Proteins and Peptides

Proteins are 1 of the 3 primary macronutrients in the body and are synthesized from individual building blocks called amino acids (AAs). Amino acids are bound together by peptide bonds, which link the amino end of one AA to the carboxy end of the next AA, generating a protein’s primary structure. The strand of AAs then undergoes additional folding, ultimately generating complex 3-dimensional structures. Proteins have a wide variety of functions, including catalytic, structural, regulatory, transport, storage, and immunologic functions. They are digested by proteases and peptidases secreted by the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach and pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas and absorbed as individual AAs in the small intestines through specialized transporters. There are countless medical conditions related to protein abnormalities, including abnormalities related to 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, receptors, membrane channels, 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, accumulation of proteins, and autoimmune disorders.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Structure

Amino acids, peptides, and proteins

  • Amino acids (AAs): individual building blocks of proteins
    • Consist of a central carbon (known as the α carbon) bonded to:
      • A carboxyl group (–COOH) → the carboxy terminus
      • An amino group (–NH2) → the amino terminus
      • An R group: different functional side chains for each AA
      • A hydrogen ion
    • Individual AAs can be:
      • Hydrophobic (nonpolar) or hydrophilic (polar)
      • Acidic or basic
      • Charged on noncharged at physiologic pH
  • Peptides: 
    • Small chains of AAs
    • AAs are joined together by peptide bonds: The carboxy terminus of one AA binds with the amino terminus of the next AA.
  • Proteins: longer chains of amino acids
Example of the amino acid phenylalanine

Example of the 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 phenylalanine

Image by Lecturio.

Formation of peptide bonds

  • Catalyzed by peptidyl transferase (an enzymatic ribosomal RNA within a ribosome)
  • Bonds the α-carboxyl carbon to the α-amine nitrogen in a trans configuration
  • Resonance with the double-bonded oxygen from the carboxyl group → peptide bonds have properties of a double bond 
  • Releases an H2O in the process

Rotational movement within polypeptide chains

  • Peptide bonds: no significant rotation 
  • Bonds with the α-carbon:
    • Free to rotate
    • Angles are limited by steric hindrance of the side-chain groups
Example of a polypeptide with four glycine

Example of a polypeptide with 4 glycine (gly) amino acids in sequence demonstrating which bonds have freedom to rotate:
Dark blue: α-carbons
Light blue: carboxyl carbons
Yellow: nitrogen
Green: oxygen
Pink: hydrogen

Image by Lecturio.

Protein folding: 4 levels of protein structure

There are 4 levels of protein structure; this is often referred to as protein folding. The levels are primary, secondary, tertiary, and quaternary structures. Proper folding requires the assistance of chaperone proteins

Primary structure: 

  • The linear sequence of the amino acids in the peptide chain
  • “Beads on a string” joined by peptide bonds
  • Determined by the mRNA sequence from which the protein is translated
Example of primary structure of a protein

Image showing the primary structure of proteins, an aggregation of amino acids

Image by Lecturio.

Secondary structure:

  • Occurs between AAs that are relatively close to each other (typically about 3‒10 AAs apart)
  • Formed primarily via hydrogen bonds between the carboxyl oxygen and the amine hydrogens
  • Common motifs: 
    • α-helix
    • β-strands (also called β-sheets)
    • Reverse turns
  • Some simple “fibrous proteins” (e.g., keratin, collagen) have only a primary and secondary structure.
Examples of α-helices and β-pleated sheets

Examples of α-helices and β-pleated sheets

Image by Lecturio.

Tertiary structure:

  • Complex looping and folding that occurs as a result of interactions between the polypeptide backbone and its aqueous surroundings
  • Created by both covalent and noncovalent bonds
  • Bonding and interactions occur between portions of the protein that are further apart from one another. 
  • Examples of interactions that create tertiary structure include:
    • Hydrophobic interactions between nonpolar side chains: orient inward away from water to create spaces of hydrophobic exclusion
    • Hydrogen bonds: form between polar side chains 
    • Disulfide bridges: strong covalent bonds that form between 2 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 bond to a metal (e.g., iron)

Quaternary structure:

  • Refers to how 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
  • Subunits can be referred to as a monomer (1 chain). 
    • Proteins can be classified according to the number of chains they contain:
      • Monomer
      • Dimer
      • Tetramer, etc.
    • Proteins can be classified according to whether the subunits are the same or different:
      • Homodimer: involves multiple copies of the same subunits
      • Heterodimer: subunits are different
  • Tertiary and quaternary folding produces several common motifs:
    • β–α–β
    • β-barrels (common in membrane channels)
    • Helix–turn–helix

Chaperone proteins

Chaperone proteins assist in protein folding.

