Alpha-Amino Acids & Ketogenic Amino Acids

• Amino acids are the building blocks of proteins

• Amino acids have a carboxyl group (-COOH), an amino group (-NH2), a hydrogen atom (-H), and a unique side chain (R group)

• Alpha-amino acids are the most important, with amino and carboxyl groups attached to the alpha-carbon

• There are over 300 amino acids in nature, but only 20 are essential for making proteins

• Some amino acids have their amino and carboxyl groups on different carbons

Classification of Amino Acids

• Amino acids can be classified based on chemical structure, nutritional or biological function, and metabolic fate

Classification I - Chemical Structure

• Chemical structure classification is based upon the amino acid side chain
• Nonpolar, Aliphatic amino acids include Glycine, Alanine, Valine, Leucine, and Isoleucine
• Aromatic Amino Acids include Phenylalanine, Tryptophan (essential), and Tyrosine (non-essential)
• Sulfur-containing amino acids are Methionine and Cysteine
• Methionine is one of the essential amino acids
• Hydroxyl-containing amino acids are Serine and Threonine, Threonine is an essential amino acid
• Acidic amino acids are Aspartate and Glutamate, they are non-essential amino acids
• Amidic amino acids are Asparagine and Glutamine, they are non-essential amino acids
• Basic amino acids are Arginine, Lysine, and Histidine, they are all charged and essential amino acids
• The imino acid is Proline; it is non-essential

Classification II - Nutritional or Biological Function

• Nutritional or biological function classification is based depending on whether the amino acids can be synthesized in the body
• Essential Amino Acids: Cannot be synthesized by the body and must be obtained from the diet, including Phenylalanine, Valine, Threonine, Tryptophan, Isoleucine, Methionine, Histidine, Arginine, Lysine, and Leucine
• Non-Essential Amino Acids: Can be synthesized by the body and are not essential in the diet, including Glycine, Cysteine, Alanine, Tyrosine, Serine, Glutamine, Asparagine, Spartate and Glutamate
• Semi-Essential Amino Acid: Essential during periods of growth, stress, or illness, including Arginine

Classification III - Metabolic Fate

• Metabolic fate classification is based upon the fate of amino acid inside the body
• Ketogenic Amino Acids: Amino acids that can be converted into ketone bodies, including Leucine and Lysine
• Glucogenic Amino Acids: Amino acids that can be converted into glucose
• Mixed Amino Acids: Amino acids that can be converted into both glucose and ketone bodies, including Phenylalanine, Isoleucine, Tyrosine, and Tryptophan

Uncommon Amino Acids

• Uncommon amino acids are, not one of the 20 fundamental amino acids, and are derived from post-translational modifications or unique synthesis processes

• They are important, because they play critical roles in protein function, structure, and biochemical pathways.

• 4-Hydroxyproline; Derived from Proline; Stabilizes collagen structure; Found in collagen

• 5-Hydroxylysine; Derived from Lysine; involved in collagen cross-linking; Found in collagen

• 6-N-Methyllysine; Derived from Lysine; Component of contractile proteins; Found in myosin

• γ-Carboxyglutamate; Derived from Glutamate; Binds calcium in blood clotting proteins; Found in prothrombin (clotting factor)

• Selenocysteine is the 21st amino acid with selenium instead of sulfur, derived from serine and introduced during protein synthesis

• Selenocysteine is found in active sites of oxidation-reduction enzymes

• Ornithine and Citrulline are intermediate in the urea cycle and play a key role in nitrogen metabolism

Properties of Amino Acids

• All amino acids are alpha-amino acids

• The amino group is attached to the alpha carbon

• Glycine is the only amino acid without an asymmetric alpha carbon

• Alpha Carbon: Asymmetric except glycine

• L-Amino Acids are found in proteins

• D-Amino Acids are found in some bacterial products

• Glycine is not optically active

• Amino acids have both acidic (COOH) and basic (NH2) groups and can act as both acids and bases depending on the pH

• At the isoelectric point (pI), an amino acid has no net charge.

