Structure and Function of Proteins PDF

06 November 2024 Structure and Function of Proteins MDP 10108 Dr. Majed A. K. Al-Mansoub Foundation, Year 1 Department of Basic Medical Sciences Biochemistry FMHS, UNIMAS  Content 1. General structure of amino acids 2. Characteriz...

06 November 2024 Structure and Function of Proteins MDP 10108 Dr. Majed A. K. Al-Mansoub Foundation, Year 1 Department of Basic Medical Sciences Biochemistry FMHS, UNIMAS  Content 1. General structure of amino acids 2. Characterizations of amino acids: based on the R-group according to incorporation into proteins if nutritionally essential or not 3. Physical and chemical properties of amino acids 4. Characteristics of peptide bonds 5. Primary, secondary, tertiary and quaternary protein structures 6. Complex and derived proteins 7. Functions of proteins 8. Examples of Medically Important Proteins  Proteins Most abundant macromolecules in living cells. Consist of linear sequences of amino acids linked together by peptide bonds. Each protein consist of a unique and specific sequence of amino acids (AAs) Have a variety of functions in living organisms Proteins can be converted into carbohydrates through gluconeogenesis. Body cannot store proteins/amino acid Amino Acids o All peptides and polypeptides α-carbon are polymers of α-amino acids o Consist of 2 functional groups: amino (NH2) and carboxyl group (COOH) Amino group o R group (side chain) distinguish Carboxyl group the various AAs and determines its unique structure and R- group or side chain properties - Aliphatic - Hydroxyl What are the exceptions to the above structural rule? - Sulphur containing - Acid Glycine Proline - Basic - Aromatic - Imino  Classification of Amino Acids Amino acids can be classified: 1. Based on the structure/ R-group 2. If they are proteinogenic or non-proteinogenic 3. Based on nutritional requirements (essential/non-essential) 4. Based on metabolic fate (ketogenic, glucogenic or both) Note: Non-proteinogenic amino acids can have various roles in biological processes, and they are often involved in specialized metabolic pathways or serve as building blocks for non-standard proteins and molecules. Some examples of non-proteinogenic amino acids include selenocysteine (Sec) (not present in all proteins) and pyrrolysine (Pyl), which are occasionally incorporated into proteins through specialized mechanisms, and various amino acids found in non-standard proteins or non-protein molecules. 1. Classification of Amino Acids based on structure (R group) NONPOLAR SIDE CHAINS UNCHARGED POLAR SIDE CHAINS ACIDIC SIDE CHAINS Glutamic acid BASIC SIDE CHAINS 2. Proteinogenic Amino Acids Amino Acid 3-Letter 1-Letter Symbol Abbreviation Alanine Ala A Proteinogenic amino acids are Arginine Arg R amino acids that are Aspartic Acid Asp D incorporated biosynthetically into Asparagine Asn N Cysteine Cys C proteins during translation Glutamine Gln Q Humans have 21 proteinogenic Selenocysteine Glutamic acid Glu E amino acids Glycine Gly G Histidine His H whereby only 20 AAs are encoded Isoleucine Ile I by the standard universal genetic Leucine Leu L code. Lysine Lys K Selenocysteine is less prevalent and Methionine Met M not present in all proteins and Phenylalanine Phe F incorporated into proteins during Proline Pro P translation via special mechanisms Serine Ser S by encoded UGA codon. Threonine Thr T Note: Pyrrolysine is not present in Tryptophan Trp W humans but found in certain Tyrosine Tyr Y archaeal and bacterial species and Valine Val V encoded by UAG codon. pyrrolysine 3. Essential and Nonessential Amino Acids aThese amino acids are called “non-essential” or “dispensable,” terms that refer to dietary requirements. Of course, within the body, they are necessary. We cannot survive without them. bAlthough the carbons of cysteine can be derived from glucose, its sulfur is obtained from the essential amino acid methionine. cArginine is not required by the adult but is required for growth. 