  • Chaperones are barrel-like proteins that take in misfolded proteins and use adenosine triphosphate (ATP) energy to refold them.
  • Chaperones can bind to hydrophobic regions of unfolded proteins, allowing proper folding to take place.
  • Found in various cellular compartments such as:
    • Cytosol
    • Mitochondria
    • Lumen of the endoplasmic reticulum
Chaperone proteins assist in protein folding

Chaperone proteins assist in protein folding

Image by Lecturio.

Denaturation of proteins

  • Denaturation: breakdown of the quaternary, tertiary, and secondary structures of proteins, resulting in nonfunctional peptide chains. 
  • The primary structure is not altered.
  • Denaturation can occur as a result of changes in:
    • Temperature
    • pH
    • Presence of certain denaturing chemicals (e.g., mercaptoethanol can break disulfide bonds)
    • Ionic concentration
  • Often irreversible, though occasionally can be reversed (i.e., protein can be refolded)
Denaturation of proteins

Proteins can become denatured (or unfolded) as a result of changes in pH, temperature, or ionic concentration.

Image by Lecturio.

Properties

A protein’s unique structure (primary, secondary, tertiary, and quaternary) will give it physical and chemical properties that are important for the protein’s function. Some of these properties include:

  • Shape/geometry:
    • May be:
      • Globular (e.g., 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)
      • Fibrous (e.g., structural proteins)
      • Membrane-bound (e.g., receptors, membrane-transport proteins)
    • Proper function depends on proper shape, which requires proper folding.
  • Polarity and/or charge: often determine where a protein is located within a cell (which affects how it functions)
  • Flexibility: ability to change shape (e.g., during enzymatic reactions)
  • Solubility:
    • May be soluble or insoluble
    • Depends on both the isoelectric point of the protein and the pH
  • Amphoteric nature: can act as bases (amino terminus) or acids (carboxy terminus)
  • Ability to bind other types of molecules, creating conjugated proteins or salts:
    • Glycoproteins: protein + carbohydrate
    • Lipoproteins: protein + lipid
    • Metalloproteins: protein + metal ions (e.g., heme)
    • Phosphoproteins: protein + phosphate group(s)
    • Salts: protein + ions
    • Other functional groups:
      • Acetyl groups
      • Methyl groups
      • Ubiquitin
  • Colloidal nature: exert osmotic pressure (“attracts” water)

Types and Functions of Proteins

Proteins have an extensive range of functions in the body, including:

  • Structural: 
    • Maintaining shape and physical integrity
    • Examples: collagen, keratin, elastin
  • Movement: 
    • Moving substances within cells (e.g., kinesin moving along microtubules)
    • Muscle contraction (e.g., myosin moving along actin filaments)
  • Catalysis (i.e., 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); some examples include:
    • Digestive 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
    • Enzymes catalyzing metabolic and catabolic processes (e.g., Krebs cycle)
    • Clotting cascade
  • Regulatory and signaling proteins, including:
    • Receptors
    • Hormones
    • Intracellular signaling molecules (e.g., kinases)
    • Transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription factors
  • Transport and storage molecules (e.g., albumin, ferritin, apolipoproteins, membrane channels)
  • Immunologic functions: 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

Overview of Protein Sources, Digestion, and Absorption

Sources of protein and protein synthesis

  • Proteins are built from AAs synthesized by the body and those consumed in the diet. 
  • Ingested proteins must be digested/broken down into individual AAs for absorption.
  • Essential versus nonessential AAs:
    • Nonessential AAs: Can be generated by the body through metabolic pathways
    • Essential AAs: Cannot be generated by the body and must be ingested
  • Once absorbed in the body, AAs are transported to cells, where they are used to synthesize proteins.
  • Good sources of dietary protein include:
    • Complete proteins:
      • Animal products: meat/poultry/fish, dairy, eggs
      • Nonanimal products: soy, quinoa, buckwheat, hemp
    • Legumes (beans, lentils, chickpeas, some nuts) + whole grains also often form complete proteins; examples include:
      • Peanut butter + whole grain bread
      • Hummus + pita
      • Rice + beans

