Zinc metalloproteinase

Direct Fibrinolytics Alfimeprase is a recombinant tmncated form of fibrolase, a fibrinolytic zinc metalloproteinase isolated from the venom of the Southern copperhead snake. It degrades fibrin directly and achieves thrombolysis independent of plasmin formation. This may result in faster recanalization and a decreased risk of hemorrhagic conversion. The initial data on the safety and efficacy of alfimeprase in peripheral arterial occlusion disease appeared very promising, but recent communication from the sponsor revealed that the phase III trials of the drug in peripheral arterial disease and catheter obstruction (NAPA-2 and SONOMA-2) failed to meet their primary and key secondary endpoints of revascularization. A trial for I AT in acute stroke (CARNEROS-1) is planned to begin soon. 

Removal of the N- and C-terminal propeptides from fully folded procollagens occurs only after transport of procollagens across the Golgi stacks and results in collagen molecules that are then able to assemble into fibrils. C-proteinase activity is possessed by members of the tolloid family of zinc metalloproteinases,... 

ACE (peptidyl dipeptidase, EC 3.4.15.1), known to catalyse the hydrolysis of dipeptides from the C-terminus of pol)rpeptides, belongs to a family of zinc metalloproteinases, which require a zinc atom in the active site. In these... 

Li J, O Hare MC, Skarzynski T, Lloyd LF, Curry VA, Clark IM, Bigg HF, Hazleman BL, Cawston , Blow DM. X-ray structure of a hydroxamate inhibitor complex of stromelysin catalytic domain and its comparison with members of the zinc metalloproteinase superfamily. Structure 1996 4 375-386. 

Coffinier, C., et al. (2007). HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells. Proc Natl Acad Sci USA 104 13432-13437. 

Aminopeptidase N (EC 3.4.11.2 aminopeptidase M CD 13) Is a zinc-metalloproteinase located in the plasma membrane. Notable neuropeptide substrates include leu-enkephalln, met-enkephalin, p-endorphin and y-endorphin. Inhibitors include amastatin and actinonin. 

Aminopeptidase A (EC 3.4.11.7 aspartate aminopeptidase glutamyl aminopeptidase BP1/6C3 antigen) is a Ca -activated zinc-metalloproteinase, which is located in the... 

Aminopeptidase P (EC 3.4.11.9 prolyl aminopeptidase) is located in the plasma membrane and is a zinc-metalloproteinase. Notable neuropeptide substrates include bradykinin, substance P, neuropeptide Y, peptide YY and enterostatin. Inhibitors include apstatin. 

Pyroglutamyi aminopeptidase II (TRH degrading hormone) is a zinc-metalloproteinase, located in the plasma membrane. Notable neuropeptide substrates Include thyro-trophin-releasing factor. There is no specific inhibitor. 

Carboxypeptidase N (EC 3.4.17.3 kininase I arginase carboxypeptidase) is a zinc-metalloproteinase. Notable substrates of this soluble enzyme include bradykinin (to form [desArg ]-BK, active at B, bradykinin receptors), enkephalins and atrial natriuretic peptide. An inhibitor used is MERGETPA. but it is not very selective. 

Endopeptidase-24.II (EC 3.4.24.11 NELP neutral endopeptidase neprilysin, enkephalinase) is a zinc-metalloproteinase, found both in soluble and plasma membrane forms. It is an important enzyme in neuropeptide degradation. Notable neuropeptide substrates include tachykinins (substance P, neurokinin A, neurokinin B), endothelins (ET-1, ET-2, ET-3), atrial natriuretic peptide, neurotensin, somatostatin and cholecystokinins. 

Endopeptidase-24.15 (EC 3.4.24.15 thimet oligopeptidase) is a zinc-metalloproteinase found in soluble and membrane forms. Notable substrates include angiotensin I, angiotensin II, bradykinin, LH-RH, neurotensin and somatostatin. Inhibitors include CPP-Ala-Ala-Tyr-pAB CPE-Ala-Ala-Phe-pAB,... 

Hite, L.A., Shannon, J.D., Bjamason, J.B., and Fox, J.W. (1992). Sequence of a cDNA clone encoding the zinc metalloproteinase hemorrhagic toxin e from crotalus atrox evidence for signal, zymogen, and disintegrin-like structures. Biochemistry 37 6203-6211. 

Since the development of fosinoprilat, a number of potent phosphinic inhibitors have been reported toward various zinc-metalloproteinases. The examples discussed below which have been selected as crystal structures are available, and thus some insights on the phosphoryl binding mode with the zinc ion can be deduced and the value of phosphinic inhibitors in unveiling enzyme catalytic residues can be illustrated. 

However, three hemorrhagic toxins also fall into this category of sequence similarity to atroxase. So a direct comparison of the primary structure of the zinc bnding region does not give any clues as to why there is a difference in proteolytic activities between hemorrhagic and nonhemorrhagic zinc metalloproteinases. 

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