glutamic acid • H, R
• Basic – with positive charge in the R-group; lysine, • Not essential in adult but essential for proper growth
arginine, histidine in children
• Hydrophobic – alanine, isoleucine, leucine, • Important in preterm infant whom a development
methionine, phenylalanine, proline, tryptophan, delay in specific enzymes involved in amino acid
valine, glycine synthesis have been demonstrated
• Hydrophilic – arginine, asparagine, aspartic acid, NON-ESSENTIAL
cysteine, glutamic acid, glutamine, histidine, lysine, • Remaining 10 amino acids
serine, threonine, tyrosine
• Hydrophobic amino acids are found in the interior of DERIVED AMINO ACIDS
proteins and hydrophilic amino acids are found in the • found in protein
exterior o additional amino acids that arise by the post-
translational modification of an amino acid
BASED ON METABOLIC FATE already present in a peptide
o e.g. hydroxyproline
• Amino acids can be metabolized to compounds that • not seen in protein
can either form glucose (glucogenic) or ketone o e.g. ornithine, citrulline – which are metabolites
bodies (ketogenic) in urea biosynthesis
• non-alpha amino acids
PURELY KETOGENIC-L o no a-carbon present in the structure
• Can enter metabolic pathway of lipid o e.g gamma amino butyric acid (GABA) derived
• Gives rise to acetyl CoA from glutamic acid, B-alanine, B-
aminoisobutyrate

PROPERTIES OF AMINO ACIDS

• all have high melting point
• all are soluble in water and alcohol (polar solvent)
but insoluble in benzene (nonpolar solvent)

