Proteolytic Mechanism

The catalytic core of the proteasome is a threonine protease. Based on the crystal structure of the proteasome, it was concluded that proteasome functions through a new kind of proteolytic mechanism. In... 

Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 1992 267 26031-26037. 

Since aiAT represents the archetype for the serpin (serine-proteinase inhibitor) superfamily of proteins, it is possible that similar oxidative or proteolytic mechanisms may function in the inactivation of other serpins that are important in controlling the inflammatory cascade. Some serpins contain a readily oxidised reactive-centre methionine residue (e.g. plasminogen activator-inhibitor [108] and a2-antiplasmin [109]), whilst all serpins (including antithrombin III [110] and protease nexin I [111]) contain an exposed loop which is susceptible to cleavage by proteinases. 

Abou-Donia, 2003 Winrow et al, 2003 O Callahan, 2003), the NTE theory has been replaced with one involving a noncholinergic, proteolytic mechanism involving cyto-skeletal proteins foimd in neurofilaments (De Wolff et al, 2002). The resulting proteolysis, accompanied by perturbed ionic gradients, cellular edema, and myelin debris, can generate neuropathy. 

Fig. 2) (9-11). Alternatively, a precursor may contain multiple related copies of the active neuropeptide. For example, proenkephalin contains four copies of (Met)enkephalin, one copy of the related (Leu)enkephalin, and one copy each of the ME-Arg-Gly-Leu and ME-Arg-Phe (Fig. 2) (12-14). Proteolysis of these precursors, especially tissue-specific proteolytic mechanisms, is required for biologically active neuropeptides to be generated. 

Vu T-KH, Hung DT, Wheaton VI, Coughlin SR. Molecular doning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cdl 1991 288 123-128... 

Fenteany etal., 1995). Meanwhile, a large number ofmutational studies with other archaeal (Maupin-Furlow et al., 1998), bacterial (Mayr et al., 1998), yeast (Chen and Hochstrasser, 1996 Arendt and Hochstrasser, 1997 Heinemeyer etal., 1997 Groll etal., 1999), and mammalian jd-type subunits (Schmidtke et al., 1996 Salzmann etal., 1999) have confirmed a common proteolytic mechanism for all kinds of proteasomes. It remains enigmatic, however, why in eukaryotic proteasomes four out of seven P subunits lack the N-terminal active-site threonine, and therefore are presumably inactive. 

The concept of a proteolytic mechanism in the production of inflammatory manifestations is supported by the demonstration of anti-inflammatory activity in various protease inhibitors, e.g. the trypsin inhibitors of the pancreas, soya bean, ovomucoid and potato . It is interesting to note that the inhibitor from potatoes exerts its effect even after the inflammation is well established , suggesting that protease action is a continuing feature of inflammation and not simply an initiating process. Various esterase inhibitors (dyflos, quinine, quinidine and chloroquine) also reduce capillary permeability induced by heat and the permeability globulins . 

Correia, M.A., K. Yao, S.A. Wrighton, D.J. Waxman, and A. Rettie (1992). Differential apoprotein loss of rat liver cytochromes P450 after their inactivation by 3,5-dicarbethoxy-2,6-dimethyl-4-ethyl-1,4-dihydrop)nidine A case for distinct proteolytic mechanisms Arch. Biochem. Biophys. 294, 493-503. 

The clearance of released hormone from the circulation is critical for the regulation of hormone concentration. The rate of clearance may vary from a few minutes for polypeptide hormones, to a few hours for steroid and glycoprotein hormones, to days for thyroid hormones. The peptide hormones are cleared from the circulation mostly by proteolytic mechanisms in lysosomes after their uptake by cells through binding to cell-surface receptors and nonreceptor hormone-binding sites. Steroid hormones are bound to carrier proteins in the blood as mentioned above. Binding to... 

Homozygous or heterozygous tti-antitrypsin deficiency offers a proteolytic mechanism and possible genetic basis for some cases of panlobular emphysema in miners (Falk and Briscoe 1970). The homozygous deficiency, which is known to be associated with emphysema, has been identified in 1 -10 % of various groups of patients (Briscoe et al. 1966, Kueppers et al. 1969, Lieberman 1969). 

Figure 23.1 Schematic representation of CatA proteolytic mechanism and CatA inactive precursor structure from Rudenko et al. The amino acids of the active site are shown in green and the activation domain in blue [5],...

These findings support the idea of a proteolytic mechanism for cata-bolite inactivation. The extremely high sensitivity of cytosolic malate dehydrogenase, in contrast to its mitochondrial isoenzyme, against proteolysis by the yeast proteinases A and B (7) also supports this idea. 

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