Proteins are large biomolecules consisting of more than 50 amino acids connected by multiple peptide bonds, while peptides are small biomolecules consisting of less than 50 amino acids. Proteins fulfill a variety of functions, including regulating physiological activity and providing structure to cells, and their functions are closely tied to their conformation. After ingestion, dietary proteins are denatured by gastric acid and subsequently cleaved by pepsin and proteases into monopeptides, dipeptides, tripeptides, and tetrapeptides. These end products are absorbed in the small intestine via proton symporter and Na+-coupled carrier proteins. Intracellularly, endogenous proteins are degraded by the ubiquitin proteasome system, while endocytosed dietary proteins are degraded by the lysosome. Accumulation of damaged or misfolded proteins/peptides has been observed in many neurological diseases such as Alzheimer disease, Parkinson disease, Huntington disease, Creutzfeldt-Jakob disease, and myotonic muscular dystrophy.
- Composition: Proteins consist of a chain of ≥ 50 amino acids (AAs) that are connected by multiple peptide bonds (polypeptide chain).
Structure: categorized into four levels
- Primary structure: the sequence of AAs in the polypeptide chain
- Secondary structure: folded structure formed based on the pattern of H+ bonds between parts of the same polypeptide chain (e.g., α-helix and β-sheets)
- Tertiary structure; : three-dimensional arrangement of the secondary and primary structures of the same polypeptide chain, determined by different types of interaction between AA side chains
- Quaternary structure: three-dimensional arrangement of two or more individual polypeptide chains (subunits) in a multi-subunit complex (i.e., multimer)
- For both tertiary and quaternary structures, folding driven by hydrophobic interactions, H+-bonds, salt bridges, disulfide bonds
- Proper protein folding must occur for a protein to be functional (see article on translation and protein synthesis)
- Protein synthesis: See article on .
- Denaturation: the breakdown of the quaternary, tertiary, and secondary structures of the protein; common causes include changes in pH, temperature, or surrounding chemicals (e.g., oxidation, deamination, glycosylation)
- Duodenum: further cleavage from pancreatic and intestinal proteases
- 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 the bloodstream and travel to the liver via the portal vein.
- Proteases: enzymes that split peptide bonds via hydrolysis
|Important proteases of the gastrointestinal tract|
|Endopeptidases: split peptide bonds within the polypeptide chain|| |
|Pancreatic elastase|| |
|Exopeptidases: split peptide bonds from end AAs||Carboxypeptidases: split unspecific end AAs from C-terminal||Carboxypeptidase A|| |
|Carboxypeptidase B|| |
|Aminopeptidase|| || || |
|Dipeptidase|| || || |
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).
- Via ubiquitination, proteins are targeted for degradation in proteasomes.
- Proteasome: a barrel-like protein complex consisting of two units that breaks down marked or damaged proteins into peptides via ATP hydrolysis of peptide bonds
- Not all ubiquitinated proteins are marked for degradation. In fact, ubiquitination may communicate changes to protein activity, location, or interactions.
- Either a single ubiquitin molecule (monoubiquitylation) or a chain of ubiquitin (polyubiquitylation) can be added to the protein.
- Ubiquitination: addition of ubiquitin to the ε-amino group of lysine residues of a substrate protein; occurs in three stages
- 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.
- Conditions that lead to increased tissue protein breakdown
- Conditions caused by increased protein breakdown
- ; and
- Pancreatitis and possibly resulting
- Malignancy induced cachexia
- Conditions caused by accumulation of damaged or misfolded proteins/peptides (see “ ” in “ ” 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)
- Myotonic muscular dystrophy
- Cardiovascular diseases
- Inflammatory responses and autoimmune diseases