ACID-BASE PROPERTY
KETOGENIC AND GLUCOGENIC – W, I, F, Y, K • amphoteric/ampholytes
• Carbon skeleton can enter ketogenic and glucogenic • the a-COOH and a-NH2 groups in amino acids are
pathways capable of ionizing (as the R-groups of the acidic and
• K- Lysine is considered in some references as purely basic amino acids)
ketogenic • charged and uncharged forms of the ionizable –
COOH and NH3+ in protonic equilibrium:
PURELY GLUCOGENIC
• Other 14 amino acids
• Yields pyruvate, or four- and five-carbon
intermediates of the citric acid cycle
• amino group – has lone pair of electron which
can impact the basic characteristics (-NH2)
• carboxyl group – possess acidic hydrogen as a
result of pi electric delocalization that stabilizes
the tricenter molecular orbital that involves -
COOH
• ionization state of an amino acid varies with pH
• in acidic solution, they are cationic in form
• the amino group is protonated (NH3+) and
carboxyl group is no dissociated (COOH)
• in alkaline solution, they behave as anions
• the carboxyl group gives its proton
• at physiological pH (7.4), carboxyl group is
unpronated and amino group is pronated
o if amino acid has no ionizable R-group – it is
electrically neutral at 7.4 pH and in dipolar
form
• when an amino acid is dissolved in water, it exists
in solution as the dipolar/zwitterion (German for
“hybrid ion”)
o Zwiterrion/ ampholyte – can be acidic or
basic in nature
▪ Molecular species that bear no net
charge (+charge = -charge)
▪ Acid – proton donor
▪ Base – proton acceptor
• As organic acids, the acidic strength of the carboxyl,
amino and ionizable R-groups in amino acids can be
defined by association constant Ks or commonly the
negative logarithm of Ka or pKa (lower pKa value =
stronger acid – can easily dissociate ion)
o pKa – acid strength of weak acids
o strong acids = low pKa value
o weak acids = high pKa value
o high Ka – high acidity
o pKa – negative logarithm of Ka (-log Ka)
o low pKa = highly acidic
• net charge (algebraic sum of all the charges in
groups present) of an amino acid depends upon the
pH of the medium
o as the pH changes, so do the charges as
observed in titration
• when net charge of an amino acid is zero, the pH
will be equivalent to an isoelectric point
ISOELECTRIC POINT(pI)
• The net charge of an amino acid depends upon the
pH of medium. As the pH changes so do the charges
• When the net charge of an amino acid is zero, the
pH will be equivalent to the pI
• The pH at which amino acid will carry no charge –
all the groups are ionized but charges cancel each
other
• No mobility in an electric field
• Solubility and buffering capacity will be minimum
• Acid-base titration - gradual addition or removal of OPTICAL PROPERTY
protons • glycine is not chiral since its R-group is H, therefore
o Amino acids have characteristics titration it is not optically active
curves unique to them
• chirality – describes handedness of a molecule
o E.g titration curve of glycine
• ability to rotate the plane of polarized light to either
• At very low pH, the predominant ionic species of
to the right (dextrorotatory, D) or to the left
glycine is the fully protonated form (+H3N – CH2 –
(levorotatory, L)
COOH)
• all amino acids are in L configuration
o Midpoint of the first titration – point of
• D-amino acids are never found in protein; they exist
inflection where the pH is equal to the pKa of
in nature as synthetic compounds like antibiotics
the protonated group being titrated
• Another point of inflection – removal of the first
proton is essentially complete and the removal of
the second has just begun
o Glycine exists as the dipolar ion: +h3N – CH2 –
COO-
• Second stage of titration: removal of a proton from
the -NH3+ group of glycine
o pH is equal to the pKa for the NH3+ group *because of the presence of asymmetric carbon atom;
mirror images are formed with reference to the alpha-
• titration is essentially complete at a pH of 12 –
carbon atom and are called D and L isomers
predominant form of glycine is H2N – CH2 – COO-
• important information about titration curves:
• Aromatic AA, such as W, Y, F, and H can absorb UV
o quantitative measure of the pKa of each of the
light with a maximum absorbance in the range of
ionizing groups
280nm
o number of regions of buffering power
• Ability of protein to absorb UV light is due to the
(depending on the number of flat portions in
presence of predominant tryptophan
the curve)
o relationship between the amino acid’s net
electric charge and pH CHEMICAL REACTIONS
▪ any amino acid has a net negative charge
at any pH abovr its pI (acidic)
➢ move toward the positive electrode REACTIONS DUE TO CARBOXYL GROUP
(anode) when placed in an electric
field • Based on the different molecules found in the
➢ at any pH below its pI, any amino structure of the protein, it can undergo different
acid will have a net positive charge chemical reactions
(basic) – move toward the negative • Decarboxylation
electrode (cathode) o Removal of the carboxyl group
➢ the farther the pH from its o Produce important amine
isoelectric point, the greater the net o Histidine – histamine and CO2
electric charge of the amino acid’s o Tyrosine – tyramine and CO2
molecules • Amide formation/ Carboxylation
• chiral – structurally asymmetrical molecule o The carboxyl group of the dicarboxylic amino
acid, other than the alpha carbon, can combine
with the ammonium to form the corresponding
substances or molecules:
▪ Aspartic acid + ammonia =
asparagine
▪ Glutamic acid + ammonia =
glutamine
• amino acids are chiral – the tetrahedral carbon with
four different substituent
 REACTIONS INVOLVING AMINO GROUP
• Transamination
o Alpha amino group is transferred to a-ketoacid
to form a new amino acid and a-ketoacid
o Glutamic acid + pyruvate a-ketoglutarate +
alanine
• Oxidative deamination
o Alpha amino group is removed from amino acid
to form the corresponding ketoacid and
ammonia
o Glutamic acid is the most common and
important amino acid that undergoes this
reaction
• Formation of Carbamino compounds
o Occurs at alkaline pH and serves as a
mechanism for the removal of CO2 from the
tissues and lungs by hemoglobin
o CO2 + amino group – carbamino group
REACTIONS DUE TO SIDE CHAIN
• Trans-methylation
o Methyl group of methionine after activation is
transferred to an acceptor which becomes
methylated and forms a homocysteine
o Methionine + methyl group – homocysteine
• Ester formation by OH group
o Involves the hydroxyl group
o The hydroxyl group of hydroxyl amino acids
(serine, threonine, and tyrosine) can form an
esters with phosphoric acid to form
phosphoproteins
• Reaction of amino group
o Side chains containing another amino group
other than a-amino group such as those found
in glutamine and asparagine can form n-
glycosidic bonds with carbohydrates to form
glycoproteins
• Reaction with sulfahydryl (-SH) group
o Amino acids containing sulfur (cysteine,
methionine) can bond with another cysteine to
form a disulfide bond
SPECIAL FUNCTIONS OF AMINO ACIDS
• GABA from glutamic acid and dopamine from
tyrosine -- neurotransmitters
• Histamine – mediator of allergic reactions
• Thyroxine – thyroid hormone
• Histidine – buffering activity, found in reactive
center of enzymes, can donate and accept electrons
• Lysine – binding of coenzymes like pyridoxal
phosphate and biotin
• Ornithine and citrulline derived from arginine –
essential in urea synthesis
PROTEINS
• Polymerization of amino acids to form the structural
framework of proteins
• Peptide bond formation is the most important
reaction of amino acids
• Peptides are used as:
o Hormones (eg insulin)
o Neurotransmitters (eg GABA)
o Antibiotics (eg Gramicidin A)
o Regulators(eg Glutathione)
o Anti-tumor agent (eg Bleomycin)
• By convention, N-terminal end is written at the left
while the C-terminal end is written at the right
• Peptide Bond
o Formed when alpha carboxyl group of one
amino acid reacts and condenses (non
enzymatically) with alpha amino group of
another amino acid with loss of water
o CO – NH bridge
o Also called amide bond
• # of peptide bonds = # of AA residues minus one
(eg a 3 amino acid residue (a tripeptide) will form
2 peptide bonds)
• Some contain unusual amino acids: in mammals
peptide hormones typically contain only the a-
amino acids of protein linked by a peptide bond.
o Other peptides, however, contain non-
protein amino acids, derivatives of amino
acids, or amino acids linked by an atypical
peptide bond

