Abstract
The deepest evolutionary branches of the trypsin/chymotrypsin family of serine proteases are represented by the digestive enzymes of the gastrointestinal tract and the multi-domain proteases of the blood coagulation and complement system. Similar to the very old digestive system, highly diverse cleavage specificities emerged in various cell lineages of the immune defense system during vertebrate evolution. The four neutrophil serine proteases (NSPs) expressed in the myelomonocyte lineage, neutrophil elastase, proteinase 3, cathepsin G, and neutrophil serine protease 4, collectively display a broad repertoire of (S1) specificities. The origin of NSPs can be traced back to a circulating liver-derived trypsin-like protease, the complement factor D ancestor, whose activity is tightly controlled by substrate-induced activation and TNFα-induced locally upregulated protein secretion. However, the present-day descendants are produced and converted to mature enzymes in precursor cells of the bone marrow and are safely sequestered in granules of circulating neutrophils. The potential site and duration of action of these cell-associated serine proteases are tightly controlled by the recruitment and activation of neutrophils, by stimulus-dependent regulated secretion of the granules, and by various soluble inhibitors in plasma, interstitial fluids, and in the inflammatory exudate. An extraordinary dynamic range and acceleration of immediate defense responses have been achieved by exploiting the high structural plasticity of the trypsin fold.
Highlights
Distinction between an Ancient Trypsin and Chymotrypsin ClusterAmide bonds in proteins are very slowly hydrolyzed by surrounding water molecules under natural conditions
One member expressed by natural killer cells and cytotoxic lymphocytes, granzyme B (GzmB), displays an arginine residue at position 226 and thereby an overall positively charged P1 binding pocket
At the stage of bony fishes more than 400 million years ago, immune cell-associated serine proteases with selectivity for basic and hydrophobic side chains already emerged in the lymphocyte and myelo-monocyte lineages [70], which gave birth to the extant Gzm A, K, and M [71] in lymphocytes and
Summary
Amide bonds in proteins are very slowly hydrolyzed by surrounding water molecules under natural conditions. 0 residue of the leaving water occupies a position vacated by the Themolecule carbonyl carbon of thejust amide bond between theP1P1 and P1′residues is atta fragment The latter hydrolyses the acyl-enzyme complex and releases the N-terminal by the polarized hydroxyl group of the Ser195. The conversion of trypsin to a active artificial chymotrypsin turned out to be a major challenge for bioengineers [11] and required multiple structural modifications of the S1A fold even in regions that do not directly contact the substrate [12] These structural differences between the present-day chymotrypsin and trypsin members occurred during a very long evolutionary process and were guided by the strong need for a very efficient catalyst irrespective of other flanking residues around the cleaved amide bond.
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