4. Classification of Amino Acids based on Metabolic Fate Amino acids can be classified as being “glucogenic” or “ketogenic” based on the type of intermediates that are formed during their breakdown or catabolism. The catabolism of glucogenic amino acids produces either pyruvate or one of the intermediates in the Krebs Cycle. The catabolism of ketogenic amino acids produces acetyl CoA or acetoacetyl CoA i. Both glucogenic and ketogenic amino acids: Isoleucine, Tyrosine, Phenylalanine and Tryptophan ii. Purely Ketogenic amino acids: Leucine and Lysine iii. Purely Glucogenic amino acids: Alanine, valine, serine, threonine, glycine, methionine, Cystine is the oxidized dimer asparagine, glutamine, cysteine, cystine, aspartic acid, glutamic form of the amino acid acid, histidine and arginine. cysteine Optical Properties of Amino Acids An α-carbon atom with 4 different chemical groups is said Mirror plane to be chiral or optically active atom. Chirality is the ability of a molecule to rotate the plane of Polarized light either to the right (dextrorotatory) or to the left (levorotatory). All proteinogenic AAs exist in the L configuration D-amino acids can’t be utilized by the digestion system and Which amino acid is not optically active although some of them are even harmful it has a D and L? however, they are often found Glycine in polypetide antibiotics Acid/Base Behaviour of Amino Acids The carboxyl group is a weak acid and can be deprotonated (depending on the pH of the solution) amphoteric The amino group is a weak base and can be protonated (depending on the pH of the solution) Because amino acids can carry a positive and a negative charge at the same time Zwitterion Depending on the pH of the solution Chemical properties of Amino Acids The chemical properties of amino acids are due to the Some examples for chemical reactions ✓ Carboxyl group ✓ Amino group ✓ Side chain or R group ✓ Both amino and carboxyl group 1. Disulphide bond (S-S bridge) 2. Formation of a peptide bond Characteristics of peptide bonds The atoms involved in the peptide bond form a rigid, planar unit Because of its partial double bond character (C-N), the peptide bond itself has no freedom of rotation However, the other bonds of the α-carbon can rotate freely Peptide bonds are extremely stable (proteolytic enzymes are required for cleavage) the other bonds of the α-carbon can rotate freely Examples of naturally occurring peptides Glutathione: helps to maintain thiol status of proteins (antioxidant properties). (gamma -glu-cys-gly) Vasopressin or ADH (increases blood pressure by water reabsorption in distal renal tubules). Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH2 Oxytocin (stimulates uterine smooth muscle contraction accelerating birth). Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Arg-Gly-NH2  Protein Structures Primary structure: linear sequence of amino acids Secondary structure: regular folding of the amino acids sequence Tertiary structure: three-dimensional arrangement of all amino acids Quaternary structure: the protein is made of more than one polypeptide chain. Primary Structure of Proteins ⚫The primary structure of proteins consists out of a polypeptide chain Many amino acids joined by peptide bonds form a polypeptide chain Also sometimes called: “backbone” Polypeptide chain Residue Peptide bond Peptide bond Peptide bond Polypeptide chains have directions Example: Insulin The primary structure of insulin is its specific sequence of amino acids. For example, human insulin consists of two chains (A and B) linked by disulfide bonds, with Chain A having 21 amino acids and Chain B having 30 amino acids. The exact order of amino acids in these chains determines insulin's Tyr-Gly-Gly-Phe-Leu differs chemically from Leu-Phe-Gly-Gly-Tyr specific properties and function. Polypeptide Chain/s Can Fold to Secondary (2°) Structure There are 3 main types of 2° structure: 1. -helix 2. -sheet 3. loops and turns Examples: Alpha-helix in Keratin Beta-sheet in Silk Fibroin Antibody Binding Site Loops Beta-Turns in Ribonuclease A  α-Helix structure ▪ In an alpha-helix, each carbonyl oxygen (C=O) forms a hydrogen bond with the amide hydrogen (N-H) four residues down the chain, stabilizing the helical structure. ▪ The alpha-helix structure has 3.6 amino acid residues/turn of the helix. This means that after every 3.6 residues, the helix completes one full 360° turn.  