Proteins and Peptides

8/20/23, 12:08 PM Proteins and Peptides - Lecturio
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 and 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, receptors, membrane
channels, hormones, accumulation of proteins, and autoimmune disorders.
Last updated: April 18, 2023
CONTENTS
Structure
Properties
Types and Functions of Proteins
Overview of Protein Sources, Digestion, and Absorption
Overview of Protein Metabolism
Clinical Relevance
References
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Structure
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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 or 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

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

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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.
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Examples of α-helices and β-pleated sheets

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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)
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Quaternary structure:
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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
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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
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Chaperone proteins assist in protein folding

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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)
Proteins can become denatured (or unfolded) as a result of changes in pH, temperature, or ionic
concentration.
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Properties
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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)
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:
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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); some examples include:
Digestive 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
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
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Digestion COMPARE PLANS(/PRICING-REDIRECT)
Protein digestion occurs mainly in the 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 or pancreas:
Pepsin
Trypsin
Chymotrypsin
Elastase
Carboxypeptidases A and B
Brush-border enzymes: bound to the luminal membrane of enterocytes
Aminopeptidase
Dipeptidases
Intracellular peptidases: break down peptides within enterocytes
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Table: Secreted enzymes involved in protein digestion
Enzyme Zymogen Activated by Notes on activity

(precursor)
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(precursor)
Gastric enzymes secreted into the stomach
Pepsin Pepsinogen Hydrochloric Most efficient

acid between
hydrophobic AAs
Pancreatic 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
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(precursor)
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.
Only AAs, 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 →
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transported through the portal circulation to the liver
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.
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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

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To synthesize proteins
Broken down so that the nitrogen can be used to build other nitrogen-containing
compounds (AA derivatives), such as:
Nucleic acids
Some hormones and neurotransmitters
NO
Porphyrins and heme
Broken down for energy
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).
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Catabolism and excretion

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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 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 (tricarboxylic acid cycle (TCA))
Ketogenesis
Fatty acid and cholesterol synthesis
Gluconeogenesis
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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 derivatives, and
catabolism. Catabolism of amino acids includes the removal of functional groups and the breakdown
of the carbon skeletons.
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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
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Kwashiorkor: severe form of protein malnutrition, resulting in 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, and diarrhea.
Conditions caused by the accumulation of damaged or

misfolded proteins
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: 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).
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
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Hypercoagulable or hypocoagulable states: Deficiencies or mutations of enzymes

involved in the coagulation cascade can result in hypercoagulable or
hypocoagulable states.
Hemophilias: deficiencies of factor VIII (hemophilia A), factor IX (hemophilia B),
or factor XI (hemophilia C), all of which are important enzymes required to
form clots. Hemophilias result in a hypocoagulable state and present with
abnormal bleeding.
Factor V Leiden: point mutation 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
leading to dysfunctional metabolism and accumulation of glycosaminoglycans,
glycoproteins, or glycolipids. Examples of LSDs include Gaucher disease,
Tay-Sachs disease, and mucopolysaccharidoses.
Glycogen storage diseases (GSDs): disorders characterized by abnormal glycogen
breakdown due to genetic defects of one of the key enzymes involved in the
process. Deficiency of these enzymes can cause 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 (DMD): X-linked recessive genetic disorder
resulting in abnormal dystrophin. Dystrophin is a structural glycoprotein linking the
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: 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, vaso-occlusive episodes, pain, and organ
damage.
Cystic fibrosis: autosomal recessive disorder caused by mutations in the gene
CFTR. The mutations lead to dysfunction of chloride channels, which results in
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Abnormal signaling and receptor proteins
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, respiratory difficulties, and progressive
weakness in the limbs, leading to difficulty in movement.
Graves' disease: autoimmune disorder characterized by the presence of circulating
antibodies against the thyroid-stimulating hormone (TSH) receptors, causing the
thyroid gland to hyperfunction.
Type 2 diabetes mellitus: due primarily to peripheral 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
secretion, which in turn results in down-regulation and a decreased sensitivity of the
insulin receptor proteins.
Complete androgen insensitivity syndrome: X-linked recessive condition in which
a genetic mutation 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 (SLE): 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,
and/or psychosis.
Rheumatoid arthritis (RA): symmetric, inflammatory polyarthritis.
Rheumatoid arthritis typically presents in middle-aged women with joint swelling,
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 bind to these citrullinated proteins, resulting in
activation of the complement system.
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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Forbes, J., Krishnamurthy, K. (2020). Biochemistry, peptide. StatPearls. Retrieved December 17, 2021,
from https://www.ncbi.nlm.nih.gov/books/NBK562260/
(https://www.ncbi.nlm.nih.gov/books/NBK562260/)
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
(https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Map%3A_Organic_Chemistry_(McMurry)
/26%3A_Biomolecules-_Amino_Acids_Peptides_and_Proteins)
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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8/20/23, 12:08 PM Proteins and Peptides - Lecturio

Last updated: April 18, 2023

Amino acids, peptides, and proteins

Example of the amino acid phenylalanine

Formation of peptide bonds

Rotational movement within polypeptide chains

Protein folding: 4 levels of protein structure

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

Examples of α-helices and β-pleated sheets

Chaperone proteins assist in protein folding

Types and Functions of Proteins

Overview of Protein Sources, Digestion, and

Digestion COMPARE PLANS(/PRICING-REDIRECT)

Protein digestion occurs mainly in the stomach and duodenum.

Table: Secreted enzymes involved in protein digestion

Enzyme Zymogen Activated by Notes on activity

Enzyme Zymogen Activated by Notes on activity

Gastric enzymes secreted into the stomach

Pepsin Pepsinogen Hydrochloric Most efficient

Pancreatic enzymes secreted into the duodenum

Trypsin Trypsinogen Enteropeptidase Able to activate:

Chymotrypsin Chymotrypsinogen Trypsin Most efficient

Carboxypeptidase Procarboxypeptidase Trypsin Attacks the

Elastase Proelastase Trypsin Same as

Enzymes bound to the brush border of enterocytes in the small intestines

Enzyme Zymogen Activated by Notes on activity

Aminopeptidase NA NA Breaks down

Dipeptidases NA NA Breaks peptide

NA: not applicable

Transport proteins on enterocyte membranes involved in protein absorption:

Overview of Protein Metabolism

How AAs are used once absorbed

Amino acid derivatives:

Catabolism and excretion

Kwashiorkor: severe form of protein malnutrition, resulting in edema, delayed

Conditions caused by the accumulation of damaged or

Hypercoagulable or hypocoagulable states: Deficiencies or mutations of enzymes

Abnormal structural proteins

Abnormal transport proteins

Myasthenia gravis: autoimmune neuromuscular disorder characterized by

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