Eglin c and Fragments
Eglin c is an 8.1 kDa protein proteinase inhibitor first isolated from the leech Hirudo medicinalis and now produced by genetic engineering as an N-acetyl derivative 1.
Eglin c belongs to the potato inhibitor I family of serineproteinase inhibitors 1.
Eglins are small protein inhibitors isolated from the leech Hirudo medicinalis by Seemueller et al.,in 1977 2.
This inhibitor is composed of a single polypeptide chain of 70 amino acid residues. It is extremely stable despite the lack of disulphide bridges. This enzyme is a 25 kDa serine proteinase synthesized and stored in the pancreas as a proenzyme which is a single polypeptide chain of 241 amino acid residues 1. Eglin consists of a four-stranded beta-sheet with an alpha-helical segment and the protease-binding loop fixed on opposite sides. This loop, which contains the reactive site Leu45I--Asp46I, is mainly held in its conformation by unique electrostatic/hydrogen bond interactions of Thr44I and Asp46I with the side chains of Arg53I and Arg51I which protrude from the hydrophobic core of the molecule. The conformation around the reactive site is similar to that found in other proteinase inhibitors. The nine residues of the binding loop Gly40I--Arg48I are involved in direct contacts with subtilisin. In this interaction, eglin segment Pro42I--Thr44I forms a three-stranded anti-parallel beta-sheet with subtilisin segments Gly100--Gly102 and Ser125--Gly127. The reactive site peptide bond of eglin is intact, and Ser221 OG of the enzyme is 2.81 A apart from the carbonyl carbon 2.
Eglin C fragments:
In a study, various peptide fragments related to eglin c, which consists of 70 amino acid residues, were synthesized by a conventional solution method and their inhibitory effects on leukocyte elastase, cathepsin G and alpha-chymotrypsin were examined. Among them, H-Arg-Glu-Tyr-Phe-OMe (eglin c 22-25) and H-Ser-Pro-Val-Thr-Leu-Asp-Leu-Arg-Tyr-OMe (Eglin c 41-49) inhibited cathepsin G and alpha-chymotrypsin but not leukocyte elastase, while H-Thr-Asn-Val-Val-OMe (Eglin c 60-63) inhibited leukocyte elastase but not cathepsin G or alpha-chymotrypsin, although eglin c potently inhibited leukocyte elastase, cathepsin G and alpha-chymotrypsin. These results indicated that the interaction sites of eglin c with leukocyte elastase, cathepsin G and alpha-chymotrypsin might be different 3. In another study, a protected C-terminal triacontapeptide of eglin c, eglin c (31–70), eglin c (22–30) and eglin c (8–70) and finally eglin c were synthesized by a conventional solution method in order to study the relationship between their structure and the inhibitory activity against human leukocyte elastase, cathepsin G and a-chymotrypsin. Although the inhibitory activity of eglin c (31–70) and eglin c (22–70) against the aforementioned enzymes did not increase dramatically, eglin c (8–70) exhibited inhibitory activity against the above enzymes with similar or rather lower Ki-values than that of N a-acetyleglin c.
Mode of Action
The interaction of Eglin with subtilisin looks quite similar to the interaction observed in the proteinase complexes of the other 'small' seine proteinase inhibitor proteins, obeying the 'standard mechanism' proposed by Laskowski and Kato. In Eglin, the binding loop is in a conformation which allows it to bind tightly to the cognate enzyme, under formation of a three-stranded (a new feature, not yet observed in other complexes) intermolecular ß-sheet. This complex is in a conformation similar to that expected for a pre-transition state complex. The relatively rigid and densely packed structure of the complex and the high association rates observed suggest that the loop structure in the free inhibitor will possess a similar conformation 2.
It potently inhibits chymotrypsin, subtilisin, neutrophil elastase and cathepsin G, forms loose complexes with bovine pancreatic trypsin and pig pancreatic elastase, and does not inhibit plasmin, thrombin and kallikrein 1. Eglin-c treatment prevents MCT-induced ventilatory dysfunction and suggest that endogenous elastase may play an important role in MCT-induced inflammation-mediated ventilatory abnormality 5.
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