β- Pleated Sheets are formed by hydrogen bonds between two extended polypeptide chains Hydrogen bond is formed between N-H group and C=O group in different polypeptide strands The polypeptide chains may run parallel or antiparallel NOTE – nice to know Super-secondary structures Example: zinc finger structure Some proteins contain an ordered organization of secondary structures (combination of α helix and β-sheet) that form distinct functional domains or structural motifs. Loops and turns are formed when a polypeptide needs to change direction loops do not have regular, periodic structure Tertiary structure of proteins Tertiary structure refers to the complete three-dimensional structure of the folded polypeptide chain It is produced by non-covalent interaction of amino acid residues that may be far from each other Note! Disulphide bridges are covalent bonds between the SH groups found in amino acids Consequences of folding? formation of functional units or domains: In enzymes the folding of the secondary structures leads to formation of catalytic center also called active site Globular proteins tend to have a hydrophobic core while the hydrophilic groups are on the outside of the protein In general; the tertiary structure makes a protein functionally active  Tertiary Structure Stabilizing Forces The tertiary structure of a protein is stabilized by: Hydrogen bonds van der Waals interaction Hydrophobic interactions Ionic interactions Disulphide linkages/bridges ** An example of a tertiary structure is myoglobin, a protein that stores and transports oxygen in muscle cells Question: Does the tertiary structure form spontaneously or is there help? Answer: Occurs spontaneously But aided by chaperone proteins (chaperonin) an ideal environment for folding is also required What about the quaternary structure? Many proteins contain 2 or more different polypeptide chains held together by the same non-covalent forces that stabilize the tertiary structures Proteins with multiple polypeptide chains are oligomeric proteins and the structure of these protein is called the quaternary structure. Example: Haemoglobin Other examples for proteins with a quaternary structure? 1. Glycolytic enzymes Aldolase LDH Pyruvate dehydrogenase 2. Creatine kinase 3. Alkaline phosphatase  Complex or derived proteins Proteins can be modified post-translationally e.g. they are conjugated with carbohydrates or lipids Conjugated Protein Conjugant Protein Haemoglobin Haem Globin Lipoprotein Lipid Protein Glycoprotein Carbohydrate Protein Nucleoprotein Nucleic Acid Protein Metalloprotein Metal Ions (Fe, Cu) Protein Phosphoprotein Phosphorus Protein Chromoprotein Coloured Ligands Protein  Functions of proteins Important to synthesize vital body structures (half of the body protein is made up of collagen, actin and myosin and haemoglobin). Maintain fluid balance Help to maintain acid-base balance Act as hormones and enzymes Contributes to the immune system Form glucose Provide energy Examples of Medically Important Proteins Haemoglobin Globular protein important for oxygen and CO2 transport Consist of polypeptide chains (2 α and 2 β chains), each containing a molecule of heme Heme, a complex of a porphyrin ring and a Fe2+ ion Myoglobin - is also a hemoprotein - But has only 1 polypeptide chain - exists in muscle (skeletal and cardiac) - storage of oxygen Examples of Medically Important Proteins Collagen Refers to a group of closely related proteins found in the extracellular matrix, the vitreous humor of the eye, and bone and cartilage Consists of tree intertwining polypeptide chains The most dominant amino acid in collagen is glycine (1/3 of all AAs) followed by proline, hydroxyproline and hydroxylysine Aggregation of collagen into long fiber: tough and tensile strength X – proline Y – hydroxyproline or hydroxylysine Examples of Medically Important Proteins Insulin A polypeptide hormone produced by the β cells of the pancreas The mature form has 51 AA in two polypeptide chains which are linked by 2 disulfide bridges regulates the metabolism of carbohydrates, fats and protein by promoting the absorption Acknowledgement to Prof. Dr. Gabriele R. A. Frömming