title: QM/MM investigation of the reaction rates of substrates of 2,3-dimethylmalate lyase: A catabolic protein isolated from Aspergillus niger.
abstract: Aspergillus niger is an industrially important microorganism used in the production of citric acid. It is a common cause of food spoilage and represents a health issue for patients with compromised immune systems. Recent studies on Aspergillus niger have revealed details on the isocitrate lyase (ICL) superfamily and its role in catabolism, including (2R, 3S)-dimethylmalate lyase (DMML). Members of this and related lyase super families are of considerable interest as potential treatments for bacterial and fungal infections, including Tuberculosis. In our efforts to better understand this class of protein, we investigate the catalytic mechanism of DMML, studying five different substrates and two different active site metals configurations using molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. We show that the predicted barriers to reaction for the substrates show good agreement with the experimental kcat values. This results help to confirm the validity of the proposed mechanism and open up the possibility of developing novel mechanism based inhibitors specifically for this target.
authors.affiliation: Department of Chemistry, Faculty of Science, Kasetsart University, 50 Ngam Wong Wan Rd., Chatuchak, Bangkok 10900, Thailand.
authors.forename: Warot
authors.initials: W
authors.lastname: Chotpatiwetchkul
authors.affiliation: Department of Social and Applied Science, College of Industrial Technology, King Mongkut's University of Technology North Bangkok, Bangkok 10800, Thailand.
authors.forename: Nathjanan
authors.initials: N
authors.lastname: Jongkon
authors.affiliation: Department of Chemistry, Faculty of Science, Kasetsart University, 50 Ngam Wong Wan Rd., Chatuchak, Bangkok 10900, Thailand.
authors.forename: Supa
authors.initials: S
authors.lastname: Hannongbua
authors.affiliation: Department of Chemistry, Faculty of Science, Kasetsart University, 50 Ngam Wong Wan Rd., Chatuchak, Bangkok 10900, Thailand. Electronic address: paul.gleeson@ku.ac.th.
authors.forename: M Paul
authors.initials: MP
authors.lastname: Gleeson
mesh_terms: D001234:Aspergillus niger / Q000201:enzymology*; D055162:Biocatalysis; D005656:Fungal Proteins / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008190:Lyases / Q000737:chemistry*; D008293:Malates / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D011789:Quantum Theory; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D005656:Fungal Proteins; D008293:Malates; C030298:malic acid; D008190:Lyases
keywords: Aspergillus niger; DMML; Molecular dynamics (MD); QM/MM