Overview of Protein Functions

Proteins have an extensive range of functions in the body. Structural proteins help maintain the physical integrity of cells and allow movement of substances within cells. Catalytic proteins are 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, which are critical in almost all biologic functions (e.g., metabolism, coagulation, digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption). Communication, signaling, and regulatory proteins are critical in coordinating responses throughout the organism, and include receptors, 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, neurotransmitters, intracellular signaling molecules (such as kinases and G-proteins), and 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. Additionally, proteins are involved in transportation of substances through the bloodstream, as well as across cell membranes. Proteins also play a critical role in the immune system.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Proteins are 1 of the 3 major macronutrients used in the body. Proteins are made up of amino acids (AAs) and have an extensive range of functions in the body, including:

  • Structural functions: 
    • Maintaining shape and physical integrity
    • E.g., collagen, keratin, elastin
  • Movement: 
    • Moving substances within cells (e.g., kinesin moving along microtubules)
    • Muscle contraction (e.g., myosin moving along actin filaments Actin filaments Fibers composed of microfilament proteins, which are predominately actin. They are the smallest of the cytoskeletal filaments. The Cell: Cytosol and Cytoskeleton)
  • 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 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

Structural Proteins

Structural proteins are important in maintaining cellular shape and physical integrity.

  • Usually have simple structures: 
    • Often only primary and secondary structure (lack more complex tertiary and quaternary structure)
    • Often have frequently repeating AAs
    • Often have a lot of glycine
    • Form long filaments
  • Important fibrous structural proteins:
    • Collagen: cartilage Cartilage Cartilage is a type of connective tissue derived from embryonic mesenchyme that is responsible for structural support, resilience, and the smoothness of physical actions. Perichondrium (connective tissue membrane surrounding cartilage) compensates for the absence of vasculature in cartilage by providing nutrition and support. Cartilage, connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue
    • Keratins: hair, nails
    • Elastin and fibrillin: connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue
  • Important globular structural proteins (which join together to make long filaments):
    • Actin: many structural and contractile functions
      • Muscle contraction
      • Forms part of 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
      • Cell motility and division
      • Movement of vesicles and organelles Organelles A cell is a complex unit that performs several complex functions. An organelle is a specialized subunit within a cell that fulfills a specific role or function. Organelles are enclosed within their own lipid bilayers or are unbound by membranes. The Cell: Organelles within the cell
    • Tubulin: forms microtubules
Formation of actin filaments from individual actin proteins

Formation of actin filaments Actin filaments Fibers composed of microfilament proteins, which are predominately actin. They are the smallest of the cytoskeletal filaments. The Cell: Cytosol and Cytoskeleton from individual actin proteins:
Free actin is activated with ATP. An activation nucleus forms and polymerization begins. Once the filament is assembled, an individual phosphate (Pi) is released from the individual actin proteins, which “deactivates” it, resulting in a stable final filament. An ADP remains bound to each actin.

Image by Lecturio.

Proteins Involved in Movement

  • Kinesin and dynein:
    • Use ATP energy to grab cargo and walk along microtubules
    • Move substances within the cell
    • Kinesin walks one way down the microtubules; dynein walks the other way
  • Myosin:
    • Uses ATP energy to walk down actin filaments Actin filaments Fibers composed of microfilament proteins, which are predominately actin. They are the smallest of the cytoskeletal filaments. The Cell: Cytosol and Cytoskeleton via a process known as cross-bridge cycling
    • Causes muscular contraction
Kinesin walking down microtubules

Example of how kinesin walks down microtubules using ATP energy:
When ATP binds to kinesin, it results in a conformational change in the molecule, which causes it to “swivel” on the tubulin. This leads to a “walking” motion of the kinesin (and its cargo) down the microtubule “highways” within the cell.
Pi: phosphate

Image by Lecturio.

Communication, Signaling, and Regulatory Proteins

Functions

These proteins are responsible for:

  • Transmitting messages between and within cells
  • Responding to the environment
  • Coordinating responses between cells and organ systems

Types of signaling and regulatory proteins

  • Membrane-bound receptors:
    • Integrated into the cell membrane Cell Membrane 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
    • Many are known as 7TM: they have 7 transmembrane coiled domains
    • Respond to an outside signal (e.g., hormone) → induces a conformational change → initiate a 2nd messenger within the cell 
  • Intracellular receptors:
    • Proteins within a cell that bind and respond to an outside signal (e.g., hormone)
    • Common with the cholesterol-derived lipophilic 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 (e.g., estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries receptor)
  • Peptide 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:
    • Travel within the blood from one location to its target cells
    • Can bind receptors on the membrane or within the cell
    • Trigger a response within the cell
    • 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, oxytocin, many others
  • Neurotransmitters:
    • AA derivatives that communicate nerve signals
    • E.g., norepinephrine, dopamine
  • Signal transduction proteins:
    • Proteins within a cell that pass the signal along
    • Primary mechanisms:
      • Creating or releasing secondary messengers (e.g., cAMP, IP3 (inositol trisphosphate), Ca2+)
      • Phosphorylation cascades: A molecule phosphorylates the next molecule, activating that molecule so that it can go on to phosphorylate another molecule, and so on.
    • Examples:
      • G-proteins: frequently coupled to membrane receptors
      • Kinases: phosphorylators → involved in phosphorylation cascades
  • Transcription factors (TFs):
    • Control which genes are transcribed (i.e., control gene expression)
    • Some of these proteins are capable of binding to specific DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure sequences (known as enhancer or repressor sequences).
    • Transcription factors may either:
      • Be required for 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 to occur
      • Prevent 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 from occurring
    • An incoming signal often affects TFs:
      • Allows the cell to respond by, for example, increasing or decreasing a particular protein product
      • That protein product may, in turn, be another TF, which controls the expression of a different gene.

