Amino Acid Overview
Amino acids are the building blocks of proteins. Understanding the basics of amino acids Basics of Amino acids Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). There are hundreds of AAs found in nature, but only 20 are the building blocks of proteins in humans (proteinogenic). Nine of these 20 are "essential," as they cannot be synthesized. Basics of Amino Acids allows a more comprehensive understanding of protein folding and modification.
Amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids structure
Amino acids that make up proteins are known as α-amino acids. Each of these amino acids has a central carbon known as the “alpha carbon,” which makes 4 bonds:
- Hydrogen ion
- Carboxyl group: made up of carboxylic acid (–COOH), creating the C-terminal end of the amino acid
- Amine group: made up of an amine group (–NH2), creating the N-terminal end of the amino acid
- R side chain: the unique functional group of an amino acid
Properties of amino acids
Amino acids may be categorized by characteristics of their R groups, which may be:
- Polar or nonpolar
- Hydrophobic or hydrophilic
- Charged or noncharged at physiologic pH
- Acidic or basic
Levels of protein structure
Protein structure, which is often referred to as protein folding, has 4 levels. These levels are:
- The primary structure is the linear sequence of the amino acids in the peptide chain.
- “Beads on a string” joined by peptide bonds
- This structure ultimately determines all the properties of the protein.
- Occurs between amino acids that are relatively close to each other (typically about 3–10 amino acids apart)
- 3 common motifs include:
- α-helix: a coil with the R groups on the outside
- β-strands and sheets:
- planar structure formed by zigzagging amino acid strands
- R groups protrude from the top and bottom of the sheet.
- Reverse turns: a short sequence, usually involving proline and/or glycine, occurring between α-helices and/or β-pleated sheets
- Secondary structures are stabilized by hydrogen bonds between the carboxyl oxygen and the amine hydrogens.
- Some simple fibrous proteins Fibrous proteins Simple proteins characterized by their insolubility and fibrous structure. Within the body, they perform a supportive or protective function. Proteins and Peptides (e.g., keratin) have only primary and secondary structures.
- Computer models are often able to predict secondary structures based on the amino acid sequence.
Tertiary structure is the complex looping and folding that occurs as a result of interactions and bonding between portions of the protein that are farther apart. Examples of interactions that create tertiary structure include:
- Hydrogen bonds: form between polar side chains
- Disulfide bridges: strong covalent bonds that form between two cysteines
- Ionic bonds: form between a positively charged/acidic R group (e.g., carboxyl group on aspartic acid) and a negatively charged/basic R group (e.g., amine group on lysine)
- Metallic bonds: 2 regions of a protein bound to a metal (e.g., iron)
- Hydrophobic interactions between nonpolar side chains: orient inward, away from water, to create spaces of hydrophobic exclusion.
In a quaternary structure, multiple subunits of a protein come together to form a single protein.
- Each subunit has its own primary, secondary, and tertiary structures.
- Subunits are held together by the same forces that generate tertiary structure:
- Hydrogen bonds
- Ionic bonds
- Disulfide bridges (covalent bonds)
- Metallic bonds
- Hydrophobic interactions
- Tertiary folding and quaternary folding produce several common motifs:
- β-barrels (common in membrane channels)
Chaperone proteins assist in protein folding.
- Chaperones are barrel-like proteins that take in misfolded proteins and use ATP energy to refold them.
- These proteins can bind to hydrophobic regions of unfolded proteins, allowing proper folding to take place.
- Found in various cellular compartments such as:
- Lumen of the endoplasmic reticulum
A denatured protein is a protein that has been unfolded and is no longer functional. This unfolding occurs under certain conditions, which include changes in:
- Ionic concentration
Proteins need to be sorted and will end up remaining in the cell, being placed on the cell wall, or being exported/secreted.
Exported and surface proteins
Proteins destined for the cell surface and/or secretion from the cell are synthesized within the rough endoplasmic reticulum (RER):
- During translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation, a signal peptide sequence on the end of the growing polypeptide chain indicates that a protein is destined for secretion from the cell.
- A signal recognition protein (SRP) binds to the signal peptide sequence, pausing elongation.
- The SRP guides the entire ribosome to the RER and associates it with a pore.
- When synthesis resumes, the growing polypeptide is deposited within the RER.
- Proteins are then directed to the lysosomes or plasma membrane or packaged for exocytosis (secretion):
- Secreted proteins follow the exocytic (secretory) pathway: RER → Golgi apparatus (GA) → plasma membrane (PM)
- Proteins destined for the GA, PM, or secretion are carried in transport vesicles.
- Proteins synthesized in the cytosol, unassociated with the RER, are kept inside the cell.
- Other specific signal peptides may direct these proteins to their final location in the cell (e.g., the nucleus).
