Medical Chemistry Lecture: Amino Acids and Peptides PDF

Week 1 Lecture 1 Medical Chemistry Lecture 2025 R Amino Acids and Peptides Csaba Hegedűs (GenMed) Beáta Lontay (Dent)...

Week 1 Lecture 1 Medical Chemistry Lecture 2025 R Amino Acids and Peptides Csaba Hegedűs (GenMed) Beáta Lontay (Dent) Department of Medical Chemistry UD Faculty of Medicine  α-AMINO ACIDS H R Dipolar ion R Functional groups: ‒ primary amino group (NH2) ‒ carboxyl group (COOH) The amino acids differ in the R side chain 2  Standard α-amino acids in proteins Nomenclature: Common names are used Three-letter One-letter Three-letter One-letter Name Name abbreviation symbol abbreviation symbol Alanine Ala A Leucine Leu L Arginine Arg R Lysine Lys K Asparagine Asn N Methionine Met M Aspartic acid Asp D Phenylalanine Phe F Cysteine Cys C Proline Pro P Glutamic acid Glu E Serine Ser S Glutamine Gln Q Threonine Thr T Glycine Gly G Tryptophan Trp W Histidine His H Tyrosine Tyr Y Isoleucine Ile I Valine Val V Memorize the 20 Amino Acids in 9 Minutes https://www.youtube.com/watch?v=PmbcA1acid7s 3  Classification of amino acids by the character of the side chain  nonpolar (hydrophobic)  polar (uncharged)  acidic (negatively charged)  basic (positively charged) 4 Amino acids with nonpolar (hydrophobic) side chains - - - - OOC OOC OOC OOC H3N+ H3N+ C H H3N+ C H H3N+ C H C H C H C H3 C H2 C H2 H C H3 Tryptophan Valine Glicine - OOC HN - H3N+ C H BCAA indole group OOC (branched Phenylalanine H3 N+ C H C H2 chain amino - acids) OOC C H3 C H C H3 H3N+ C H C H3 Alanine C H2 - Leucine - OOC OOC >< Lysine C H2 H3N+ C H Metionine C H S H2N+ C H C H3 C H3 Proline C H2 C H3 Isoleucine  Amino acids with polar (uncharged) side chains - OOC - - - - OOC OOC OOC OOC H3N+ C H H3N+ C H H3 N+ C H N+ H3 C H H3 N+ C H C H2 C H2 C H2 C H2 C H2 C H2 OH SH C O C O N H2 N H2 Serine Cysteine thiol group Asparagine Glutamine OH - OOC Tyrosine H3N+ C H HC OH C H3 Threonine 6 Amino acids with polar (uncharged) side chains Disulfide bond - OOC H3N+ C H C H2 Oxidation disulfide bond Cysteine Reaction Process Reduction 2 Cysteine molecules react, and their thiol groups (-SH) form a disulfide bond (-S-S-) through oxidation. This results in cystine, a more stable dimer with a disulfide linkage. 2C----Oxi----> C + 2e-+ 2H+ Where It Happens This reaction commonly occurs in extracellular environments or within certain cellular compartments (like the endoplasmic reticulum), especially in proteins like keratin or insulin, where disulfide bonds are critical for function and structure. In antioxidant systems, cystine can be reduced back to cysteine to maintain cellular redox balance. 7  Disulfide bonds between Cys residues in ribonuclease A Ribonuclease A (RNase A) with the four disulfide bonds enlarged and highlighted in green 8  Amino acids with acidic (negatively charged) side chains - OOC - - OOC - OOC OOC H3 N+ C H H3 N+ C H H3N+ C H H3 N+ C H C H2 C H2 C H2 C H2 C H2 Asparagine* C O C OO - C H2 Glutamine* - C OO C O N H2 N H2 Aspartate Glutamate 9 *Amino acids with polar (uncharged) side chains  Amino acids with basic (positively charged) side chains - OOC - OOC - OOC The amino group is on the epsilon carbon. H3N+ C H H3N+ C H H3N+ C H C H2 C H2 C H2 C H2 C H2 + HN imidazole C H2 C H2 NH C H2 NH N H3+ C NH Histidine Lysine N H3+ The guanidino group is on the delta carbon. Arginine Amino acid carbons are named in sequence using the Greek alphabet (, , , , ) starting at the 10 carbon between the carboxyl and amino groups.  Histidine and Tryptophan - OOC H3N+ C H Histidine is an imidazole-substituted alanine. C H2 + HN NH Histidine - OOC Tryptophan is an indole-substituted alanine. H3N+ C H C H2 Tryptophan HN  Essential Amino Acids Humans cannot synthesize: phenylalanine, valine, threonine, tryptophan, methionine, leucine, isoleucine, lysine, and histidine. Conditionally essential in the human diet: arginine, cysteine, glycine, glutamine, proline and tyrosine. Humans can synthesize: alanine, aspartate, asparagine, glutamate and serine. 