HOW TO DRAW A PEPTIDE BOND
1. Use a zigzag to represent the main chain or backbone
(HN-CH-C=O). By convention, peptides are written
with the residue that bears the free a-amino group
at the left.
2. Add the main chain atoms: a-nitrogen, a-carbon,
carbonyl carbon
3. Add a hydrogen atom to each a-carbon and to each
peptide nitrogen, and an oxygen to the carbonyl
group.
4. Add the appropriate R-groups to each a-carbon
atom.
5. Three-letter abbreviations linked by straight lines
represent an unambiguous primary structure. Lines
are omitted for a single-letter abbreviations (eg Asp-
Ala-Ser)
CHARACTERISTICS OF PEPTIDE BOND
• Partial double bond; no freedom of rotation
• Rigid and planar (O, C, N, and H atoms of a peptide
bond are coplanar)
• Trans in nature (except proline)
• Side chains are free to rotate on either side of
peptide bond
PEPTIDES ARE POLYELECTROLYTES
• The peptide bond is uncharged at any pH of
physiologic interest
• Formation of peptide is accompanied by a net loss of
one positive and one negative charge per peptide
bond formed
o Peptides are charged molecules at
physiologic pH owing to their COOH and
NH3 terminal groups, and, where
present, their acidic or basic R-groups
PEPTIDE BOND HAS PARTIAL DOUBLE-BOND
CHARACTER
• Peptides are written as if a single bond linked to the
a-COOH and a-NH3 atoms, this bond exhibits partial
double bond character
• There is no freedom of rotation about the bond that
connects the carboxyl carbon and the nitrogen of a
peptide bond.
• The imposed semi rigidity of peptide binds has
important consequences for higher orders of protein
structure
NON-COVALENT FORCES CONSTRAIN PEPTIDE
CONFORMATION
• Folding of a peptide probably occurs coincident with
its biosynthesis
• The physiological conformation reflects the
collective contributions of the amino acid sequence,
steric hindrance, and non-covalent interactions
between residues
• Peptides and proteins with specific conformations
STRUCTURE OF PROTEINS
• Configuration
o Geometric relationship between a given set of
atoms
o L- and D- amino acids or L- and D-isomers
• Conformation
o Spatial relationship of every atom in a molecule
o 3-D arrangement
o Inter-conversion between conformers that
occurs between covalent bond without rupture
• Rotation about a single bond
o Proteins have different levels of structural
organization: primary, secondary, tertiary,
quaternary
o In that folding, it occurred that the amino acids
are of the opposite charge; hence they attract
each other and form ionic bonds. But if they had
like chares, they will repel
o Proteins have different levels of structural
organization: primary, secondary, tertiary, and
quaternary

