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Maple Syrup Urine Disease (MSUD) and Phenylketonuria (PKU)

Glycine (Gly), Phenylalanine (Phe), Tyrosine (Tyr), Tryptophan (Trp), Glutamate (Glu)

Protein misfolding can cause aggregation and formation of toxic species that disrupt cellular function, contributing to diseases such as Alzheimer’s disease, Creutzfeldt–Jakob disease, Kuru, Mad Cow disease, and Parkinson’s disease.

The two mirror-image forms are D (dextro, right) and L (levo, left). Only L-amino acids are incorporated into proteins.

Amino acids exist as zwitterions, with the amino group protonated (-NH3+) and the carboxyl group deprotonated (-COO–) at physiological pH.

Phenylalanine, Valine, Tryptophan, Threonine, Isoleucine, Methionine, Histidine, Arginine, Leucine, Lysine (mnemonic: PVT TIM HALL).

Disulfide bonds (cystine bridges) form between the thiol groups of two cysteine residues and help stabilize protein folding and maintain tertiary structure.

Hydrolysis of a peptide bond breaks the bond by adding a hydrogen to the amino nitrogen and a hydroxyl to the carbonyl carbon; water is consumed and the reaction is catalyzed by acids, bases, or proteolytic enzymes.

Peptide bonds form by a dehydration (condensation) reaction when the amine group of one amino acid bonds to the carbonyl carbon of another, releasing a molecule of water.

Vitamin C is required as a cofactor for the hydroxylation of proline and lysine residues (formation of 4-hydroxyproline and 5-hydroxylysine), which is essential for stable collagen triple-helix formation.

γ-Carboxyglutamate is a post-translationally modified residue that enhances calcium ion binding in proteins such as several blood clotting factors; formation requires Vitamin K as a cofactor.

MSUD causes accumulation of branched-chain amino acids (isoleucine, leucine, valine) and their ketoacids, producing a characteristic sweet, maple syrup–like odor in urine and leading to neurotoxicity and developmental delay if untreated.

PKU results from deficiency of phenylalanine hydroxylase (or its cofactor tetrahydrobiopterin), causing phenylalanine accumulation that impairs neurotransmitter synthesis and myelination, leading to intellectual disability and a musty odor (phenylacetate) in urine.

Serine and tyrosine residues are commonly phosphorylated on their hydroxyl (-OH) groups, a reversible post-translational modification that regulates enzyme activity and signaling pathways.

Phenylalanine is hydroxylated to tyrosine by phenylalanine hydroxylase. Tyrosine is a precursor for DOPA, dopamine, norepinephrine (nor-epinephrine), epinephrine, melanin, and thyroxine.

Primary structure is the linear amino acid sequence of a polypeptide, joined by peptide bonds and read from the N-terminal to the C-terminal; it determines folding and function and mutations can cause genetic diseases.

Knowledge of primary structure is critical because amino acid substitutions can alter folding and function, underlying many genetic diseases and functional defects in proteins.

β-Turns connect segments of antiparallel β-sheets and allow abrupt directional changes; stabilized by a hydrogen bond between the carbonyl oxygen of residue 1 and the amide hydrogen of residue 4. Proline is often at position 2 and glycine at position 3.

Disulfide bonds covalently link two cysteine residues (forming cystine), creating bridges that stabilize tertiary structure by connecting distant parts of a polypeptide chain.

Super-secondary structures are common folding motifs formed by specific arrangements of secondary structures and side-chain interactions; example: β–α–β motif.

A disulfide bond (-S-S-) is a covalent bond formed between the sulfhydryl groups (-SH) of two cysteine residues, resulting in a cystine residue. It contributes to the stability of a protein's three-dimensional shape and helps prevent denaturation in the extracellular environment.

Hydrophobic interactions cause amino acids with nonpolar side chains to be located in the interior of the polypeptide, while polar or charged side chains are found on the surface. This segregation is energetically favorable and plays a crucial role in protein folding and stability.

The quaternary structure of a protein reflects its composition of multiple polypeptides, which can be identical or non-identical. These subunits are held together by non-covalent interactions and disulfide bonds, allowing for cooperative binding of ligands and increasing the protein's stability.

Protein folding involves several stages:

1. Formation of secondary structures driven by the hydrophobic effect.
2. Combination of small structures into larger ones.
3. Stabilization of secondary structures and initiation of tertiary structure formation.
4. Achieving the fully folded, native (functional) form characterized by a low-energy state.

Chaperones may assist in this process to prevent misfolding.

Prions are infectious particles composed solely of protein, lacking DNA or RNA. They are believed to cause neurodegenerative diseases by acting as templates for misfolding normal proteins. Prion diseases can be acquired through infection or inherited mutations.

Amyloidosis is a group of diseases characterized by the accumulation of amyloid protein. This misfolding can occur spontaneously or due to mutations, leading to altered proteins. Some normal proteins can also misfold after abnormal proteolytic cleavage, forming long, fibrillar assemblies.

Amyloids are insoluble fibrous protein aggregates implicated in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. In Alzheimer's disease, the dominant component of amyloid plaques is amyloid β (Aβ), while in Parkinson's disease, the abnormal accumulation of the protein α-synuclein leads to the formation of Lewy bodies.