Digestion

  • Protein digestion occurs mainly in the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach and duodenum.
  • Recall that peptide bonds join the amino terminus of one AA to the carboxy terminus of the next AA.
  • Protein digestion occurs via enzymatic hydrolysis of peptide bonds breaking down proteins into: 
    • Small peptides 
    • Individual AAs
  • Enzymes involved are:
    • Secreted by the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach or pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas:
      • Pepsin
      • Trypsin
      • Chymotrypsin
      • Elastase
      • Carboxypeptidases A and B
    • Brush-border 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: bound to the luminal membrane of enterocytes
      • Aminopeptidase
      • Dipeptidases
    • Intracellular peptidases: break down peptides within enterocytes
Table: Secreted 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 involved in protein digestion
Enzyme Zymogen (precursor) Activated by Notes on activity
Gastric 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 secreted into the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach
Pepsin Pepsinogen Hydrochloric acid Most efficient between hydrophobic AAs
Pancreatic 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 secreted into the duodenum
Trypsin Trypsinogen Enteropeptidase
  • Able to activate:
    • More trypsinogen → trypsin
    • All other pancreatic zymogens
  • Most efficient between lysine and arginine
Chymotrypsin Chymotrypsinogen Trypsin Most efficient between hydrophobic AAs
Carboxypeptidase Procarboxypeptidase Trypsin
  • Attacks the carboxy end of peptide chains
  • Generates individual AAs or very short peptide chains
Elastase Proelastase Trypsin Same as carboxypeptidase
Enzymes bound to the brush border of enterocytes in the small intestines
Aminopeptidase NA NA Breaks down small peptides from their amino end (i.e., N-terminus)
Dipeptidases NA NA Breaks peptide bonds between 2 AAs → 2 single AAs
NA: not applicable

Absorption

  • Absorption occurs in the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine.
  • Only AAs and dipeptides and tripeptides can be absorbed across the apical membrane into the enterocyte.
  • Only individual AAs can be absorbed across the basolateral membrane into the interstitial space.
  • Individual AAs:
    • Are absorbed into the enterocytes across the apical membrane via specialized Na+/AA cotransporters:
      • Uses the Na+ gradient created by an Na+/K+-ATPase pump on the basolateral membrane 
      • Na+ is high in the lumen but low in the enterocyte → moves down its concentration gradient into the cell, bringing an AA with it 
    • Absorbed across the basolateral membrane by specialized transporters (different types of transport proteins for different types of AAs)
  • Dipeptides and tripeptides:
    • Absorbed into the enterocytes across the apical membrane via specialized H+/peptide cotransporters
    • Uses the H+ gradient created by an H+/Na+ exchanger on the apical membrane (which pumps 1 H+ ion into the lumen and brings 1 Na+ into the enterocyte)
    • Peptides are broken down into individual AAs by peptidases within the enterocytes. 
    • Absorbed across the basolateral membrane in the same fashion as AAs as explained above
  • Once in the interstitial space, AAs are absorbed into the venous circulation → transported through the portal circulation to the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
Protein absorption

Transport proteins on enterocyte membranes involved in protein absorption:
The Na+/K+-ATPase on the basolateral membrane generates a Na+ gradient within the cell. A Na+/H+ exchanger (NHE) on the apical membrane also generates the H+ gradient. Individual amino acids (AAs; green balls) are absorbed via a Na+/AA cotransporter, where Na+ flows across the apical membrane into the enterocytes down its concentration gradient, bringing the AA with it (despite moving against the chemical AA gradient). Small peptides are absorbed via the H+/PepT cotransporter with H+ flowing down its concentration gradient into the cell, bringing the small peptides with it. Peptides are broken down into individual AAs by peptidases within the enterocytes. All AAs are then absorbed through specialized transporters on the basolateral membrane.

Image by Lecturio.

Overview of Protein Metabolism

Protein metabolism refers to a group of biochemical processes responsible for both anabolism (the synthesis of proteins and AAs) and catabolism (the breakdown of proteins and AAs).

