Although butyrylcholinesterase (BChE) is ubiquitous in the human system, its physiological function has often been questioned. Yet BChE has been the subject of active research since its discovery six decades ago. From an evolutionary view point, its stabilized existence even in absence of physiological function spared it from extinction. Herein, we present results on the amino acid residues essential for its stability using CUPSAT server. Out of the 523 amino acids analyzed, 168 were identified to be vital for stability of the protein, and further categorized into three classes. The first class has 82 sites wherein any amino acid substitution results in instability. The second class has 52 sites where on one amino acid substitution alone stability is observed, while the third class has 34 sites where even on two different substitutions, stability is maintained. These sites are distributed throughout the different categories of protein secondary structure, with the order of priority: random coils, alpha-helices and beta-strands. Multiple sequence alignment of BChE showed that most of these residues (85.1%) are within the conserved region, while the few that are not at the conserved region are proposed to be unique residues (14.9%) to the protein which do not show identity with other known homologs. Moreover, majority of the amino acid residues in the functional regions of human BChE do not show instability upon point mutation, indicative of the residue-wise separation for stability and function. Specifically, the active site S198 on mutation does not show instability, while L318P is highly unstable. In addition, S53, G212 and W430 are not involved in its stability and in fact the protein is stable even with all other 19 substitutions. In conclusion, this study bodes well as a forerunner for mutation and protein engineering studies of BChE.
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