Protease-activated receptors reaction

Most GPCRs interact with and activate more than one G-protein subfamily, e.g., with Gs plus Gq/n (histamine H2, parathyroid hormone and calcitonin recqrtors), Gs plus G (luteinising hormone receptor, 32-adrenoceptor) or Gq/11 plus G12/13 (thromboxane A2, angiotensin ATb endothelin ETA receptors). Some receptors show even broader G-protein coupling, e.g., to Gi, Gq/n plus Gi n ( protease-activated receptors, lysophosphatidate and sphingosine-1-phosphate receptors) or even to all four G-protein subfamilies (thyrotropin receptor). This multiple coupling results in multiple signaling via different pathways and in a concerted reaction of the cell to the stimulus. 

Trypsin is typically considered an enzyme found in the pancreas and small intestine. However, trypsin, thrombin, and plasmin are also widely expressed in endothelium, including epithelial immune cells as well as neurons. Upregulated expression and release occurs during both acute and chronic inflammation [60], Autocrine release of trypsin and thrombin causes activation of protease-activated receptors (PARs) reaction leading to cellular proliferation and inflammation [4], This response includes release of proteins by all cells during chronic inflammation. Bik prevents PAR activation on cell surfaces. 

The two platelet membrane glycoproteins for which the strongest evidence exists at the present time that they are thrombin receptors are a specific form of the GPIb-DC-V conq>lex and PARI, the protease-activated thrombin receptor these will be discussed next in this review. Based on their apparent ability to form complexes with a hrombin, several other proteins had previously t en proposed as thrombin receptors but in only a few cases were the necessary further studies carried out to test these hypotheses. Protease nexin 1 was proposed as a thrombin receptor based on the similar time courses of complex formation and platelet activation but it was subsequently found that protease nexin 1 cannot be a receptor since it is an internal conq>onent of platelets that is expressed on the surface only ater activation. Glycoprotein V has also been proposed as a thrombin receptor based on the feet that it can be cleaved by low concentrations of a-thrombin but subsequent studies (reviewed in ) showed that there was no consistent relationship between the rate or extent of GPV hydrolysis and the extent of platelet activation induced by a-thrombin. Another thrombin-activatable receptor, PAW, has been identified in mouse platelets but not in human platelets using a reverse transcriptase/ polymerase chain reaction approach (unpublished data and S.Coughlin, personal communication). PAR3 has, however, been reported cloned from a human platelet cDNA library. ... 

For the enantiopure production of human rhinovirus protease inhibitors scientists from Pfizer developed a kinetic resolution and recycling sequence (Scheme 6.14 A). The undesired enantiomer of the ester is hydrolysed and can be racemised under mild conditions with DBU. This enzymatic kinetic resolution plus racemisation replaced a significantly more expensive chemical approach [52]. An enzymatic kinetic resolution, in combination with an efficient chemically catalysed racemisation, is the basis for a chiral building block for the synthesis of Talsaclidine and Revatropate, neuromodulators acting on cholinergic muscarinic receptors (Scheme 6.14B). In this case a protease was the key to success [53]. Recently a kinetic resolution based on a Burkholderia cepacia lipase-catalysed reaction leading to the fungicide Mefenoxam was described [54]. Immobilisation of the enzyme ensured >20 cycles of use without loss of activity (Scheme 6.14 C). 

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