How AAs are used once absorbed

  • To synthesize proteins
  • Broken down so that the nitrogen can be used to build other nitrogen-containing compounds (AA derivatives), such as:
    • Nucleic acids Nucleic Acids Nucleic acids are polymers of nucleotides, organic molecules composed of a sugar, a phosphate group, and a nitrogenous base. Nucleic acids are responsible for storage, replication, and expression of genetic information. The 2 nucleic acids most commonly seen in eukaryotic cells are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Nucleic Acids
    • Some 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 and neurotransmitters
    • NO
    • Porphyrins and heme
  • Broken down for energy
Amino acid derivatives

Amino acid derivatives:
Amino acids (in blue) are combined with certain cofactors or other substrates (in pink) to make several biologically-important substances (in green).

Image by Lecturio.

Catabolism and excretion

  • AAs are broken down into ammonium (NH4+) + carbon skeleton via 3 main processes:
    • Transamination: transferring the amino group to another molecule
    • Deamination: removing the amino group
    • Decarboxylation: removing the carboxyl group
  • Excess nitrogen enters the urea cycle Urea Cycle The catabolism of amino acids results in the release of nitrogen in the form of ammonium. This excess nitrogen is transported to the liver and kidneys and eliminated from the body in the form of urea via the urine. The urea cycle (or ornithine cycle) takes place mainly in the liver and comprises the synthesis of urea from ammonium, CO2, aspartate, and bicarbonate. Urea Cycle as NH4+ → excreted as urea
  • Carbon skeleton:
    • All 20 AAs can be broken down into 1 of 6 intermediates:
      • Pyruvate
      • Acetyl–coenzyme A (CoA)
      • Oxaloacetate
      • α-ketoglutarate
      • Succinyl-CoA
      • Fumarate
    • These intermediates are then used in:
      • Citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle (tricarboxylic acid cycle (TCA))
      • Ketogenesis
      • Fatty acid and cholesterol synthesis
      • Gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis
Amino acid catabolism diagram

Schematic diagram of the metabolism of amino acids, including the 3 major pathways: reutilization in the synthesis of new proteins, union with cofactors to produce 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 derivatives, and catabolism. Catabolism of amino acids Catabolism of amino acids Amino acids (AAs) can be acquired through the breakdown of intracellular or ingested dietary proteins. Amino acids can enter 3 metabolic routes within the body. They can 1) be recycled to synthesize new proteins; 2) combine with cofactors and substances to create amino acid derivatives; or 3) be catabolized into their functional groups and carbon skeletons. Catabolism of Amino Acids includes the removal of functional groups and the breakdown of the carbon skeletons.

Image by Lecturio.

Clinical Relevance

A countless number of clinical disorders are caused by abnormalities or deficiencies of proteins and/or abnormal protein metabolism. A few examples are listed below.

Protein deficiency

  • Kwashiorkor: severe form of protein malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries, resulting in edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, delayed growth, and frequent infections. Kwashiorkor is seen in starving children.
  • Protein-losing enteropathy: excessive loss of serum proteins through the GI tract, often due to leakage of lymphatic fluid into the intestines, resulting in hypoalbuminemia, edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, and diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea.

Conditions caused by the accumulation of damaged or misfolded proteins

  • Alzheimer disease Alzheimer disease As the most common cause of dementia, Alzheimer disease affects not only many individuals but also their families. Alzheimer disease is a progressive neurodegenerative disease that causes brain atrophy and presents with a decline in memory, cognition, and social skills. Alzheimer Disease: neurodegenerative disease that causes brain atrophy and presents clinically with progressive dementia. Protein abnormalities include hyperphosphorylated tau proteins, which form abnormal aggregates within cells known as neurofibrillary tangles, and an accumulation of toxic β-amyloid proteins, which form plaques that disrupt the normal function of surrounding cells.  
  • Parkinson disease: chronic, progressive neurodegenerative disorder, presenting clinically with resting tremor, bradykinesia, rigidity, and postural instability. The disease can be confirmed only on autopsy, with the presence of Lewy bodies in the brain; Lewy bodies are eosinophilic, intracytoplasmic neuronal inclusions containing abnormal alpha-synuclein proteins.
  • Prion diseases: protein-misfolding diseases that occur when a normal, ⍺-helical, protein is converted into an abnormal, β-pleated, protein, which is resistant to degradation. The abnormal proteins accumulate in the CNS, leading to encephalopathies. The most common prion disease is Creutzfeldt-Jakob disease.
  • Amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis: pathologic extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently by-products of other pathologic processes (e.g., multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma). Misfolded proteins are deposited in various tissues, interfere with normal organ functions, and cause tissue-specific disease (e.g., renal amyloidosis causes proteinuria).