• The COOH group is negatively charged, and the NH2 group is positively charged

• Zwitterion: A molecule with both positive and negative charges

Effects of pH on Amino Acid Behavior

• At Low pH (Acidic): High hydrogen ion (H+) concentration and both amino and carboxyl groups are protonated

• At Neutral pH: Amino acid exists as a zwitterion with NH3+ (positively charged) and COO- (negatively charged)

• At High pH (Basic): Low hydrogen ion (H+) concentration and both the amino and carboxyl groups lose protons

• In addition to their role as building blocks of proteins and peptides, amino acids serve a variety of functions.

• Glycine: Detoxification and Synthesizes heme

• Methionine: Methyl donor in metabolism

• Tyrosine: Synthesizes thyroid hormones (T3, T4), epinephrine, norepinephrine, and melanin

• Tryptophan: Synthesizes niacin (Vitamin B3) and serotonin

• Histidine: Synthesizes histamine

• Aspartate and Glutamine: Involved in pyrimidine synthesis

• Glycine, Aspartic Acid, Glutamine: Involved in purine synthesis

Introduction to Proteins

• Proteins (polypeptides) are polymers of amino acids, linked by peptide bonds

• Their structure and function are dictated by the sequence of amino acids

• They play crucial roles in various biological processes

• Peptides range in size from two to many thousands of amino acids

• Biological activities aren't always related to size or molecular weight.

• Even small peptides can have significant biological effects

• Example: Aspartame (dipeptide L-aspartyl-L-phenylalanine methyl ester), a low-calorie artificial sweetener.

Examples of Small Peptides

• Oxytocin: 9 amino acids, stimulates uterine contractions during childbirth
• Bradykinin: 9 amino acids, inhibits inflammation and mediates pain
• Thyrotropin-Releasing Factor: 3 amino acids. stimulates the release of thyroid-stimulating hormone (TSH) from the pituitary.
• Gluthathione: 3 amino acids, is an antioxidant, protects cells from oxidative stress
• Amanitin (toxic peptide): 8 amino acids, inhibits RNA polymerase in cells, leading to cell death
• Gramicidin A (antibiotic): Variable amino acids. disrupts bacteria cell membranes, leading to bacterial cell death.

Examples of Slightly Larger Peptides and Oligopeptides

• Insulin: 51 amino acids. regulates glucose metabolism by promoting glucose uptake in cells
• Glucagon: 29 amino acids, raises blood glucose levels by stimulating glycogen breakdown
• Corticotropin: 39 amino acids. stimulates the adrenal cortex to release cortisol in response to stress

Proteins

• Proteins are long chains of amino acids with specific sequences.
• Their structure is directly influenced by the gene sequence.
• Even a single amino acid change can alter function (e.g., sickle cell anemia)

Classifications of Proteins

• Proteins can be classified based on function, shape, and composition

Classification based on Shape

• Globular Protein: spherical, compact, water-soluble, less stable, biologically active
• Examples: Insulin, Myoglobin, Antibodies, Enzymes
• Fibrous Protein: linear, structural, insoluble in water, more stable
• Examples: Keratin, Collagen, Elastin, Myosin

Classification Based on Function

• Transport Function: Proteins that transport molecules across the body, for example Hemoglobin, Transferrin
• Catalytic Function: Enzymes speed up biochemical reactions, for example Lactase, Pyruvate kinase
• Storage Function: Store vital molecules for later use, for example Myoglobin, Ferritin
• Defense Function: Proteins involved in the immune defense, for example Immunoglobulins