Catalytic Proteins (i.e., Enzymes)

Enzymes

  • A class of proteins capable of catalyzing reactions
  • Bind substrates in their binding site and cause some type of reaction (e.g., hydrolysis)
  • Binding sites are highly specific to a particular antigen
  • Can speed up the rate of a reaction by more than a quadrillion times
  • Involved in a wide variety of biologic functions, including:
    • Metabolism
    • Cellular respiration
    • Growth and development
    • Digestion
    • Coagulation

Models for understanding enzyme function

There are 2 primary models that help explain how 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 work:

  • Fischer lock and key model (older model):
    • Postulates that the substrate fits into the enzyme’s binding site like a key fitting into a lock
    • Describes the specificity of antigen/substrate to enzyme, but not how the actual catalyzation works
  • Koshland induced fit model (newer model):
    • Postulates that the enzyme’s binding site is close to fitting, but not a perfect fit for, the substrate
    • This means that when the substrate binds, there is a slight conformational shift in the enzyme → tension is stored as potential energy
    • This tension/energy then acts on the substrate, causing the reaction to occur.
Enzyme-substrate interaction

Image showing the 2 theories of enzyme–substrate interaction

Image by Lecturio.

Transport and Storage Proteins

Another important function of proteins is to transport and/or store biomolecules, including substances such as oxygen, vitamins and minerals, 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 more.

Circulating proteins

Circulating proteins carry substances through the blood and/or interstitial spaces; examples include:

  • Heme and myoglobin:
    • Heme’s properties make it an excellent O2 transport molecule:
      • Affinity for O2 varies depending on the surrounding O2 concentration 
      • Readily binds O2 when O2 concentration is high → easily binds up O2 in the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs during inhalation
      • Readily releases O2 when O2 concentrations are low → easily releases O2 in the tissues
    • Myoglobin’s properties make it an excellent O2 storage molecule.
      • Affinity for O2 is high, even at low O2 concentrations
      • Readily binds O2, regardless of the surrounding O2 concentration
      • Highly concentrated in muscles, where O2 is stored until needed during exercise
  • Albumin: 
    • Binds to many other substances (e.g., 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, drugs) and transports them throughout the body
    • Also the primary modulator of plasma oncotic pressure
  • Ferritin: an iron-binding protein that serves as the primary storage form of iron in the body (an iron reservoir)
Affinity of hemoglobin and myoglobin for oxygen

Affinity of hemoglobin and myoglobin for oxygen (O2) depending on O2 saturation:
Note how hemoglobin’s affinity varies based on the surrounding O2 saturation. This means that hemoglobin will readily bind O2 when O2 is plentiful (e.g., during inhalation in the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs), but will readily release it when O2 saturation is low (e.g., in the tissues).
This makes hemoglobin an excellent O2 transport molecule. On the other hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand, myoglobin has a high affinity for O2 regardless of the surrounding O2 saturation, meaning it will readily bind O2 and will not release it until the surrounding O2 saturation is nearly 0. This makes myoglobin an excellent O2 storage molecule.
P50: pressure at which 50% of the molecules (hemoglobin or myoglobin) are saturated with O2/p> Image by Lecturio.

Membrane-bound proteins

Membrane-bound proteins move substances through the cell membrane Cell Membrane 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. Examples include:

  • Channels: 
    • Allow a particular molecule to travel through the membrane
    • Examples:
      • Epithelial sodium channels (ENaCs): channels that reabsorb Na+ in the distal convoluted tubules in the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys (site of action for amiloride, a K+-sparing diuretic)
      • AA channels
  • Symporters (i.e., cotransporters): 
    • Transport 2 molecules in the same direction
    • E.g., Na-K-2Cl cotransporter (NKCC2): a transmembrane protein that moves 1 Na+, 1 K+, and 2 Cl into the renal tubular cells in the loop of Henle (site of action of loop diuretics Loop diuretics Loop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent. Loop Diuretics)
  • Antiporters (i.e., exchangers): 
    • Transport 2 molecules in opposite directions
    • E.g., HCO3Cl exchanger involved in Cl and HCO3 reabsorption and excretion
  • ATPase/pumps:
    • Channels that require ATP energy in order to move substances through them (usually moving a substance against its electrochemical gradient)
    • E.g., Na+/K+-ATPase: 
      • A critically important transmembrane pump 
      • Moves 3 Na+ out of the cell and 2 K+ into the cell (both ions are moving against their concentration gradients)
      • Requires ATP energy
      • Establishes an electrochemical gradient that is used in multiple processes (e.g., nerve transmission, nutrient absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption)
Functioning of the na/k-atpase transporter

Image showing the functioning of the Na/K-ATPase transporter, which is a major function of proteins
Pi: phosphate

Image by Lecturio.