Enzyme abnormalities/deficiencies

  • Hypercoagulable or hypocoagulable Hypocoagulable Hypocoagulable conditions, also known as bleeding disorders or bleeding diathesis, are a diverse group of diseases that result in abnormal hemostasis. Physiologic hemostasis is dependent on the integrity of endothelial cells, subendothelial matrix, platelets, and coagulation factors. The hypocoagulable states result from abnormalities in one or more of these contributors, resulting in ineffective thrombosis and bleeding. Hypocoagulable Conditions states: Deficiencies or mutations of 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 involved in the coagulation cascade can result in hypercoagulable Hypercoagulable Hypercoagulable states (also referred to as thrombophilias) are a group of hematologic diseases defined by an increased risk of clot formation (i.e., thrombosis) due to either an increase in procoagulants, a decrease in anticoagulants, or a decrease in fibrinolysis. Hypercoagulable States or hypocoagulable Hypocoagulable Hypocoagulable conditions, also known as bleeding disorders or bleeding diathesis, are a diverse group of diseases that result in abnormal hemostasis. Physiologic hemostasis is dependent on the integrity of endothelial cells, subendothelial matrix, platelets, and coagulation factors. The hypocoagulable states result from abnormalities in one or more of these contributors, resulting in ineffective thrombosis and bleeding. Hypocoagulable Conditions states.
    • Hemophilias: deficiencies of factor VIII ( hemophilia Hemophilia The hemophilias are a group of inherited, or sometimes acquired, disorders of secondary hemostasis due to deficiency of specific clotting factors. Hemophilia A is a deficiency of factor VIII, hemophilia B a deficiency of factor IX, and hemophilia C a deficiency of factor XI. Patients present with bleeding events that may be spontaneous or associated with minor or major trauma. Hemophilia A), factor IX ( hemophilia Hemophilia The hemophilias are a group of inherited, or sometimes acquired, disorders of secondary hemostasis due to deficiency of specific clotting factors. Hemophilia A is a deficiency of factor VIII, hemophilia B a deficiency of factor IX, and hemophilia C a deficiency of factor XI. Patients present with bleeding events that may be spontaneous or associated with minor or major trauma. Hemophilia B), or factor XI ( hemophilia Hemophilia The hemophilias are a group of inherited, or sometimes acquired, disorders of secondary hemostasis due to deficiency of specific clotting factors. Hemophilia A is a deficiency of factor VIII, hemophilia B a deficiency of factor IX, and hemophilia C a deficiency of factor XI. Patients present with bleeding events that may be spontaneous or associated with minor or major trauma. Hemophilia C), all of which are important 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 required to form clots. Hemophilias result in a hypercoagulable Hypercoagulable Hypercoagulable states (also referred to as thrombophilias) are a group of hematologic diseases defined by an increased risk of clot formation (i.e., thrombosis) due to either an increase in procoagulants, a decrease in anticoagulants, or a decrease in fibrinolysis. Hypercoagulable States state and present with abnormal bleeding.
    • Factor V Leiden: point 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 resulting in resistance to factor Va degradation by protein C → ↑ factor Va → ↑ clot formation
  • Phenylketonuria: metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene that encode the enzyme PAH, which converts phenylalanine to tyrosine. This conversion leads to an accumulation of phenylalanine, which causes damage to white matter tracts and myelin through unknown mechanisms, leading to neurologic deficits. In most cases, tyrosine levels are normal or slightly low.
  • Lysosomal storage diseases (LSDs): genetic mutations of lysosomal 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 leading to dysfunctional metabolism and accumulation of glycosaminoglycans, glycoproteins, or glycolipids. Examples of LSDs include Gaucher disease Gaucher disease Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease, Tay-Sachs disease Tay-Sachs disease Tay-Sachs disease is an autosomal recessive lysosomal storage disorder caused by genetic mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot on physical examination. Tay-Sachs Disease, and mucopolysaccharidoses Mucopolysaccharidoses The mucopolysaccharidoses, a subset of the lysosomal storage diseases, are a group of inherited disorders characterized by absent or defective enzymes needed to break down carbohydrate chains called glycosaminoglycans (GAGs). These disorders lead to the accumulation of GAGs within cells. Mucopolysaccharidoses.
  • Glycogen storage diseases (GSDs): disorders characterized by abnormal glycogen breakdown due to genetic defects of one of the key 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 involved in the process. Deficiency of these 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 can cause hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia and/or abnormal glycogen deposition in tissues. The most common GSDs include von Gierke, Pompe, Cori, and McArdle diseases.

