ABSTRACT
Amyloid-ß (Aß)-degrading enzymes are known to degrade Aß peptides, a causative agent of Alzheimer's disease. These enzymes are responsible for maintaining Aß concentration. However, loss of such enzymes or their Aß-degrading activity because of certain genetic as well as nongenetic reasons initiates the accumulation of Aß peptides in the human brain. Considering the limitations of the human enzymes in clearing Aß peptide, the search for microbial enzymes that could cleave Aß is necessary. Hence, we built a three-dimensional model of angiotensin-converting enzyme (ACE) from Stigmatella aurantiaca using homology modeling technique. Molecular docking and molecular dynamics simulation techniques were used to outline the possible cleavage mechanism of Aß peptide. These findings suggest that catalytic residue Glu 434 of the model could play a crucial role to degrade Aß peptide between Asp 7 and Ser 8. Thus, ACE from S. aurantiaca might cleave Aß peptides similar to human ACE and could be used to design new therapeutic strategies against Alzheimer's disease.
Subject(s)
Amyloid beta-Peptides/metabolism , Peptidyl-Dipeptidase A/metabolism , Stigmatella aurantiaca/metabolism , Amino Acid Sequence , Catalytic Domain , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Sequence Data , Peptidyl-Dipeptidase A/chemistry , Protein Conformation , Proteolysis , Sequence Homology, Amino AcidABSTRACT
Cysteine protease is known to degrade amyloid beta peptide which is a causative agent of Alzheimer's disease. This cleavage mechanism has not been studied in detail at the atomic level. Hence, a three-dimensional structure of cysteine protease from Xanthomonas campestris was constructed by homology modeling using Geno3D, SWISS-MODEL, and MODELLER 9v7. All the predicted models were analyzed by PROCHECK and PROSA. Three-dimensional model of cysteine protease built by MODELLER 9v7 shows similarity with human cathepsin B crystal structure. This model was then used further for docking and simulation studies. The molecular docking study revealed that Cys17, His87, and Gln88 residues of cysteine protease form an active site pocket similar to human cathepsin B. Then the docked complex was refined by molecular dynamic simulation to confirm its stable behavior over the entire simulation period. The molecular docking and MD simulation studies showed that the sulfhydryl hydrogen atom of Cys17 of cysteine protease interacts with carboxylic oxygen of Lys16 of Aß peptide indicating the cleavage site. Thus, the cysteine protease model from X. campestris having similarity with human cathepsin B crystal structure may be used as an alternate approach to cleave Aß peptide a causative agent of Alzheimer's disease.
Subject(s)
Amyloid beta-Peptides/chemistry , Bacterial Proteins/chemistry , Cysteine Proteases/chemistry , Molecular Docking Simulation , Structural Homology, Protein , Xanthomonas campestris/enzymology , Cathepsin G/chemistry , HumansABSTRACT
Mycobacterium tuberculosis is a Gram positive, acid-fast bacteria belonging to genus Mycobacterium, is the leading causative agent of most cases of tuberculosis. The pathogenicity of the bacteria is enhanced by its developed DNA repair mechanism which consists of machineries such as nucleotide excision repair. Nucleotide excision repair consists of excinuclease protein UvrABC endonuclease, multi-enzymatic complex which carries out repair of damaged DNA in sequential manner. UvrC protein is a part of this complex and thus helps to repair the damaged DNA of M. tuberculosis. Hence, structural bioinformatics study of UvrC protein from M. tuberculosis was carried out using homology modeling and molecular docking techniques. Assessment of the reliability of the homology model was carried out by predicting its secondary structure along with its model validation. The predicted structure was docked with the ATP and the interacting amino acid residues of UvrC protein with the ATP were found to be TRP539, PHE89, GLU536, ILE402 and ARG575. The binding of UvrC protein with the DNA showed two different domains. The residues from domain I of the protein VAL526, THR524 and LEU521 interact with the DNA whereas, amino acids interacting from the domain II of the UvrC protein included ARG597, GLU595, GLY594 and GLY592 residues. This predicted model could be useful to design new inhibitors of UvrC enzyme to prevent pathogenesis of Mycobacterium and so the tuberculosis.