12 Ionization state of amino acids as a function of pH Bronsted acid acid or base Bronsted base cation dipolar ion anion 13  Bronsted acid acid or base Bronsted base 1 2 +NH 3 COOH K a +NH 3 COO-- K a NH 2 COO-- C H C H C H R R R cation kation ikerionion dipolar anion [acid] pK a  pH  log [base] [cation] pK1a  pK COOH  pH  log [dipolar ion] [dipolar ion] pK a2  pK NH2  pH  log [anion] 14  Titration curve of amino acids cation dipolar ion anion In the inflection points: [cation] pK1  pK COOH  pH  log [dipolar ion] [cation]  [dipolar ion] pK1  pK COOH  pH  log 1 [dipolar ion] pK 2  pK NH2  pH  log [anion] pK 2  pK NH2  pH  log 1 Isoelectric point: the pH at which a molecule’s net charge is In the inflection zero (the total amount of the amino acid is in points, the two dipolar ion form) forms are present in almost equal pK COOH  pK NH amounts pI  2 2 15  Acid-base properties of amino acids Some amino acids have ionizable hydrogens on their side chains. pK1  pK R 2.19  4.25 pK 2  pK R 9.17  6.0 pI    3.22 pI    7.59 2 2 2 2  The charge on glutamate varies from +1 to -2, and on histidine varies from +2 to -1, depending on pH  The green arrows point to the pI (net charge on the molecule 16 is zero)  Reactions of the amino acids betain-HCl (gastric juice supplement) Alkylation COO- COO- Alkylation is a chemical process that involves the transfer of an alkyl group (a group of carbon and hydrogen atoms arranged in a chain) from one molecule to another. H3N+ C H (CH3)3N+ C H (CH3)2SO4 H H glycine betaine Reaction with ninhydrin investigators spray the papersheets with ninhydrin 17 ninhydrin-hydrate + amino acid  Reactions of the amino acids Reaction with nitrous acid COOH COOH H2N C H + O N OH HO C H + N2 + H O 2 R R -amino acid + nitrous acid -hydroxy-acid related to CARBONYL GROUP Reaction with oxo compounds (Schiff base formation) COOH COOH R' R' C O + H2N C H C N C H R" R -H2O R" R oxo compound + -amino acid Schiff‘s base 18  Reactions of the amino acids Transamination COO- COO- H3N+ C H C =O R1 R2 -amino acid1 -keto acid2 Transaminases interconvert an amino acid with its transamination corresponding 2-oxoxacid (keto-acid) using the cofactor pyridoxal phosphate COO- COO- C =O H3N+ C H R1 R2 Two transaminases are among the enzymes that provide -keto acid1 -amino acid2 information about the functioning of the liver: GOT (glutamate oxaloacetate transaminase), GPT (glutamate pyruvate transaminase). Elevated serum levels indicate liver damage. 19  Decarboxylation of amino acids Decarboxylation of amino acids refers to the removal of a carboxyl group (COOH) from an amino acid, resulting in the release of carbon dioxide (CO) and the formation of an amine Biologically important amines, neurotransmitters (produced by AA decarboxylation) Examples: Histidine  histamine Tryptophan  serotonin Tyrosine  L-DOPA  dopamine Glutamic acid  gamma-aminobutyric acid (GABA) 20  - OOC H3N+ C H Derivatives of amino acids Tyrosine derived neurotransmitters C H2 OH Tyrosine (3,4-dihydroxy-L-phenylalanine) 21  Derivatives of amino acids - OOC Neurotransmitters derived from tryptophan H2N C H C H2 Tryptophan (Trp) HN Serotonin 5-hydroxy-tryptamine Serotonin has different effects on different organs. In our brain, it performs many control and management functions. Under its influence, anxiety decreases, we react in a balanced way, we are satisfied, H Melatonin IUPAC name Serotonin and melatonin hormones together regulate our N-[2-(5-methoxy-1H-indole-3-yl)ethyl] ethane-amide sleep-wake cycle.  Amino acids in proteins with unusual genetic coding It doesn’t have a unique genetic code in the "64-word" code dictionary, codedby one of the stop codons, UGA. Essential amino acid. (Sec, U) 21st amino acid (eukaryotes, prokaryotes) It has no original genetic code in the 64 "word" code dictionary, it is encoded by another stop codon, UAG. Found in only a few species of methanogenic archaea. Pyrrolysine (Pyl, O) 22nd amino acid (in some prokaryotes)  Non-standard (modified) amino acids Modifications take place on normal amino acids, after the synthesis of proteins (post-translationally), with the help of enzymes Most of them are reversible Modifications usually have a signaling role  Non-standard amino acids NOT found in proteins -alanine β α Animals require pantothenic acid to synthesize coenzyme-A (CoA), as well as to synthesize and metabolize proteins, carbohydrates, and fats. Carnosine (-alanyl-L-histidine) Pantothenic acid, vitamin B5 -alanine is involved in the formation of carnosine and pantothenic acid (vitamin B5). Beta-alanine plays a role in balancing the production and breakdown of lactic acid, by regulating 25 the carnosine level. Non-standard amino acids NOT found in proteins Ornithine has one less  methylene group than lysine. Ornithine is an intermediate in biosynthesis of polyamines. O H2 H2N  C C GABA is an inhibitory C C OH neurotransmitter. H2 H2 -aminobutyric acid, GABA Formed by the decarboxylation of glutamic acid 26 Optical isomerism of amino acids enantiomer and mirror THE CONFIGURATION OF THE AMINO ACIDS IN THE PROTEINS: L Except glycine, all amino acids have asymmetric (chiral) carbon so they are optically active. Optical isomers of alanine