After a polypeptide is synthesized, it undergoes further modification in order to form a functional protein. This modification may include cleaving off portions of the polypeptide chain or adding a functional group.
Protein cleavage is the process of removing certain polypeptides in order for the protein to become functional.
- Many proteins are not functional immediately after translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation; these proteins are called pro-proteins.
- Polypeptides are cleaved by proteolytic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes.
- Examples of amino acids or peptides that are typically cleaved off:
- The first amino acid (methionine) matches the start codon in mRNA, signaling the start of translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation.
- Signal peptides assist the protein in getting to its proper location but are not part of the functional protein itself.
- Enzymes and hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview are frequently translated as pro-proteins, which require cleavage in order to become functional/active (e.g., insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin precursor (proinsulin) C-peptide is cleaved in GA).
Addition of a functional group
Proteins are further modified by the covalent addition of functional groups and other molecules.
- Common modifications include:
- Common sites that are modified:
- Hydroxyl groups in serine, threonine, and tyrosine
- Amine groups in lysine, arginine, and histidine
- Carboxylate groups in aspartate and glutamate
- The N- and C-terminals
- General principles:
- Hydrophobic groups may help a protein incorporate into a membrane.
- Addition of cofactors can enhance enzymatic activity.
- Addition of phosphoryl group (most common)
- Common functions:
- Regulates enzymatic activity
- Cellular energy exchange: ATP, guanosine triphosphate (GTP), nicotinamide adenine dinucleotide phosphate Nicotinamide adenine dinucleotide phosphate Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5'-phosphate (nmn) coupled by pyrophosphate linkage to the 5'-phosphate adenosine 2. Pentose Phosphate Pathway ( NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5'-phosphate (nmn) coupled by pyrophosphate linkage to the 5'-phosphate adenosine 2. Pentose Phosphate Pathway)
Acetylation and methylation
- Addition of acetyl group or methyl group
- Common functions:
- Activates many pharmaceuticals
- Regulates gene expression and protein synthesis
- Histone modifications
- Addition of ubiquitin
- Targets proteins for degradation in proteasome
- Histone modifications
- Addition of carbohydrate to create a glycoprotein
- Types of glycoproteins include:
- N-glycoproteins: bound to nitrogen on the side chain of asparagine
- O-glycoproteins: bound to oxygen on the side chain of serine or threonine
- Glycosylated proteins are commonly associated with the
A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules.
The Cell: Cell Membrane or are secreted; common examples include:
- Immune system functions (e.g., found in some antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins)
- Cellular identity (e.g., ABO blood types)
- Glycosylation affects many different cellular processes and is implicated in:
- Alzheimer’s disease
- Addition of a lipid molecule to create a proteolipid
- Typically occurs on proteins associated with a phospholipid membrane
- Examples of lipidation:
- Addition of a glycosylphosphatidylinositol (GPI) “anchor”: commonly used to anchor cell surface proteins
- N-myristoylation: addition of a myristoyl group to some proteins involved in signal transduction, oncogenesis, and host defense
- Prenylation or palmitoylation: addition of a prenyl or a palmitic acid group to membrane proteins, making them more hydrophobic
Abnormalities in post-translational modification and/or protein folding or sorting can lead to a number of clinically important medical conditions.
- Protease inhibitors: HIV uses the process of proteolysis during its life cycle to create functional structural proteins from precursors. These proteases are a target of the anti-HIV drugs Anti-HIV drugs Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs called protease inhibitors.
- Alzheimer’s disease: neurodegenerative disease resulting in dementia: It is thought that misfolded and/or abnormally modified proteins, including the β-amyloid peptide and tau proteins, are associated with Alzheimer’s disease. Whether Alzheimer’s disease results in increased misfolded proteins or the misfolded proteins cause the disease is still being explored.
- Parkinson’s disease: progressive neurodegenerative movement disorder that presents with tremors, stiffness, and slowing of movement: Parkinson’s disease is thought to be caused at least in part by accumulation of a protein called α-synuclein in the neurons of the nigrostriatal pathway, leading to the death of these neurons. Misfolding of α-synuclein leads to the formation of insoluble aggregates, which accumulate and disrupt signaling.
- Cystic fibrosis Cystic fibrosis Cystic fibrosis is an autosomal recessive disorder caused by mutations in the gene CFTR. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. Cystic Fibrosis (CF): autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder caused by mutations in the CFTR gene. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. There are 5 classes of mutations. Class II is a group of mutations that cause abnormal post-translational processing; because of these abnormalities, the proteins are not brought to the correct cellular locations (and are often defective). This class includes the common mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations F508del. Common presentations of CF include chronic respiratory infections, failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive, and pancreatic insufficiency.
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