ArticleACS catalysis2017
Distinct Roles of Catalytic Cysteine and Histidine in the Protease and Ligase Mechanisms of Human Legumain As Revealed by DFT-Based QM/MM Simulations.
Article in ACS catalysis, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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34 citing papers in PubMed, 65 citations in OpenAlex.
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- Computational Study of the Inhibition of RgpB Gingipain, a Promising Target for the Treatment of Alzheimer's Disease.Journal of chemical information and modeling · 2023Article
- Structural basis for proenzyme maturation, substrate recognition, and ligation by a hyperactive peptide asparaginyl ligase.The Plant cell · 2022Article
- Bis(thio)carbohydrazone Luminogens with AIEE and ACQ Features and TheirChemistrySelect · 2022Article
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6 authors at 1 institution in 1 country.
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Abstract
The cysteine protease enzyme legumain hydrolyzes peptide bonds with high specificity after asparagine and under more acidic conditions after aspartic acid [Baker E. N.J. Mol. Biol.1980, 141, 441-484; Baker E. N.; J. Mol. Biol.1977, 111, 207-210; Drenth J.; Biochemistry1976, 15, 3731-3738; Menard R.; J. Cell. Biochem.1994, 137; Polgar L.Eur. J. Biochem.1978, 88, 513-521; Storer A. C.; Methods Enzymol.1994, 244, 486-500. Remarkably, legumain additionally exhibits ligase activity that prevails at pH > 5.5. The atomic reaction mechanisms including their pH dependence are only partly understood. Here we present a density functional theory (DFT)-based quantum mechanics/molecular mechanics (QM/MM) study of the detailed reaction mechanism of both activities for human legumain in solution. Contrasting the situation in other papain-like proteases, our calculations reveal that the active site Cys189 must be present in the protonated state for a productive nucleophilic attack and simultaneous rupture of the scissile peptide bond, consistent with the experimental pH profile of legumain-catalyzed cleavages. The resulting thioester intermediate (INT1) is converted by water attack on the thioester into a second intermediate, a diol (INT2), which is released by proton abstraction by Cys189. Surprisingly, we found that ligation is not the exact reverse of the proteolysis but can proceed via two distinct routes. Whereas the transpeptidation route involves aminolysis of the thioester (INT1), at pH 6 a cysteine-independent, histidine-assisted ligation route was found. Given legumain's important roles in immunity, cancer, and neurodegenerative diseases, our findings open up possibilities for targeted drug design in these fields.
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