1. Amino acids Peptides Medical Chemistry Lecture 13 2007 (J.S.)

2. Amino acids The name "amino acid" can be used for any compound that contains both carboxyl (or other acidic group) and an amino group. Over several hundred different amino acids in such a general meaning occur in nature. In biological sciences, the term "amino acid" is used predominantly for. 20 standard (also proteinogenic or coded ) amino acids from 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 2 S configuration (according to R / S system). (2 S )-configuration of L- amino acids ≡

4. CH 2 –CH 2 –CH–COOH CH 3 – S NH 2 CH CH 3 CH 3 CH – NH 2 COOH CH CH 3 CH 3 CH – NH 2 COOH CH 2 CH – NH 2 COOH CH 3 CH CH 3 CH 2 Val Leu Ile H 3 C–CH–COOH NH 2 H–CH–COOH NH 2 Gly Ala Amino acids with non-polar side chains Phe Trp Met Pro

5. Amino acids with polar – unionized side chains OH Tyr CH 2 –CH–COOH OH NH 2 Ser CH 3 –CH 2 –CH–COOH OH NH 2 Thr CH 2 –CH–COOH SH NH 2 Cys H 2 N-CO –CH 2 –CH–COOH NH 2 Asn H 2 N-CO –CH 2 –CH 2 –CH–COOH NH 2 Gln

6. Acidic amino acids At physiological pH values, there is a negative electric charge (carboxylate anion) in the side chain: HOOC–CH 2 –CH–COOH NH 2 Asp HOOC–CH 2 –CH 2 –CH–COOH NH 2 Glu

7. Basic amino acids At physiological pH values, there is a positive electric charge (imidazolium, ammonium, guanidinium cation) in the side chain: CH 2 –CH 2 –CH 2 – CH 2 – CH – COOH NH 2 NH 2 Lys NH C H 2 N NH NH 2 CH 2 –CH 2 –CH 2 –CH–COOH Arg N N H CH 2 – CH – COOH NH 2 His

8. Non-standard amino acids – components of peptides or proteins ( products of posttranslational processing of proteins ) Examples: 4-hydroxyproline and 3-hydroxyproline 5-hydroxylysine allysine, lysinonorleucine, desmosine or isodesmosine  -carboxyglutamic acid pyroglutamic acid (5-oxoproline) methylated Lys, His, Arg acetylated Lys, Ser, Arg N -formyl Met phosphorylated Ser, Thr, Tyr

9. 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)

10. Ionization of amino acids Amino acids are amphoteric – they are ampholytes with independent ionization of their ionizable groups. The degree of ionization of all ionizable groups is determined by the pH value of the environment and by the p K A value of the particular group without 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 –NH 2 , 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.

11. Ionization of amino acids depends on the pH value of their solutions Percentage of particles present 100 % 50 % 0 0 2 4 6 8 10 12 14 pH of the solution p K 1 p K 2 p K 3 p I isoelectric point – NH 2 – NH 3 + – COOH – COO – Net charge : 1 + 0 1 – 2 – For example, glutamic acid :

14. Names of aminoacyl residues and three- and one-letter abbreviations

15. Peptides

16. Peptides 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 represents the primary structure of a peptide. Peptides are amides , in which amino acids are joined in linear 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 .

17. The most simple peptides are dipeptides : H 2 N –CH– CO–NH –CH– COOH R R the NH 2 -end the amino end the COOH-end the carboxyl end peptide bond Nomenclature of peptides Peptides are taken as N -aminoacyl derivatives of amino acids or peptides. E.g. , glycyl- alanine and alanyl- glycine are two different peptides: H 2 N–CH 2 –CO–NH–CH–COOH CH 3 H 2 N–CH–CO–NH–CH 2 –COOH CH 3 Gly-Ala Ala-Gly

18. Main chains of peptides as well as of proteins (called peptide backbones) consist of regularly alternating sequences of atoms –N–C α –C– : Amino terminal residue Carboxyl terminal residue the 2 nd residue Side chains – groups or chains attached to the α-carbons. Direction of the sequence of a polypeptide chain

19. 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 that the 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) and there is no free rotation round the C–N bond .

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

21. The peptide main chain can take various conformations due to rotation of peptide-bond planes round the bonds C α –N and C α –CO. C N C N C O H O H C C R H R H H R α α α

22. For example, torsion angle  describes rotation round the N–C  bond Torsion angles C  N H C carbonyl C O Torsion angle  – rotation round the C  –C carbonyl bond Torsion angle  – free rotation round the C carbonyl –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  :    

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

24. Examples of peptides of biological importance: The numbers of amino acyl residues are in parentheses. Gastrointestinal peptides gastrin (17) , secretin (27) , cholecystokinin-pancreozymin (33) Vasoactive peptides VIP (28) , angiotensin II (8) , bradykinin (9) , endothelin (21) , Arg 8 - vasopressin (ADH, 9 ) Hormones calcitonin (32) , glucagon (29) , somatostatin (14) , thyroliberin (TRH, 3 ), adrenocorticotropin (ACTH, 39 ), atrial natriuretic peptide (28) Neuropeptides β- endorphin (31) , Leu- enkephalin (5) , substance P (11) Toxins amatoxins (8), phallotoxins (7), mellitin (26) Antibiotics bacitracin (16), actinomycin D (10), valinomycin (6),

25. α - Amanitine ( Amanita phalloides , the deathcap) Arg 8 - vasopressin (antidiuretic hormone, ADH) Oxytocin causes contraction of smooth muscles, used in obstetrics to induce parturition Thyroliberin (TRH) pyroglutamyl histidyl prolinamide Aspartam synthetic methyl ester of aspartyl- phenylalanine, an artificial sweetener Phalloidin