AminoAmino AcidsAcids & & ProteinProtein
Amino AcidsAmino Acids
•What are amino acids?•Structure
•Classification
•Understand pK
•Peptides and Peptide bond
•Examples of related compounds
IntroductionIntroduction
What are amino What are amino acids?acids?
Building Building BlocksBlocks
Amino acidsAmino acids
Building blocks of proteinsBuilding blocks of proteins
20 are present in mammalian 20 are present in mammalian proteins ( standard aa)proteins ( standard aa)
Have amphoteric propertyHave amphoteric property
Amino acid: Basic unit Amino acid: Basic unit of proteinof protein
COO-NH3+ C
R
H
An amino acid
Amino group Carboxylic acid group
Groups attached to α- carbon•a carboxyl group•an amino group•a side chain
ProlineProline imino acidimino acid
– Has a secondary amino groupHas a secondary amino group
Amino acids have primary amino group except?????Amino acids have primary amino group except?????
Asymmetrical Carbon Asymmetrical Carbon Atom ?= optical Atom ?= optical propertiesproperties
Amino acid: Basic unit Amino acid: Basic unit of proteinof protein
COO-NH3+ C
R
H
An amino acid
Amino group Carboxylic acid group
Groups attached to α- carbon•a carboxyl group•an amino group•a side chain
Stereoisomers, Stereoisomers, Enantiomers,Optical Enantiomers,Optical IsomersIsomers
L-amino acids – natural amino L-amino acids – natural amino acids found in proteinacids found in protein
D-amino acids are found in D-amino acids are found in antibiotics (like Gramicidin-S, antibiotics (like Gramicidin-S, Actinomycin-D and Valinomycin) Actinomycin-D and Valinomycin) and in plant and bacterial cell and in plant and bacterial cell walls walls
Glycine an exception- Glycine an exception- no optical no optical activityactivity
Rotate plane polarized light to Rotate plane polarized light to
give levorotatory & dextrorotatory formsgive levorotatory & dextrorotatory forms
Classification of Classification of amino acidsamino acids
Neutral , acidic and basicNeutral , acidic and basic Essential or non essentialEssential or non essential Glucogenic , ketogenic, or bothGlucogenic , ketogenic, or both According to the side chain According to the side chain
propertiesproperties
Classification of Amino Classification of Amino AcidsAcidsaccording to properties according to properties of their side chainof their side chain
Classification on the Classification on the basis of side chainbasis of side chain Non-polarNon-polar
– Side chain does not bind Side chain does not bind or give off protonsor give off protons
– Promote hydrophobic Promote hydrophobic interactioninteraction
– In aqueous solution- In aqueous solution- clustered in the interiorclustered in the interior
– Helps giving a 3-D shapeHelps giving a 3-D shape
Non-Polar Uncharged Non-Polar Uncharged Amino AcidsAmino Acids
Classification on the basis of Classification on the basis of side chain (cont.)side chain (cont.)
PolarPolar– unchargeduncharged– AcidsAcids– BasesBases
HydrophilicHydrophilic
Polar Charged Amino AcidsPolar Charged Amino Acids
Negatively chargedNegatively charged Positively chargedPositively charged
Polar uncharged amino acidsPolar uncharged amino acidsHave zero net charge at neutral pH
Sickle Cell DiseaseSickle Cell Disease
It is a pathology that results from It is a pathology that results from the the
substitution of substitution of polar glutamatepolar glutamate by by the the non-non-
polar valinepolar valine in the B subunit of in the B subunit of hemoglobinhemoglobin
Acidic & Basic Acidic & Basic Properties of Amino Properties of Amino AcidsAcids
Pag
e 65 Acidic carboxylic group
Basic amino group
General structural formula for α-amino acids
Pag
e 65
• It is the ability of an acid to It is the ability of an acid to donate a proton (dissociate)donate a proton (dissociate)
• Also known as pKa or acid Also known as pKa or acid dissociation constantdissociation constant
It is the pH at which 50% of It is the pH at which 50% of the acid is dissociated .the acid is dissociated .