Antibodies

Overview

  • Globular glycoproteins produced by the adaptive immune system
  • Recognize and bind to specific molecules (called antigens)
  • Functions:
    • Neutralize toxins and pathogens by binding to and “covering” attachment sites
    • Activate the complement system 
    • Opsonization (coating pathogens that enhance phagocytosis)
  • Present in 2 forms:
    • Soluble: secreted in the blood
    • Membrane-bound

Structure

  • Consist of 4 polypeptide chains:
    • 2 heavy chains: form a Y shape joined by disulfide bonds
    • 2 light joins: bound to the heavy chains along the upper arms of the Y by disulfide bonds
  • 2 primary regions:
    • Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables regions:
      • Located at the tips of the light and heavy chains
      • Responsible for identifying antigens
      • Can produce an incredibly wide variety of variable regions owing to DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure shuffling
    • Constant regions: regions that are relatively consistent in structure among 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 within the same class
Structure of the antibody (regions)

Structure of the antibody (regions):
Antibody has a unique variable region (formed by heavy and light chains) capable of binding a different antigen and a constant region (formed by heavy chains).

Image: “Figure 42.22” by OpenStax. License: CC BY 4.0, cropped by Lecturio.

Functions of the different Ig classes

There are 5 different classes of immunoglobulins Immunoglobulins 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

  • IgM: 
    • Main antibody in the primary immune response
    • Facilitates activation of the B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells by binding to helper T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells
    • Fixes complement, leading to lysis of microorganisms
    • Can agglutinate pathogens, thus facilitating pathogen elimination
    • Monomer form serves as a B-cell receptor (BCR) in naive B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells.
  • IgG: 
    • Main antibody in secondary immune response
    • Fixes complement
    • Enhances phagocytosis
  • IgA: 
    • Major Ig in secretions: tears, saliva, colostrum, mucus
    • Can be transported across the mucosa
    • Prevents bacterial colonization of mucosal surfaces
  • IgE: 
    • Binding of allergen to IgE triggers release of inflammatory mediators from mast cells and basophils (allergic response)
    • Important in elimination of parasites: eosinophils bind to IgE-coated helminths → kills the parasite
  • IgD: together with IgM, constitutes the BCR of naive B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells
Table: The 5 Ig classes
IgM pentameter IgG monometer Secretory IgA dimer IgE monomer IgD monomer
Heavy chains μ γ α ε δ
Number of antigen-binding sites 10 2 4 2 2
Molecular weight (daltons) 900,000 150,000 385,000 200,000 180,000
Percentage of total antibody in serum 6% 80% 13% 0.002% 1%
Crosses placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity No Yes No No No
Fixes complement Yes Yes No No No
Fc binds to Phagocytes Mast cells and basophils
Function Main antibody of primary responses, best at fixing complement; the monomer form of IgM serves as the B-cell receptor Main blood antibody of secondary responses, neutralizes toxins, opsonization Secrets into mucus, tears, saliva, colostrum Antibody of allergic and antiparasitic activity B-cell receptor

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.

Enzyme abnormalities/deficiencies

  • 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: 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 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 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 PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration) gene that encode the enzyme PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration, 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: a 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’s muscular dystrophy (DMD): an 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). 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 Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries).

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

  1. Forbes, J., Krishnamurthy, K. (2020). Biochemistry, peptide. StatPearls. Retrieved December 17, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK562260/
  2. Kennepohl, D., et al. (2020). Biomolecules—amino acids, peptides, and proteins. Chapter 26 of Organic ChemistryLibreTexts. Retrieved December 17, 2021, from https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Map%3A_Organic_Chemistry_(McMurry)/26%3A_Biomolecules-_Amino_Acids_Peptides_and_Proteins
  3. Jessica Forbes, Karthik Krishnamurthy. (2020). Biochemistry, peptide. https://www.ncbi.nlm.nih.gov/books/NBK562260/
  4. Rodwell, V. W., Kennelly, P.J. (2006). Chapter 3: Amino acids and peptides; Chapter 4: Proteins determination of primary structure; Chapter 5: Higher orders of structure. In: Rodwell, V. W., et al. (Eds.), Harper’s Illustrated Biochemistry. McGraw-Hill, pp. 14–40.

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