More Functions of Proteins

• Structural Function: Provides structure, strength, and elasticity, for example Collagen, Keratin
• Nutrient Function: Provides nutrients for biological systems, for example Casein, Albumin
• Infective Agents: Prions act as infective proteins causing disease, for example Prions
• Buffering Function: Plasma proteins act as buffers to maintain pH balance, for example Albumin, Haptoglobin
• Gene Expression: Involved in gene regulation and packaging, for example Histones, Nucleoproteins
• Regulatory Function: Controls physiological processes through protein hormones, for example Insulin, Hormone receptors

Classification Based on Composition

• Simple proteins: Proteins are composed only of amino acids, for example Albumins and Globulins
• Derived proteins: Proteins are derived from simple or complex proteins after hydrolysis or denaturation, for example Casein and Peptones
• Complex proteins: Proteins are made from amino acids combined with non-protein parts, for example Glycoproteins and Metalloproteins

Conformation of Proteins

• Proteins have unique three-dimensional structures, known as their conformation
• Their function is determined by this structure
• Proteins have four structural levels; primary, secondary, tertiary, and quaternary

Primary Structure

• The sequence of amino acids in a polypeptide chain.
• Held together by peptide bonds
• Determines the protein's final structure and function
• Starts with the N-terminal amino acid (free amino group) and ends with the C-terminal amino acid (free carboxyl group).
• The protein sequence is read from left to right
• The remaining amino acids in the chain are called amino acid residues

Secondary Structure

• Local folding of the polypeptide chain into structures.
• Alpha helix: Right-handed spiral, stabilized by hydrogen bonds.
• Beta sheet: Extended structure with hydrogen bonds between chains

Secondary Structure: α-helix

• It is a spiral structure with peptide bonds coiled tightly inside and side chains sticking out.
• It is a right-handed helix (coils turn clockwise), which is more stable than the left-handed version.
• There are 3.6 amino acids per turn of the helix.
• a-helices are usually found inside the protein structure.
• The a-helix is stabilized by hydrogen bonds within the chain (intra-chain).
• These bonds are individually weak, but together, help keep the helix stable

Secondary Structure: β-pleated sheet

• ẞ-pleated sheet: A more extended structure than the a-helix.
• The structure is pleated because the C-C bonds are tetrahedral and can't be straight.
• Stabilized by hydrogen bonds between NH and C=O of adjacent peptide segments.
• The segments may run in the same direction (parallel ẞ-sheet) or in opposite directions (antiparallel ẞ-sheet).
• Beta bends (U-turns in the chain) are stabilized by disulfide bridges.
• In an antiparallel ẞ-sheet, the chains are oriented in opposite directions, and the amino acid side chains alternate above and below the plane of the sheet.
• Hydrogen bonding occurs between different chains (interchain bonding)

Tertiary Structure

• The overall 3D folding of a protein. Cysteine
• Influenced by covalent bonds and noncovalent bonds (hydrophobic forces, ionic bonds, and hydrogen bonds).
• Hydrophobic side chains in the interior, and hydrophilic side chains on the exterior

Quaternary Structure

• Arrangement of multiple polypeptide chains in a protein.

• Not all proteins have a quaternary structure.

• Each polypeptide chain is called a subunit, and it has its own primary, secondary, and tertiary structure.

• The polypeptide chains are held together by the same forces that stabilize tertiary structure

• Monomer: 1 subunit

• Dimer: 2 subunits

• Tetramer: 4 subunits

• Example: Insulin is made up of two subunits, linked by two disulfide bridges

• Haemoglobin is a tetramer made up of two identical dimers

• Quaternary structure of haemoglobin is tightly held together by hydrophobic interactions

Types of Polymers

• A homopolymer is made up of identical subunits.
• A heteropolymer is made up of different subunits.
• Insulin is a heteropolymer.

Proteins are classified based on function, shape, and composition

• Protein structure determines function.
• Classification helps to understand diverse biological roles.

Examine the relationship between amino and carboxyl groups in alpha-amino acids. Learn about ketogenic amino acids. Explore the metabolic fates of amino acids in low-carb diets and uncontrolled diabetes.