PROTEOSOME ENZYME AS NEW TARGET FOR

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PROTEOSOME ENZYME AS NEW TARGET FOR DRUG
THERAPY

• Mohannad A. AL-Shibani, Ahmed F. Basilim,
• Thamer M. AL-Qurashi
• (Pharm. D. Candidates)

• Proteasomes enzyme
• Are large protein complexes inside all eukaryotes
  and archaea, as well as in some bacteria
• The main function of the proteasome is to degrade
  intracellular proteins, a process that requires
  metabolic energy and unneeded or damaged proteins
  by proteolysis
• The proteasome is made up of two subcomplexes a
  catalytic core particle (CP also known as the
  20S proteasome) and one or two terminal 19S
  regulatory particle(s) (RP) that serves as a
  proteasome activator
• The ubiquitin pathway is the principal mechanism
  for protein catabolism in the mammalian cytosol
  and nucleus

• Structure of proteasome
• .

• The Ubiquitin conjugation mechanism
• Ubiquitin, an essential protein of 76 amino
  acids, represents one of the most conserved
  polypeptides in eukaryotes
• It is expressed as three different precursors a
  polymeric head-to-tail concatemer of identical
  units (polyubiquitin) and two N-terminal
  ubiquitin moieties, UbL40 and UbS27, that fused
  to the polypeptides L40 and S27

• BORTEZOMIB (Velcade ).
• It is proteosome inhibitor inhibiting 26S
  proteasome and antineoplastic agent that is used
  for many cancer diseases.

• Adverse Effects of BORTEZOMIB
• Most common thrombocytopenia, peripheral
  neuropathy, neutropenia, lymphopenia,
  hyponatremia, and periphral neuropathy
• acute development or exacerbation of congestive
  heart failure
• new onset of decreased left ventricular ejection
  fraction have been reported
• Pregnancy Category D.

Diseases related to aberrations in the
Ubiquitin system Liddles syndrome Cystic
fibrosis Parkinsons disease Alzheimers
disease CAG expansion (poly Q) diseases Angelman
syndrome Muscle wasting Immune and inflammatory
response BRCA1 and BARD1

• Therapeutic uses of BORTEZOMIB
• Mantle cell lymphoma.
• Metastatic prostate cancer.
• Multiple myeloma.
• Waldenstrom's macroglobulinemia.

• Conclusions
• Proteasomes are enzymes with a complex structure
  and function.
• Protein degradation by proteasomes is an
  essential cellular function, so proteasome
  inhibitors can lead to death of cancer cells by
  apoptosis.
• Cancer cells are more sensitive to the effects of
  proteasome inhibitor.

Under supervision of Dr. Ahmed A.
El-Berry, Assistant Professor of Clinical
Pharmacy, Faculty of Pharmacy, KAU