Proteins and peptides

Protein structure

  • 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).

References:[1]

Digestion and absorption of dietary proteins

  • Process
    1. Stomach
    2. Duodenum: further cleavage from pancreatic and intestinal proteases
    3. Enterocytes:
      1. Absorption of di-, tri-, and tetrapeptides: likely via a proton symporter
      2. Absorption of single amino acids: via Na+-coupled carrier proteins for specific AA groups (neutral, branched-chain, aromatic, acidic, basic)
    4. AAs enter bloodstream liver (via portal vein)

  • Zymogens: proteases that are first secreted in an inactive form to avoid damage to the immediate surrounding tissue
Important proteases of the gastrointestinal tract
Proteases Location Reaction Product
Endopeptidases: split peptide bonds within the polypeptide chain

Pepsin

  • Zymogen pepsinogen activated to pepsin by gastric acid
  • Preferably cleaves bonds involving phenylalanine, tyrosine and leucine

Trypsin

  • Zymogen trypsinogen activated to trypsin by enteropeptidase
  • Preferably cleaves bonds of the C-terminal of basic AAs lysine and arginine
  • Oligopeptides
Chymotrypsin
  • Oligopeptides

Exopeptidases: split peptide bonds from end AAs Carboxypeptidases: split unspecific end AAs from C-terminal Carboxypeptidase A
  • Activated from zymogen procarboxypeptidase A by trypsin
  • Cleaves bonds involving aromatic AAs
  • AAs
Carboxypeptidase B
  • Activated from zymogen procarboxypeptidase B by trypsin
  • Cleaves bonds involving basic AAs
  • AAs
Aminopeptidase
  • Intestinal mucosa
  • Cleaves unspecific end AAs from N-terminal
  • AAs
Dipeptidase
  • Intestinal mucosa
  • Cleaves dipeptides
  • AAs

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)

  • Description: Proteins are targeted via ubiquitination for degradation in proteasomes.
  • Pathway
    1. Ubiquitination: addition of ubiquitin to the ε-amino group of lysine residues of a substrate protein; it consists of 3 parts
      1. Activation: performed by ubiquitin-activating enzymes (E1s)
      2. Conjugation: performed by ubiquitin-conjugating enzymes (E2s)
      3. Ligation: performed by ubiquitin ligases (E3s)
    2. Degradation:
      1. Polyubiquitinated proteins are recognized by proteasomes.
      2. Proteins are broken down into peptides via hydrolysis of peptide bonds.

Lysosomes

Examples of diseases associated with aberrant proteolysis

There are many diseases associated with aberrant proteolysis; this list is not exhaustive.

References:[8]

  • 1. Rapley R, Whitehouse D. Molecular Biology and Biotechnology. Royal Society of Chemistry; 2015.
  • 2. Hall JE. Guyton and Hall Textbook of Medical Physiology. Philadelphia, PA: Elsevier; 2016.
  • 3. Blackman D. The Logic of Biochemical Sequencing. CRC Press; 1993.
  • 4. Berg JM, Tymoczko JL, Stryer L. Biochemistry. W H Freeman & Company; 2002.
  • 5. Feher JJ. Quantitative Human Physiology. Academic Press; 2017.
  • 6. Barrett KE, Barman SM, Boitano S, Brooks HL. Ganong's Review of Medical Physiology (Enhanced EB). New York, NY: McGraw Hill Professional; 2009.
  • 7. Chatterjea M, Shinde R. Textbook of Medical Biochemistry. New Delhi, India: JP Medical Ltd; 2011.
  • 8. Cooper GM. The Cell: A Molecular Approach. Sunderland, MA: Sinauer Associates; 2000.
  • Kaplan. USMLE Step 1 Lecture Notes 2016: Physiology. Kaplan Publishing; 2015.
last updated 10/18/2018
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