Protein denaturation is the unfolding and disorganization of a protein's secondary and tertiary structures without breaking peptide bonds. Causes of denaturation include:

1. Increasing or decreasing pH
2. Altering ionic strength with high salt concentrations
3. Increasing temperature (heating)
4. Adding denaturing agents like urea and mercaptoethanol
5. Adding surface-active detergents like sodium dodecyl sulfate (SDS)

Globular proteins are generally soluble in water and exist in a compact spherical conformation. Most functional proteins are globular. Examples include:

• Myoglobin
• Hemoglobin

Sickle Cell Anemia is caused by a point mutation in both genes coding for the β-chain of hemoglobin, specifically a substitution of glutamic acid (Glu) with valine (Val) at position 6 (B6 Glu→Val). This mutation leads to polymer formation and decreased solubility of deoxyhemoglobin, resulting in sickle-shaped hemoglobin, hemolysis, and pain.

Fibrous proteins are generally insoluble in water and exist in an elongated and rigid conformation, serving structural roles, while globular proteins are soluble and compact, primarily functioning in metabolic processes. Examples of fibrous proteins include collagen and keratin.

Fibrous proteins are long, extended proteins enriched in specific amino acids and unique secondary structures, which provide structural functions in the body. They exhibit unique mechanical properties such as tensile strength, flexibility, and stability, essential for maintaining the integrity of connective tissues.

Collagen has a triple helix structure composed of three polypeptides wound around each other. It is characterized by repeating sequences of -Gly-X-Y, where X is often proline and Y is often hydroxyproline or hydroxylysine. This structure provides tensile strength and is crucial for the integrity of connective tissues in the body.

Ehlers-Danlos Syndrome (EDS) is a family of inherited disorders caused by genetic defects in fibril-forming collagen or enzymes involved in its processing. Patients may experience hyperextensible skin and hypermobile joints due to defects in collagen that lack tensile strength, affecting the structural integrity of connective tissues.

The chemical nature of the side chains of amino acids determines their role in a protein, particularly in how the protein folds into its native conformation. The interactions between different side chains influence the overall structure and stability of the protein.

The Henderson-Hasselbalch equation describes the relationship between pH, pKa, and the concentrations of protonated and deprotonated forms of an acid. It predicts the buffering capacity of amino acids, indicating that buffering occurs within ±1 pH unit of pKa, which is crucial for maintaining physiological pH in biological systems.

The essential amino acids are:

• Phenylalanine
• Valine
• Threonine
• Isoleucine
• Methionine
• Histidine
• Arginine
• Leucine
• Lysine
• Tryptophan They can be remembered using the mnemonic PVT TIM HALL.

The ketogenic only amino acids are Leucine and Lysine. This can be remembered with the mnemonic KiLL.

In globular proteins:

• Hydrophilic amino acids (e.g., Lysine, Aspartic acid) tend to reside on the protein surface.
• Hydrophobic amino acids (e.g., Phenylalanine) tend to sequester within the protein interior.

Disulfide bonds are formed by the oxidation of the sulfhydryl (-SH) group of cysteine residues in the lumen of the rough endoplasmic reticulum. These bonds are crucial for the stability of secreted proteins. The oxidizing environment necessary for their formation does not exist in the cytoplasm due to high concentrations of the antioxidant glutathione.

Parkinson's disease is primarily caused by the loss of conversion of dihydroxyphenylalanine (dopa) to the neurotransmitter dopamine due to the destruction of neural tissue. The most common treatment is the administration of levodopa (L-dopa), a metabolic derivative of the amino acid Tyrosine.

Maple Syrup Urine Disease (MSUD) is a rare autosomal disease caused by a deficiency of branched-chain α-keto acid dehydrogenase (BCKD) activity. It leads to the accumulation of branched-chain amino acids in urine, giving it a characteristic odor. Treatment involves feeding a synthetic diet that limits branched-chain amino acids (Isoleucine, Leucine, Valine). In some mild cases, thiamine supplementation may restore BCKD activity.

Phenylketonuria (PKU) is caused by defects in the activity of phenylalanine hydroxylase. This leads to the accumulation of Phenylalanine, which is converted to Phenylpyruvate, phenyllactate, and phenylacetate. These compounds disrupt neurotransmission and block amino acid transport in the brain, resulting in severe impairment of brain function. The urine of affected patients may have a musty odor due to phenylacetate.

The amino acids commonly found in the middle of a β-turn are Glycine (Gly) and Proline (Pro).

The amino acids that are repeatedly found in the collagen triple helix are:

• Glycine
• Hydroxyproline
• Hydroxylysine

Deficiency of ascorbic acid (vitamin C) leads to scurvy, characterized by abnormal integrity of connective tissues and skin, resulting in easy bruising. Vitamin C is a cofactor for the enzymes prolyl hydroxylase and lysyl hydroxylase, which convert proline to hydroxyproline and lysine to hydroxylysine.

Sickle cell anemia is caused by a point mutation that replaces glutamic acid (Glu) with valine (Val) in the β-globin chain of hemoglobin (HbS). This change from a polar, acidic amino acid to a nonpolar, neutral one causes deoxyhemoglobin to aggregate in red blood cells, leading to a distorted (sickled) shape and rigid structure, which contributes to their aggregation in capillaries.

Prions are proteinaceous infectious particles that consist only of protein, lacking DNA or RNA. They are believed to cause neurodegenerative diseases by acting as templates for misfolding of normal proteins, leading to conditions such as Creutzfeldt-Jakob disease (CJD) and mad cow disease.

In Creutzfeldt-Jakob disease, there is a conversion of α-helices into β-sheets in the prion proteins, which is a key feature in the formation of scrapie prion proteins.

Creutzfeldt-Jakob disease typically causes personality changes, anxiety, depression, and memory loss, usually developing within a few months.

Amyloid proteins are modified proteins that aggregate into deposits characterized by β-strands. In Alzheimer's disease, β-amyloids deposit in the brain, contributing to the disease's pathology.