pK ValuepK Value
The pK values of The pK values of αα--carboxyliccarboxylic groupgroup is in the is in the range of 2.2range of 2.2
The pK values of The pK values of an-amino an-amino groupgroup is in the range of is in the range of 9.49.4
RememberRemember The smaller the pK the stronger the acid, the The smaller the pK the stronger the acid, the
larger the pK the weaker the acidlarger the pK the weaker the acid
The maximum buffering capacity occurs at a pH= The maximum buffering capacity occurs at a pH= pKa (a range ± 1)pKa (a range ± 1)
BufferBuffer: is a solution that resists : is a solution that resists change in pH following the change in pH following the addition of an acid or a baseaddition of an acid or a base
It can be created by mixing a It can be created by mixing a weak acid (HA) with its conjugate weak acid (HA) with its conjugate base (Abase (A- - ))
Titration curve of Titration curve of glycineglycine
Pag
e 70
An amino acid can act as both an An amino acid can act as both an acid and a base (has amphoteric acid and a base (has amphoteric property)property)
Zwitter ionsZwitter ions
pI = pH at which the pI = pH at which the molecule is electrically molecule is electrically neutralneutral
At physiological pH, most At physiological pH, most amino acids contain both amino acids contain both positive and negative positive and negative charges with a net charges with a net charge of zerocharge of zero
Some biologically produced Some biologically produced derivatives of “standard” derivatives of “standard”
amino acids and amino acids amino acids and amino acids that are not components of that are not components of
proteinsproteins
Pag
e 77
Gamma amino butyric acid Gamma amino butyric acid (GABA, a derivative of glutamic (GABA, a derivative of glutamic acid) and dopamine (from acid) and dopamine (from tyrosine) are tyrosine) are neurotransmittersneurotransmitters
Histamine (Histidine) is the Histamine (Histidine) is the
mediator of mediator of allergic reactionsallergic reactions
Thyroxine (Tyrosine) is an Thyroxine (Tyrosine) is an
important important thyroid hormonethyroid hormone
PeptidesPeptides
PeptidesPeptides
Amino acids can be Amino acids can be polymerized to form chainspolymerized to form chains
2 a.a. - dipeptide2 a.a. - dipeptide 3a.a. -tripepeptide3a.a. -tripepeptide 4a.a.-tetrapeptide4a.a.-tetrapeptide Few (~ 10)- oligo peptideFew (~ 10)- oligo peptide more- polypeptidemore- polypeptide
Polymers of amino acidsPolymers of amino acids
R1
NH3+
C CO
H
R2
NH C CO
H
R3
NH C CO
H
R2
NH3+
C COOー
H+
R1
NH3+
C COOー
H+
H2OH2O
Peptide bond
Peptide bond
A AFNG
GS T
SD
K
A carboxylic acid condenses with an amino group with the release of a water
Amino acids are joined Amino acids are joined together in a chain by together in a chain by peptide bond [CO–NH peptide bond [CO–NH linkage]linkage]
Known as Known as peptide bondpeptide bond Each amino acid in a chain Each amino acid in a chain
makes two peptide bonds makes two peptide bonds exceptexcept ??? ???
Glutathione (abbreviated GSH) is a tripeptide composed of
glutamate, cysteine and glycine that has numerous important
functions within cells:
a reductant ; is conjugated to drugs to make them more
water soluble;
•a cofactor
•aids in the rearrangement of protein disulfide bonds
Glutathione
Take Home MessageTake Home Message
ProteinsProteins
Protein StructureProtein Structure
•What are proteins?•Four levels of structure (primary, secondary, tertiary, quaternary)•Protein folding and stability•Protein denaturation•Protein misfolding and diseases•Structure-function relationship
What are What are proteins?proteins?
Proteins are polymers of Proteins are polymers of amino acids joined together amino acids joined together by peptide bondsby peptide bonds
Proteins play key roles Proteins play key roles in a living systemin a living system
Three examples of protein Three examples of protein functionsfunctions
– Catalysis:Catalysis:Almost all chemical reactions Almost all chemical reactions in a living cell are catalyzed in a living cell are catalyzed by protein enzymes.by protein enzymes.
– Transport:Transport:Some proteins transports Some proteins transports various substances, such as various substances, such as oxygen, ions, and so on.oxygen, ions, and so on.
– Information transfer:Information transfer:For example, hormones.For example, hormones.
Alcohol dehydrogenase oxidizes alcohols to aldehydes or ketones
Haemoglobin carries oxygen
Insulin controls the amount of sugar in the blood
Close relationship Close relationship between protein structure between protein structure and its functionand its function
enzyme
A
B
A
Binding to A
Digestion of A!