Abnormal structural proteins

  • Scurvy: dietary deficiency of vitamin C resulting in abnormal collagen. Vitamin C is required for the hydroxylation of proline in collagen fibers. The hydroxyproline allows the formation of many hydrogen bonds, linking collagen fibers together, which is very important for collagen strength. 
  • Duchenne muscular dystrophy Duchenne muscular dystrophy Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder that is caused by a mutation in the DMD gene. The mutation leads to the production of abnormal dystrophin, resulting in muscle-fiber destruction and replacement with fatty or fibrous tissue. Duchenne Muscular Dystrophy (DMD): X-linked recessive genetic disorder resulting in abnormal dystrophin. Dystrophin is a structural glycoprotein linking the cytoskeleton Cytoskeleton A cell's cytosol is the liquid inside the cell membrane that surrounds the organelles and cytoskeleton. The cytosol is a complex solution where many biochemical processes take place. The Cell: Cytosol and Cytoskeleton and the extracellular matrix of muscle (required for normal muscle function). Because it is unable to regenerate normally, the muscle tissue is replaced with fibrous and fatty tissue.

Abnormal transport proteins

  • Sickle cell anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview: group of genetic disorders in which an abnormal hemoglobin protein (hemoglobin S) transforms RBCs into a sickle-shaped cell. This transformation results in chronic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, vaso-occlusive episodes, pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, and organ damage.
  • 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: 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. 

Abnormal signaling and receptor proteins

  • Myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis: autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. Myasthenia presents with fatigue, ptosis, diplopia, dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. 
  • Graves’ disease: autoimmune disorder characterized by the presence of circulating 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 against the thyroid-stimulating hormone (TSH) receptors, causing the thyroid gland Thyroid gland The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland to hyperfunction.
  • Type 2 diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus: due primarily to peripheral 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 resistance. Insulin itself is a peptide hormone that is responsible for maintaining normal blood glucose levels. Chronically elevated blood glucose results in chronically elevated 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 secretion, which in turn results in down-regulation and a decreased sensitivity of the 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 receptor proteins.
  • Complete androgen insensitivity syndrome Androgen insensitivity syndrome Androgen insensitivity syndrome (AIS) is an X-linked recessive condition in which a genetic mutation affects the function of androgen receptors, resulting in complete (CAIS), partial (PAIS), or mild (MAIS) resistance to testosterone. All individuals with AIS have a 46,XY karyotype; however, phenotypes vary and include phenotypic female, virilized female, undervirilized male, and phenotypic male individuals. Androgen Insensitivity Syndrome: X-linked recessive condition in which a genetic 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 affects the function of androgen receptors, leading to testosterone resistance. Individuals will have a 46,XY karyotype and undescended testes, with external female genitalia and breast development (due to peripheral conversion of the excess testosterone to estrogen).

Autoimmune disorders

  • Systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus ( SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus): chronic, autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Notable clinical features include a malar rash, nondestructive arthritis, lupus nephritis, serositis, cytopenias, thromboembolic disease, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, and/or psychosis. 
  • Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis (RA): symmetric, inflammatory polyarthritis. Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis typically presents in middle-aged women with joint swelling, pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, and morning stiffness. The pathophysiology is incompletely understood, but in many individuals, there is an increased expression of the enzyme converting arginine to citrulline; 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 bind to these citrullinated proteins, resulting in activation of the complement system. 
  • IgA nephropathy IgA nephropathy IgA nephropathy (Berger's disease) is a renal disease characterized by IgA deposition in the mesangium. It is the most common cause of primary glomerulonephritis in most developed countries. Patients frequently present in the second and third decades of life and, historically, with a preceding upper respiratory or GI infection. IgA Nephropathy (Berger disease): renal disease characterized by IgA deposition in the mesangium. Berger disease is the most common cause of primary glomerulonephritis in most developed countries. Common presenting features are gross hematuria or asymptomatic, microscopic hematuria on urinalysis with a preceding upper respiratory or GI infection.

References

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