Relative configuration, D-L system: The structure of the optically active biomolecules is compared to the enantiomers of glyceraldehyde In the case of amino acids, the position of the amino group is compared to the OH group of glyceraldehyde. L-glyceraldehide D-glyceraldehide L-alanine D-alanine 27 L-alanine Optical isomerism of amino acids Amino acids with two chiral carbons COOH COOH COOH Relative configuration, D-L system: H2N C* H H C* NH2 H2N C* H H C* OH HO C* H C* The structure of the optically active biomolecules is H CH3 compared to the enantiomers of glyceraldehyde CH3 CH3 C2H5 In the case of amino acids, the position of the amino L-threonine L-Thr D-threonine D-Thr L-isoleucine L-Ile group is compared to the OH group of glyceraldehyde. COOH COOH H2N C* H H C* NH2 THE CONFIGURATION OF THE AMINO OH C* H H C* HO ACIDS IN THE PROTEINS: L CH3 CH3 L-allo-threonine L-allo-Thr D-allo-threonine D-allo-Thr 28 The Peptide Bond An amide bond links the amino group of one α-amino acid and the carboxyl group of another. An amide bond of this type is referred to as a peptide bond. 29  The peptide bond is characterized by a planar geometry X-ray diffraction studies of crystals of small peptides by Pauling and Corey indicated that the peptide bond is rigid, and planar. Pauling pointed out that this is a consequence of the resonance interaction of the amide, or the ability of the amide nitrogen to delocalize its lone pair of electrons onto the carbonyl oxygen. Because of this resonance, the C=O bond is actually longer than normal carbonyl bond, and the N–C bond of the peptide bond is shorter than the N–Cα bond. Notice that the carbonyl oxygen and amide hydrogen are in a trans configuration. Resonance structures of the peptide bond: H H C N C N C C C C O O 30  The Backbone of a Polypeptide Chain Rotation is permitted about the N-C (phi, ) and C-C (psi, ) bonds in the peptide backbone. Thus, the backbone of a polypeptide chain can be pictured as a series of rigid planes with consecutive planes sharing a common point of rotation at C. The rigid peptide bonds limit the range of conformations possible for a polypeptide chain. Note that the peptide bond occurs in a trans configuration 99.6 % of the time. Cis peptide bonds are very rare (eg. proline-rich sequences). amino acid amino acid amino acid residue residue residue  Peptides and proteins Peptides and proteins consist of amino acids connected by peptide bonds. Peptide: a short chain of amino acids, typically between 2 and 50 amino acids in length. Peptides are classified based on the number of amino acids. Protein: polypeptide chains of at least 50, but usually more than 100 amino acids. They can consist of one or more peptide subunits. 32  Peptides and proteins Amino acid units in a peptide are called residues Amino acid sequence (primary structure): N-terminal amino acid→ C-terminal amino acid Amino Ser Gly Tyr Ala Leu Carboxy terminal terminal end end A pentapeptide: Ser-Gly-Tyr-Ala-Leu or SGYAL 33  Naturally Occuring Peptides Glutathione, a reducing agent γ-L-glutamyl-L-cysteinyl-glycine Inactivates reactive oxidizing species, ROS (peroxides, free radicals): 2 GSH + R2O2 → GSSG + 2 ROH (R = H, alkyl) 2 GSH + 2 R˙ → GSSG + 2 RH  Naturally Occuring Peptides Enkephalins are pentapeptides Enkephalins are ligands of opioid receptors. EXTRACELLULAR ENKEPHALIN LEVELS SURGED WHEN RATS BEGAN TO EAT MILK CHOCOLATE M&MS. THE MAGNITUDE OF THE ENKEPHALIN INCREASE IN INDIVIDUALS CORRELATED WITH THEIR LATENCY TO EAT THEIR FIRST M&M: HIGHER ENKEPHALIN INCREASE FOR THE FASTEST EATERS. 35  Naturally Occuring Peptides Peptide Hormones Bradykinin modulates inflammation of tissues. Vasopressin regulates the body’s retention of water; it is released in response to stress. Oxytocin induces labor and stimulates milk production.  Naturally Occuring Peptides Oxytocin, a cyclic nonapeptide Oxytocin is is involved in childbirth and breast-feeding. It is also associated with empathy, trust, sexual activity, and relationship-building. The two main actions of oxytocin in the body are contraction of the womb (uterus) during childbirth and lactation. Oxytocin stimulates the uterine muscles to contract and also increases production of prostaglandins, which increase the contractions further. During breastfeeding, oxytocin promotes Instead of having its amino acids the movement of milk through the ducts in the breast. linked in an extended chain, two cysteine residues are joined by an S—S bond→disulfide bridge.  Naturally Occuring Peptides Insulin Insulin processing two interchain disulfide bridges one intrachain disulfide bridge