enzyme
Matching the shape to A
Hormone receptor AntibodyExample of enzyme reaction
enzyme
substrates
Hierarchical nature of protein Hierarchical nature of protein structurestructure
Primary structurePrimary structure (Amino acid sequence) (Amino acid sequence)↓↓
Secondary structureSecondary structure (( αα-helix, -helix, ββ-sheet-sheet ))↓↓
Tertiary structureTertiary structure (( Three-dimensional Three-dimensional structure formed by assembly of secondary structure formed by assembly of secondary
structuresstructures ))↓↓
Quaternary structureQuaternary structure (( Structure formed Structure formed by more than one polypeptide chainsby more than one polypeptide chains ))
Proteins are linear Proteins are linear polymers of amino acidspolymers of amino acids
R1
NH3+
C CO
H
R2
NH C CO
H
R3
NH C CO
H
R2
NH3+
C COOー
H+
R1
NH3+
C COOー
H+
H2OH2O
Peptide bond
Peptide bond
The amino acid sequence is called
as primary structure A AF
NGG
S TS
DK
A carboxylic acid condenses with an amino group with the release of a water
Primary StructurePrimary Structure It is the linear sequence of amino acidsIt is the linear sequence of amino acids Many genetic diseases result in Many genetic diseases result in
proteins with abnormal aa sequence, proteins with abnormal aa sequence, which cause improper folding & which cause improper folding & abnormal functioningabnormal functioning
Peptide bond is a covalent bond that is Peptide bond is a covalent bond that is not broken by broken by condition that not broken by broken by condition that denature proteins as heating or high denature proteins as heating or high concentrations of urea.concentrations of urea.
•αα helix is right-handed•It has 3.6 amino acid residues per turn
•Stabilized by hydrogen bonding•Between 1st carboxylic group and 4th amino group
•The side chains point outward and downward from the helix
•The core of the helix is tightly packed
αα helix
b Sheetsb Sheets Usually Two or more polypeptide Usually Two or more polypeptide chains make hydrogen bonding with chains make hydrogen bonding with each othereach other
Also called pleated sheets because Also called pleated sheets because they appear as folded structures with they appear as folded structures with edgesedges
Antiparallel Antiparallel ββ sheets sheets Two or more hydrogen-Two or more hydrogen-
bonded polypeptide chains bonded polypeptide chains run in opposite directionrun in opposite direction
Hydrogen bonding is more Hydrogen bonding is more stablestable
Parallel Parallel ββ sheets sheets Two or more hydrogen-Two or more hydrogen-
bonded polypeptide chains bonded polypeptide chains run in the same directionrun in the same direction
Hydrogen bonding is less Hydrogen bonding is less stable (distorted)stable (distorted)
Other SecondaryOther Secondary StructuresStructures Turns (reverse turns)Turns (reverse turns) LoopsLoops ΒΒ bends bends Random coilsRandom coils
Fibrous ProteinsFibrous Proteins
•Provide mechanical support
•Often assembled into large cables or threads
• a-Keratins: major components of hair and nails
• Collagen: major component of tendons, skin, bones and teeth
Collagen – a triple Collagen – a triple helixhelix
A fibrous proteinA fibrous protein Part of connective tissues: Part of connective tissues:
bone, teeth, cartilage, bone, teeth, cartilage, tendon, skin, blood vesselstendon, skin, blood vessels
Contains three left-handed Contains three left-handed coiled chains coiled chains
Three residues per turn:-Three residues per turn:-Gly-X-Y (X= Gly-X-Y (X= proline,Y=hydroxyproline proline,Y=hydroxyproline or hydroxylysine)or hydroxylysine)
Glycine and Proline in Glycine and Proline in collagencollagen
Rich in glycine & proline a.a.Rich in glycine & proline a.a. Proline facilitates helical Proline facilitates helical
conformation of each conformation of each αα-chain -chain by causing kinksby causing kinks
Glycine , the smallest a.a. fits Glycine , the smallest a.a. fits into the restricted spaces into the restricted spaces where the three chains of the where the three chains of the helix come togetherhelix come together
Non-standard amino acids in Non-standard amino acids in collagencollagen
Proline is converted to Proline is converted to 4-hydroxyprolyl residue 4-hydroxyprolyl residue by by prolyl hydroxylaseprolyl hydroxylase enzyme( it stabilizes enzyme( it stabilizes the triple-helical the triple-helical structure of collagen by structure of collagen by maximaizing interchain maximaizing interchain hydrogen formation).hydrogen formation).
