- Proteolysis of dietary protein begins in stomach through the action of pepsin, protease, non-specific hydrolysis
- Pepsin - active enzyme
> Originally synthesized as an inactive zymogen, pepsinogen

> Hydrolyzes proteins in a random, non-specific manner, that is not linked to specific protein sequence

- Pepsinogen - inactive zymogen
> zymogen is defined as an inactive substance which is converted into an enzyme when activated by another enzyme

> Extra 44 amino acids blocks the active site
> Must be clipped away -> when it hits the low pH in the stomach -> unfolds (autoproteolysis) 

> Synthesized and released into stomach

> Activated by low pH in the stomach

- Low pH breaks salt bridges to make this extra piece vulnerable to proteolysis
- Extra 44 amino acids become vulnerable to pepsinogen
- Pepsinogen undergoes autoproteolysis
- Benefits of low pH - activation of pepsinogen and denaturation of dietary proteins to random coils, which are more accessible to protease
- pH 7.3 -> pH 2
- Aspartate is protonated
> There is aspartate in the active site that are responsible for catalytic activity of pepsin

> No longer binds to lysine

- Salt bridge between lysine and aspartate is broken, protein unfolds enough for the inhibitory section of the zymogen to be vulnerable to proteolysis
- Pepsin is a random cleaver - no AA sequence it favors


Protein Breakdown in the Stomach

As partially digested food enters the small intestine (beginning in the duodenum), it mixes with bile and pancreatic juices. Bicarbonate in these secretions raises the luminal pH, which deactivates the stomach enzyme pepsin. The pancreas secretes inactive protein-digesting enzymes, known as zymogens, including trypsinogen, chymotrypsinogen, proelastase, and procarboxypeptidase. On the brush border surface of the intestinal cells, the enzyme enteropeptidase cleaves trypsinogen to form active trypsin. Trypsin then initiates an activation cascade, converting the remaining pancreatic zymogens into their active protease forms (chymotrypsin, elastase, and carboxypeptidase). These active proteases then further cleave dietary proteins into smaller peptides and amino acids.

Protein Breakdown in the Small Intestine

Michigan State University

Protein Degradation

Endogenous protein breakdown is the catabolism of a cell's own proteins, occurring primarily in proteasomes and lysosomes.

Reasons for degrading endogenous protein:
- Regulation through turnover: degrade the right protein at the right time.
- Quality control: misfolded, mistranslated, or error-containing proteins. Chaperones first attempt correction; if that fails, lysosomes and proteasomes degrade the protein.
- Source of amino acids: released amino acids serve as fuel and as anabolic precursors.

Sequence features influence protein half-life:
- The N-terminal residue affects longevity (e.g., an N-terminal serine gives a long half-life of >20 hours, whereas aspartate gives a very short one of <3 minutes).
- A PEST sequence (rich in proline (P), glutamate (E), serine (S), and threonine (T)) marks a protein for rapid turnover; its residues may be phosphorylation sites that promote recognition by the ubiquitination machinery.

Key step: ubiquitination tags the target protein for proteasomal degradation.

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