Amino acidsPeptides

Medical ChemistryLecture 13 2007 (J.S.)

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Amino acidsThe name "amino acid" can be used for any compound that containsboth carboxyl (or other acidic group) and an amino group. Over several hundred different amino acids in such a general meaningoccur in nature.

In biological sciences, the term "amino acid" is used predominantly for.

20 standard (also proteinogenic or coded) amino acidsfrom which the polypeptide chains of proteins are built up on ribosomes.

All twenty standard amino acids are α-amino acids and have L-configuration (according to Fischer convention) at the α-carbon that corresponds to 2S configuration (according to R/S system).

(2S)-configurationof L-amino acids

≡

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Quite formally, standard amino acids may be classified according to their structureas

aliphatic – monocarboxylic - with one amino group - with two basic groups,

– dicarboxylic,

aromatic, and

heterocyclic.

Classification according to the polarity of the side chains

Side chains of amino acids determine secondary and tertiarystructure of proteins as well as all other properties of proteins:

Amino acids (at physiological pH values) with

non-polar side chains

polar – unionized side chains (without an electric charge)

– positively charged side chains of "basic" amino acids

– negatively charged side chains of "acidic" amino acids

Standard amino acids

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CH2–CH2–CH–COOH

CH3–S NH2

CH

CH3 CH3

CH–NH2

COOH

CH

CH3 CH3

CH–NH2

COOH

CH2

CH–NH2

COOH

CH3

CH

CH3CH2

Val Leu Ile

H3C–CH–COOH

NH2

H–CH–COOH

NH2

Gly Ala

Amino acidswith non-polar side chains

Phe Trp

Met

Pro

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Amino acidswith polar – unionized side chains

OH

Tyr

CH2–CH–COOH

OH NH2

Ser

CH3–CH2–CH–COOH

OH NH2

Thr

CH2–CH–COOH

SH NH2

Cys

H2N-CO–CH2–CH–COOH

NH2

Asn

H2N-CO–CH2–CH2–CH–COOH

NH2

Gln

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Acidic amino acids

At physiological pH values, there is a negative electric charge(carboxylate anion) in the side chain:

HOOC–CH2–CH–COOH

NH2

Asp

HOOC–CH2–CH2–CH–COOH

NH2

Glu

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Basic amino acidsAt physiological pH values, there is a positive electric charge(imidazolium, ammonium, guanidinium cation) in the side chain:

CH2–CH2–CH2–CH2–CH–COOH

NH2NH2

Lys

NHC

H2N

NH

NH2

CH2–CH2–CH2–CH–COOH

Arg

N

NH

CH2–CH–COOH

NH2

His

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Non-standard amino acids– components of peptides or proteins (products of posttranslational processing of proteins)

Examples:4-hydroxyproline and 3-hydroxyproline5-hydroxylysineallysine, lysinonorleucine, desmosine or isodesmosine

-carboxyglutamic acidpyroglutamic acid (5-oxoproline)

methylated Lys, His, Argacetylated Lys, Ser, ArgN-formyl Metphosphorylated Ser, Thr, Tyr

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Non-standard amino acids– that occur as free derivatives of standard amino acids (and are not components of proteins)

Examples:-alanine (decarboxylated aspartic acid)-aminobutyric acid (GABA, decarboxylated glutamic acid)

homocysteine, homoserine, S-adenosylmethionine (from Met)

ornithine, citrulline (from arginine)

5-hydroxytryptophan (from tryptophan)

dihydroxyphenylalanine (DOPA), thyronines (from tyrosine)

taurine (from cysteine)

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Ionization of amino acids

Amino acids are amphoteric – they are ampholytes with independentionization of their ionizable groups.

The degree of ionization of all ionizable groups is determined by thepH value of the environment and by the pKA value of the particular groupwithout any respect to the degree of ionization of the other ionizable groups.

Although amino acid are sometimes drawn as compounds with undissociated carboxyls –COOH and unprotonized amino groups –NH2, it is a high degree of simplification – those uncharged structures don´t exist.

In solutions at physiological pH values, amino acids with one amino group and one carboxyl ("neutral" amino acids) exist as dipolar compounds – amphions.

