Proteins and peptides
Protein structure
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Composition: Proteins consists of a chain of > 100 amino acids (AAs) that are connected through multiple peptide bonds (polypeptide chain).
- Peptide: a chain of < 100 connected AAs
- Peptide bond: A covalent bond (–CO–NH–) is formed when the carboxyl group (COOH) of an AA reacts with the amino group (NH2) of another AA and causes the release of an H2O molecule (also known as a condensation reaction).
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Structure: broken down into 4 levels
- Primary structure: the sequence of AAs in the polypeptide chain
- Secondary structure: structural folding that occurs based on patterns of H+-bonds between parts of the same polypeptide chain
- Tertiary structure: 3-dimensional structure of secondary structures
- Quaternary structure: 3-dimensional structure of ≥ 2 individual polypeptide chains (subunits) = multimer
- For both tertiary and quarternary, folding driven by: hydrophobic interactions, H+-bonds, salt bridges, disulfide bonds
- Proper protein folding must occur for a protein to be functional (see learning card on translation and protein synthesis)
- Protein synthesis: See learning card on translation and protein synthesis.
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Denaturation: the undoing of correct protein structure
- Causes: pH changes, temperature changes, change in surrounding chemicals (oxidation, deamination, glycosylation, etc.)
References:[1]
Digestion and absorption of dietary proteins
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Process
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Stomach
- Gastric acid causes denaturation
- Cleavage via pepsin
- Duodenum: further cleavage from pancreatic and intestinal proteases
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Enterocytes:
- Absorption of di-, tri-, and tetrapeptides: likely via a proton symporter
- Absorption of single amino acids: via Na+-coupled carrier proteins for specific AA groups (neutral, branched-chain, aromatic, acidic, basic)
- AAs enter bloodstream → liver (via portal vein)
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Stomach
- Proteases: enzymes that split peptide bonds via hydrolysis
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Zymogens: proteases that are first secreted in an inactive form to avoid damage to the immediate surrounding tissue
- For example, pancreatic proteases are first secreted as inactive precursors (zymogens) before being activated in the duodenum.
Important proteases of the gastrointestinal tract | |||||
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Proteases | Location | Reaction | Product | ||
Endopeptidases: split peptide bonds within the polypeptide chain |
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Chymotrypsin |
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Pancreatic elastase |
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Exopeptidases: split peptide bonds from end AAs | Carboxypeptidases: split unspecific end AAs from C-terminal | Carboxypeptidase A |
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Carboxypeptidase B |
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Aminopeptidase |
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Dipeptidase |
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Trypsinogen is first activated by enteropeptidase via proteolytic cleavage at the N-terminal. The resulting trypsin then activates other zymogens, including further trypsinogen (positive feedback loop).
The inactive zymogen pepsinogen is activated to pepsin by gastric acid.
References:[2][3][3][4][5][6][7]
Protein degradation and associated diseases
Protein degradation
Endogenous proteins (those synthesized in cells) are degraded by proteasomes. Exogenous proteins are degraded by lysosomes.
Ubiquitin proteasome system (UPS)
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Description: Proteins are targeted via ubiquitination for degradation in proteasomes.
- Proteasome: a barrel-like protein complex consisting of 2 units that breaks down marked proteins into peptides via ATP hydrolysis of peptide bonds
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Pathway
- Ubiquitination: addition of ubiquitin to the ε-amino group of lysine residues of a substrate protein; it consists of 3 parts
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Degradation:
- Polyubiquitinated proteins are recognized by proteasomes.
- Proteins are broken down into peptides via hydrolysis of peptide bonds.
Some cases of Parkinson disease have been linked to defects in the ubiquitin proteasome system.
Lysosomes
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Process
- Foreign proteins are endocytosed into cells and form an endosome.
- Endosomes merge with lysosomes.
- Lysosomal hydrolases break down proteins into peptides via hydrolysis of peptide bonds.
Examples of diseases associated with aberrant proteolysis
There are many diseases associated with aberrant proteolysis; this list is not exhaustive.
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Conditions that lead to increased tissue protein breakdown
- Chronic inflammatory diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, Sjögren disease)
- Diabetes mellitus
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Conditions caused by increased protein breakdown
- Emphysema ; and α1-antitrypsin deficiency
- Pancreatitis and possibly resulting exocrine pancreatic insufficiency
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Malignancy induced cachexia
- Pro-inflammatory cytokines (e.g. IL-1, IL-6, and TNF-α) released from tumor cells induce ubiquitination and proteasomal degradation of cellular proteins; → Degradation of myosin chains in skeletal muscle cells leads to increased muscle catabolism
- TNF-α activates the extrinsic pathway of apoptosis
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Conditions caused by accumulation of damaged or misfolded proteins/peptides (see protein misfolding in the learning card on translation and protein synthesis for more details)
- Age-related neurological diseases/neurodegenerative diseases (e.g., Alzheimer disease, Parkinson disease, Huntington disease)
- Prion-related conditions (e.g., Creutzfeldt-Jakob disease)
- Amyloidosis
- Myotonic muscular dystrophy
- Cardiovascular diseases
- Inflammatory responses and autoimmune diseases
- Malignancy
References:[8]