The enzyme The enzyme requires vitamin C requires vitamin C for its functionfor its function
Collagen diseasesCollagen diseases
Scurvy: due to vitamin C Scurvy: due to vitamin C deficiencydeficiency
Super-secondary Super-secondary structures or motifsstructures or motifs
β α ββ α β motif: motif: a helix connects two a helix connects two ββ sheetssheets
ββ hairpin: hairpin: reverse turns connect reverse turns connect antiparallel antiparallel ββ sheets sheets
α αα α motif: motif: two two αα helices together helices together ββ barrels: barrels: rolls of rolls of ββ sheets sheets
β barrels
β α β
β hairpin α α
Crosssover connectionReverse turn/loop
loop
Tertiary StructureTertiary Structure
It is the It is the 3-D structure3-D structure of of an entire polypeptide an entire polypeptide chain including side chain including side chainschains
It includes the folding of It includes the folding of secondary structure (secondary structure (αα helix and helix and ββ sheets) and sheets) and side chainsside chains
The primary structure of The primary structure of apolypeptide chain apolypeptide chain determines its tertiary determines its tertiary structurestructure
Globular proteinsGlobular proteins
•Usually water soluble, compact, roughly spherical
•Hydrophobic interior, hydrophilic surface
•Globular proteins include enzymes, carrier and regulatory proteins
DomainsDomains
Polypeptide chains (>200 amino Polypeptide chains (>200 amino acids) fold into two or more acids) fold into two or more clusters known as domainsclusters known as domains
Domains are functional units Domains are functional units that look like globular proteinsthat look like globular proteins
Domains are parts of protein Domains are parts of protein subunitssubunits
Quaternary StructureQuaternary Structure Many proteins contain two or Many proteins contain two or
more polypeptide chainsmore polypeptide chains Each chain forms a three-Each chain forms a three-
dimensional structure called dimensional structure called subunitsubunit
It is the 3D arrangement of It is the 3D arrangement of different subunits of a proteindifferent subunits of a protein
The subunits may be structurally The subunits may be structurally related or totally unrelated.related or totally unrelated.
Hemoglobin & Hemoglobin & MyoglobinMyoglobin
Both can bind to oxygen Both can bind to oxygen Both are globular proteinsBoth are globular proteins Myoglobin is only formedMyoglobin is only formed
of one subunit? of one subunit? A multisubunit protein is called A multisubunit protein is called
oligomeroligomer Hb is composed of Hb is composed of α α 22 β β 22
subunits (4 subunits)subunits (4 subunits)
Forces that stabilize Forces that stabilize 3ry& 4ry protein 3ry& 4ry protein structurestructure
Hydrophobic effect:Hydrophobic effect:– Nonpolar groups to minimize their contacts Nonpolar groups to minimize their contacts
with waterwith water– Nonpolar side chains are in the interior of a Nonpolar side chains are in the interior of a
proteinprotein Hydrogen bondingHydrogen bonding
– A weak electrostatic bond between one A weak electrostatic bond between one electronegative atom like O or N and a electronegative atom like O or N and a hydrogen atomhydrogen atom
Electrostatic interactions (ion pairing):Electrostatic interactions (ion pairing):– Between positive and negative chargesBetween positive and negative charges
Disulphide Disulphide bonds: covalent bonds which bonds: covalent bonds which prevents proteins from being denatured in prevents proteins from being denatured in the extra cellular enviromentthe extra cellular enviroment
Protein DenaturationProtein Denaturation
Denaturation: Denaturation: A process in which a A process in which a protein looses its native structureprotein looses its native structure
Factors that cause denaturation:Factors that cause denaturation:– Heat: Heat: disrupts hydrogen bondingdisrupts hydrogen bonding– Change in pH: Change in pH: alters ionization states alters ionization states
of aaof aa– Detergents: Detergents: interfere with interfere with
hydrophobic interactionshydrophobic interactions– Chaotropic agents: Chaotropic agents: ions or small ions or small
organic molecules that disrupt organic molecules that disrupt hydrophobic interactionshydrophobic interactions
Protein MisfoldingProtein Misfolding
Every protein must fold to achieve Every protein must fold to achieve its normal conformation and functionits normal conformation and function
Abnormal folding of proteins leads to Abnormal folding of proteins leads to a number of diseases in humansa number of diseases in humans
Alzheimer’s disease:Alzheimer’s disease:– ββ amyloid protein is a misfolded protein amyloid protein is a misfolded protein– It forms fibrous deposits or plaques in It forms fibrous deposits or plaques in
the brains of Alzheimer’s patientsthe brains of Alzheimer’s patients
Creutzfeldt-Jacob or Prion Creutzfeldt-Jacob or Prion disease:disease:
– Prion protein is present in normal brain tissuePrion protein is present in normal brain tissue– In diseased brains, the same protein is In diseased brains, the same protein is
misfolded from a-helix to B-sheetsmisfolded from a-helix to B-sheets– Therefore it forms insoluble fibrous Therefore it forms insoluble fibrous
aggregates that damage brain cellsaggregates that damage brain cells
Take Home MessageTake Home Message
Proteins are key players in our living Proteins are key players in our living systems.systems.
Proteins are polymers consisting of Proteins are polymers consisting of 20 kinds of amino acids.20 kinds of amino acids.
Each protein folds into a unique Each protein folds into a unique three-dimensional structure defined three-dimensional structure defined by its amino acid sequence.by its amino acid sequence.
Protein structure has a hierarchical Protein structure has a hierarchical nature.nature.
Protein structure is closely related Protein structure is closely related to its function.to its function.
Protein misfolding leads to diseasesProtein misfolding leads to diseases
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