Protein degradation via ubiquitous pathway In general science, a ubiquitous pathway refers to a biochemical or metabolic pathway that is: 1. *Widely present*: Found in many different organisms, tissues, or cells. 2. *Conserved*: Remains relatively unchanged across different species or contexts. Examples of ubiquitous pathways include: 1. *Glycolysis*: The process of breaking down glucose for energy, found in nearly all living organisms. 2. *Citric acid cycle (Krebs cycle)*: A key metabolic pathway involved in energy production, present in many cells. 3. *Pentose phosphate pathway*: A metabolic pathway involved in energy production and antioxidant defenses, found in many organisms. These pathways are essential for life and have been conserved across evolution, highlighting their importance for cellular function and survival.

1. PROTEIN DEGRADATION-
UBIQUITIN PATHWAY
By
KAVIYA PRIYAA
(23PBT007)
II MSc Biotechnology

2. PROTEIN DEGRADATION
 Protein degradation is the process by which proteins are
naturally destroyed in a cell in order to maintain protein
homeostasis, or an equilibrium of proteins in the human
body.
 The body is constantly making and remaking proteins
(creation), while also removing ones that have become
inactive or mutated (degradation).
 When a cell is unable to degrade certain proteins, the
proteins can accumulate, causing diseases like cancer.
 The end product of protein degradation is amino acids.

3. TYPES OF PROTEIN DEGRADATION
 Proteasomal pathway
In general, proteasomes eliminate short-lived proteins and
soluble misfolded proteins by the ubiquitin–proteasome
system.
 Lysosomal Pathways
In contrast, lysosomes are responsible for degradation of
long-lived proteins, insoluble protein aggregates and
intracellular parasites (e.g. certain bacteria) via
endocytosis, phagocytosis, or autophagy pathways.

4. LYSOSOMAL PATHWAYS
Protein degradation via three distinct lysosome pathways.
 Cell surface proteins arrive at endosome after endocytosis. They
could be degraded by lysosome, or transported to the plasma
membrane or other cellular organelles for recycling.
 In the phagocytic pathway, cells engulf large extracellular
particles, such as invading pathogens and dead cells, and then
degrade them by lysosome.
 Misfolded or aggregated proteins, damaged organelles, and
intracellular pathogens, are removed by the autophagy–lysosome
pathway.

5. There are three different forms of autophagy:
1. Macro autophagy
2. Micro autophagy
3. Chaperone-mediated autophagy.
Lysosomes:
• A lysosome is a membrane-bound cell organelle that
contains digestive enzymes.
• The digestive enzymes that require this acid, low-pH
environment. Those enzymes are called hydrolytic
enzymes.

7. UBIQUITINATION PATHWAY
 The addition of ubiquitin to a substrate protein is
called ubiquitylation (or, alternatively, ubiquitination or
ubiquitinylation).
 Ubiquitylation affects proteins in many ways: it can mark them
for degradation via the proteasome.
UBIQUITIN
 Ubiquitin is a small regulatory protein found in most tissues of
eukaryotic organisms.
 Include its C-terminal tail and the 7 lysine residues.
 It is highly conserved throughout eukaryote evolution.

8. STRUCTURE OF UBIQUITIN

9. PROTEOSOME
 Proteasomes are complex
intracellular proteases that
function in regulated
degradation of cellular
proteins
 Proteasomes of
eukaryotes are two types,
the 20S and 26S
proteasomes.

11. ENZYMES INVOLVED IN
UBIQUITINATION
1.Ubiquitin-activating enzymes (E1S)
Carboxyl end of ubiquitin is linked to the E1 enzyme through bond
with the help of ATP .
2.Ubiquitin -conjugating enzymes (E2s)
Activated ubiquitin is transfer to residue of E2
3.Ubiquitin ligases (E3s)
Transfer the ubiquitin to the targeted proteins.
4.Deubiquitinating enzymes (DUBs)
Destructions of isopeptide bond and the removal of monoubiqutin and
polyubiquitin chains from proteins.

12. MECHANISM OF UBIQUITIN PATHWAY
 Ubiquitin modification is an ATP-dependent process carried out
by three classes of enzymes.
ACTIVATION
 “ubiquitin activating enzyme” (E1) forms a thio-ester bond
with ubiquitin, a highly conserved 76-amino acid protein.
CONJUGATION
 This reaction allows subsequent binding of ubiquitin to a
“ubiquitin conjugating enzyme” (E2), followed by the formation
of an isopeptide bond between the carboxyl-terminus of
ubiquitin and a lysine residue on the substrate protein.

13. LIGATION
The latter reaction requires a “ubiquitin ligase” (E3)
1. Synthesis of protein substrate-anchored polyubiquitin
chain.
2. Degradation of the polyubiquitin-conjugated substrate
by the proteasome.

15. APPLICATION
1. Preventing formation of Cancer cells.
2. Maintains homeostasis of cell.
3. Regulates equilibrium of cells.
4. Protac-induced Protein degradation in drug
discovery.
5. Targeted protein degradation using intracellular
Antibodies for neurodegenerative disease

16. THANK YOU
https://youtu.be/jbc1QCu9hFg?si=NQdNFK4AA1OkgzfA