Drugs and protein degradation
The proteins are renewed permanently, i.e. biosynthesis and degradation exist simultaneously. The rate of renewal or turnover is very different according to proteins, with T1/2 going from a few minutes to one day for intracellular proteins and much more for extracellular proteins like hemoglobin.
It was thought that the lysosomes, intracellular organelles containing proteolytic enzymes involved in endocytosis and phagocytosis, played a big role in breakdown of endogenous intracellular proteins. Actually the degradation of these proteins is achieved essentially by the proteasome.
The proteasome, word resulting from the combination of “protease” and “some“ which means particle or organelle, is a hollow cylindrical protein complex, measuring about 10 nm diameter and 15 nm length, with cytosolic and intranuclear localization. The proteasome 26S is constituted of a complex 20S forming the central cylinder and of 2 regulating complexes 19S located at each end of the cylinder. The proteolytic activity of the proteasome 20S is controlled by the protein 19S and a protein 11S. The proteolytic activity of this complex is located inside the cylinder in which the ubiquitinated substrate enters for being hydrolyzed.
To be degraded by the proteasome 26S, the intracellular proteins must in general be previously ubiquinated. Ubiquitin is itself a protein of 76 amino-acids, present in all cells. Through enzymes called E1 (activator), E2 (conjugase) and E3 (ligase) and in the presence of ATP, there is biosynthesis of a poly-ubiquitin chain which is bound by the group - COOH of a terminal glycine residue to the - NH2 group of a lysine residue of the protein to be degraded. The protein thus poly-ubiquinated is a substrate for the proteasome 26S which hydrolyze it into peptides of 3 to 25 amino-acids and partly into amino-acids, which could be re-used by the cell. The molecules of ubiquitin released by de-ubiquitination will be also re-used. The ubiquitin-proteasome 26S degrades a great number of proteins, receptors, carriers, enzymes, viral proteins.
Among compounds acting on the ubiquitin-proteasome 26S are natural substances like lactacystine and epoxomycine and synthetic compounds like bortezomib.
Bortezomib is an inhibitor of the proteasome 26S. Its indication is the treatment of the relapsing or refractory multiple myeloma.