Proteasomes

One of the most fascinating recent developments in biology has been the discovery of numerous highly complex biopolymer assemblies (see also section C2.14.2.3) such as the ribosome or the bacterial flagellum [93, 94 and 95], the envy of nanoteclmologists seeking to miniaturize man-made mechanical devices (note that the word machinery is also sometimes used to refer to multienzyme complexes such as the proteasome [96]), and an entire... 

Baumeister W, Walz J, Zuhl F and Seemuller E 1998 The proteasome paradigm of a self-oompartmentalizing protease Cell 92 367-80... 

On pharmacodynamic grounds, tumor resistance may be caused by such diverse mechanisms as the mutation or redundancy of topo II, the overexpression and preferred nuclear localization of proteasome a-type subunits (leading to a anomalous degradation of topo II), genetic deletion or loss-of-function mutations of p53, overexpression of ROS-detoxifying enzymes, overexpression of Bcl-2 (leading to a diminished cyt c release), etc. However, none of these factors would universally predict the development of anthracycline-resistance in a given tumor or another. 

Antineoplastic agents that cannot be grouped under subheadings 1-9 include miltefosine which is an alkylphosphocholine that is used to treat skin metastasis of breast cancer, and crispantase which breaks down asparagine to aspartic acid and ammonia. It is active against tumor cells that lack the enzyme asparaginase, such as acute lymphoblastic leukemia cells. Side effects include irritation of the skin in the case of miltefosine and anaphylactic reactions in the case of crispantase. Another recent development is the proteasome inhibitor bortezomib which is used to treat multiple myeloma. 

Emerging evidence suggests that dysfunction of the ubiquitin-proteasome system may be part of the pathophysiology of sporadic Parkinson s disease, especially... 

In addition to protein proteolysis during mitosis, ubiquitin-mediated protein degradation ( ubiquitin/ proteasome) is also required at the G1 to S transition... 

The human genome contains more than 90 different DUBs. Besides cleaving ubiquitin from distinct substrates, DUBs are also responsible for the recycling of free ubiquitin from ubiquitin chains and processing of ubiquitin- or ubiquitin like precursor proteins. Certain DUBs are also associated with the proteasome in order to detach ubiquitin chains before proteolysis. 

Transforming Growth Factor-Beta Ubiquitin/Proteasome... 

ER-Associated Degradation, when proteins mis-fold in the ER due to mutation or environmental conditions, they are selectively exported to the cytosol for degradation by the proteasome. 

F-adjacent Transcript-10 (FAT 10) is composed of two ubiquitin-like domains and capable to mark conjugated proteins for proteasomal degradation independent of ubiquitin. FAT10 is inducible by IFN-y and TNF and induces apoptosis when over expressed. 

Threonine peptidases (and some cysteine and serine peptidases) have only one active site residue, which is the N-terminus of the mature protein. Such a peptidase is known as an N-terminal nucleophile hydrolase or Ntn-hydrolase. The amino group of the N-terminal residue performs the role of the general base. The catalytic subunits of the proteasome are examples of Ntn-hydrolases. 

PB T1 T01.010 Proteasome catalytic subunit 1 Potential use in cancer, rheumatoid arthritis and psoriasis that are characterized by these processes... 

An enzyme in which the single catalytic residue is at the N-terminus of the protein. Many Ntn-hydrolases are synthesized as precursors and autoactivate the precursors are therefore peptidases, even if the mature enzyme has no further proteolytic activity. Three of the beta subunits of the proteasome are Ntn-hydrolases. 

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