PRIMARY STRUCTURE
• Denotes the number and sequence of amino
acids in protein
• Polymerization of amino acids – polypeptide
chain
• Each amino acids in the chain is called residue
• Structure is linear and linkage is maintained by
peptide bond
• Higher levels of organization are decided by
primary structure
• Each polypeptide chain has a unique amino acid
sequence decided by the gene sequence as
encoded in the genetic code
• Gene codes not only determine the order of
amino acids in a protein, but they also determine
a protein’s structure and function
• Shen sequence is changed, polypeptide is also
changed
• Primary structure determines biologic activity
o A single amino acid change (mutation) in a
linear sequence may have profounf effect on
the function
o Example in normal hemoglobin (Hb A);
amino acid in the beta chain -- glutamic acid
but in sickle cell anemia it is changed to
valine
SECONDARY STRUCTURE
• Protein or portions of protein exhibit regularly
repeating types of structures
• Two common regular conformations – alpha
helix and beta pleated sheet
o Stabilized by hydrogen bond, formed
between the carbonyl group one amino acid
to amide group of another amino acid
ALPHA HELIX
• it is the common structure of globular class
• Polypeptide chain is twisted to form coil spiral
• Tightly coiled peptide backbone forms the inner part
and side chains extend outward
• Stabilized by intrachain of hydrogen bond
• Carbonyl carbon (CO) of one amino acid forms H
bond with amine hydrogen (NH) of another amino
acid that is situated four residues further down the
chain
• Essentially all alpha helices are right handed
• Amino acids that favor alpha helix formation –
alanine, aspartic acid, glutamic acid, leucine,
isoleucine, methionine
• Disrupts helix (produces bend) – glycine, proline
• Example of structures with alpha helix – keratin,
collagen, fibrin
BETA PLEATED SHEET
• Amino acid residues form a zigzag or pleated pattern
in which R-groups of adjacent residues point in
opposite directions
• Composed of stretches of at least 5 – 10 amino acids
called beta strands
• Peptide backbone is highly extended
• Derives much of its stability from hydrogen bonds
between the carbonyl oxygens and amide hydrogens
of peptide bonds
physical task such as binding of a substrate
or other ligand
• Accurate 3D structure-folding is assisted by a
chaperone inside the cell
• Incorrect folding may produce an alteration in
protein structure (Prion Disease)

*example of tertiary structure proteins

NON REGULAR SECONDARY STRUCTURES
• Include bends and loops that reside on the surface of
proteins and constitute accessible sites (epitopes)
for recognition and binding of anitbodies
• Important features of the tertiary structure
o Interior formed by amino acids with
hydrophobic side chains/R-groups
o Surface formed largely of hydrophilic amino
acids that interact with aqueous environment