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Ionization of amino acids depends on the pH value of their solutions

Percentage of particles present100 %

50 %

00 2 4 6 8 10 12 14 pH

of the solution pK1 pK2pK3

pIisoelectric point

–NH2–NH3+–COOH –COO–

Net charge: 1 + 0 1 – 2 –

For example, glutamic acid:

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Names of aminoacyl residuesand three- and one-letter abbreviations

Gly glycyl G Asp aspartyl D

Ala alanyl A Asn asparaginyl N

Val valyl V Glu glutamyl E

Leu leucyl L Gln glutaminyl Q

Ile isoleucyl I Lys lysyl K

Pro prolyl P Arg arginyl R

Ser seryl S His histidyl H

Thr threonyl T Phe phenylalanyl F

Cys cysteinyl C Tyr tyrosyl Y

Met methionyl M Trp tryptophyl W

Peptides

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PeptidesPeptides are amides, in which amino acids are joined inlinear chains: the α-carboxylate groups of amino acids form amides with the α-amino groups of other amino acids or peptides. The resulting amide bond is called a peptide bond.

The terms dipeptide, tripeptide, oligopeptide, and polypeptide indicate the number of aminoacyl residues in the chain

(not the number of peptide bonds).

By convention, peptide structures are written with the residue with a free α-amino group (the amino terminal residue) at the left to the carboxyl terminal residue at the right.

The sequence of amino acyl residues representsthe primary structure of a peptide.

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The most simple peptides are dipeptides:

H2N–CH–CO–NH–CH–COOH

R R

the NH2-endthe amino end

the COOH-endthe carboxyl endpeptide bond

Nomenclature of peptidesPeptides are taken as N-aminoacyl derivatives of amino acidsor peptides.

E.g., glycyl-alanine and alanyl-glycine are two different peptides:

H2N–CH2–CO–NH–CH–COOH

CH3

H2N–CH–CO–NH–CH2–COOH

CH3

Gly-Ala Ala-Gly

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Main chains of peptidesas well as of proteins (called peptide backbones) consist ofregularly alternating sequences of atoms –N–Cα–C– :

Amino terminal residue

Carboxyl terminal residue

the 2nd residue

Side chains – groups or chains attached to the α-carbons.

Direction of the sequenceof a polypeptide chain

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Peptide bond –CO-NH–

Similarly to other amides, the peptide group –CO-NH– has a rigid planar structure, all four atoms are coplanar.

The peptide bond is a resonance hybrid of two extreme structures.The π-electrons of the C=O bond are shared by three atoms, so thatthe bond C–N exhibits a partial (about 40%) double-bond character.

Therefore, the nitrogen atom in –CO-NH–is not a basic one (as in other amides) andthere is no free rotation round the C–N bond.

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In most peptides and proteins, peptide bonds havetrans-configuration, the H atom occupies trans-position to the oxygen atom.

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CN C

NC

O

H O

H

CC

R H R H

H R

ααα

The peptide main chain can take various conformationsdue to rotation of peptide-bond planes

round the bonds Cα–N and Cα–CO.

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For example, torsion angle describes rotation round the N–C bond

Torsion angles

CNH

CcarbonylCO

Torsion angle – rotation round the C–Ccarbonyl bond

Torsion angle – free rotation round the Ccarbonyl–N is not possible, either trans-peptide bond = 180°, or rare cis-peptide bond = 0°

= + 60° = – 120°

Any conformation can be described by the torsion angles , , and :

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Glutathione (reduced form)-glutamyl cysteinyl glycine, -Glu-Cys-Gly

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Examples of peptides of biological importance:The numbers of amino acyl residues are in parentheses.

Gastrointestinal peptidesgastrin (17), secretin (27), cholecystokinin-pancreozymin (33)

Vasoactive peptidesVIP (28), angiotensin II (8), bradykinin (9),endothelin (21), Arg8-vasopressin (ADH, 9)

Hormonescalcitonin (32), glucagon (29), somatostatin (14),thyroliberin (TRH, 3), adrenocorticotropin (ACTH, 39),atrial natriuretic peptide (28)

Neuropeptidesβ-endorphin (31), Leu-enkephalin (5), substance P (11)

Toxinsamatoxins (8), phallotoxins (7), mellitin (26)

Antibioticsbacitracin (16), actinomycin D (10), valinomycin (6),

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α-Amanitine(Amanita phalloides, the deathcap)

Arg8-vasopressin(antidiuretic hormone, ADH)

Oxytocincauses contraction of smooth muscles,used in obstetrics to induce parturition

Thyroliberin (TRH)pyroglutamyl histidyl prolinamide

Aspartamsynthetic methyl ester of aspartyl-

phenylalanine, an artificial sweetener

Phalloidin