BONDS FORMING THE TERTIARY

STRUCTURE
• Interaction between R-groups of the amino acids
would favor formation of additional hydrogen bond,
hydrophobic bond, ionic/ electrostatic bonds, Van
der Waals forces, and disulfide bridge
HYDROPHOBIC BONDS
• These are formed by the interaction between
nonpolar hydrophobic side chains
SUPER SECONDARY STRUCTURES • Bonds cause nonpolar molecules to adhere to
• Formed by combination of secondary structure another
elements (alpha helices, beta sheets, nonregular ELECTROSTATIC/ IONIC BONDS
sequences) • These are attractive forces between two opposite
• Considered as a structural motif intermediate charges or repulsion between two like charges
between secondary and tertiary structures Type of Charges
• ie helix loop helix motif Charge- Charge Refers to attraction
between oppositely-
TERTIARY STRUCTURE charged amino acids
Charge – Dipole Refers to the interaction
• Refers to the complete 3D structure of polypeptide of ionized R groups with
units of a given protein dipole water
• Denotes how the secondary features assemble to Dipole – Dipole Interaction of R-groups of
form domains and how these domains relate amino acids
spatially to one another
o Domain – section of a protein structure VAN DER WAALS FORCES
sufficient to perform a particular chemical or
• These are weak forces of attraction between polar
and nonpolar molecules therefore molecules should
be nearer
• These forces are the summation of various forms of
energy resulting from momentary random
fluctuation in the distribution of electrons around
any atom which give rise to a transient unequal
distribution of electron or an electric dipole
DISULFIDE BOND
• Covalent bonding between the R-groups of cysteine
amino acids
QUATERNARY STRUCTURE
• Multiple polypeptide chains assembled into
oligomeric proteins
• The stabilizing forces that hold the polypeptide
subunits together are the same forces that are
responsible for tertiary structure stabilization
• Describes the arrangement and position of each of
the subunits in a multiunit protein
“a major force stabilizing the quaternary structure is the
hydrophobic interaction among nonpolar side chains at
the contact regions of the subunits. Additional stabilizing
forces include interactions between side chains of the
subunits, including electrostatic interaction between
ionic groups of opposite charge: hydrogen bonds
between polar groups; and disulfide bonds.”
2 TYPES
• Homo-oligomers – with identical subunits
• Hetero-oligomers – with several distinct subunits
• Eg hemoglobin – with 2 alpha and 2 beta subunits
PROTEIN FOLDING
• Folding is modular and considered as dynamic
process
• Occurs via stepwise process
• Stages:
o First: short segments of newly synthesized
polypeptide fold into secondary structural units
o Second: hydrophobic regions aggregate into
interior of the protein forming a “molten
globule”
• Molten globule
o A partially folded polypeptide in which modules
of secondary structure rearrange until mature
conformation is attained
• Each element of secondary or supersecondary
structure facilities proper folding by directing the
folding process toward the native conformation and
away from unproductive alternatives
• Proteins that assist in folding: protein disulfide
isomerase, proline-cis, trans-isomerase, and
chaperones
• Chaperones
o Binds to short sequences of hydrophobic amino
acids in newly synthesize polypeptides,
shielding from solvent
o Prevent aggregation
o Provide opportunity for formation of
appropriate secondary elements and formation
of molten globules
COMPLEX PROTEINS
GLYCOPROTEINS
• Covalently conjugated
• Present in the surface of RBC, used in blood typing
LIPOPROTEINS
• Associated with lipids which aid in storage and
transport of other lipids
• Eg HDL and LDL
 CLINICAL SIGNIFICANCE
• Collagen
o Most abundant structural protein
o Alterations of collagen due to abnormal
genes or abnormal processing results in
following disorders:
▪ Ehleres- Danlos syndrome
▪ Osteogenic imperfecta
▪ Marfan’s syndrome
• Familial hypercholesterolemia
o Due to genetic defect in gene encoding the
receptor for LDL
• Carcinogenesis
o Basic structure of protein is disrupted by
mutation in their genes