Abstract
Staphylococcus aureus a natural inhabitant of nasopharyngeal tract mainly survives as biofilms and possess complete Krebs cycle which plays major role in its pathogenesis. This TCA cycle is regulated by Isocitrate dehydrogenase (IDH) we have earlier cloned, sequenced (HM067707), expressed and characterized this enzyme from S. aureus ATCC12600. We have observed only one type of IDH in all the strains of S. aureus which dictates the flow of carbon thereby controlling the virulence and biofilm formation, this phenomenon is variable among bacteria. Therefore in the present study comparative structural and functional analysis of IDH was undertaken. As the crystal structure of S. aureus IDH was not available therefore using the deduced amino sequence of complete gene the 3D structure of IDH was built in Modeller 9v8. The PROCHECK and ProSAweb analysis showed the built structure was close to the crystal structure of Bacillus subtilis. This structure when superimposed with other bacterial IDH structures exhibited extensive structural variations as evidenced from the RMSD values correlating with extensive sequential variations. Only 24% sequence identity was observed with both human NADP dependent IDHs (PDB: 1T09 and 1T0L) and the structural comparative studies indicated extensive structural variations with an RMSD values of 14.284Å and 10.073Å respectively. Docking of isocitrate to both human IDHs and S. aureus IDH structures showed docking scores of -11.6169 and -10.973 respectively clearly indicating higher binding affinity of isocitrate to human IDH.
Highlights
Staphylococcus aureus is a Gram positive human pathogen causes biofilms which makes the organism to resist antibiotics, severe community and hospital acquired infections which range with the occurrence of multidrug resistant strains of S. aureus from minor skin infections to life threatening diseases like where high reductive conditions prevails the elevated biofilm endocarditis, toxic shock syndrome and pneumonia [1]
In S. aureus TCA cycle is suppressed upon depletion of rapidly catabolizable carbon sources; this coincides with the transition to producing only formylated δ-toxin and results in an increased inflammatory response and subsequent biofilm formation suggesting that there is an important linkage between bacterial TCA cycle and pathogenesis [3, 5]
In S. aureus the TCA cycle which plays pivotal role in the growth of the organism and this cycle is regulated by isocitrate dehydrogenase (IDH) whose expression makes carbon to enter into Krebs cycle in post-exponential growth phase [21]
Summary
Staphylococcus aureus is a Gram positive human pathogen causes biofilms which makes the organism to resist antibiotics, severe community and hospital acquired infections which range with the occurrence of multidrug resistant strains of S. aureus from minor skin infections to life threatening diseases like where high reductive conditions prevails the elevated biofilm endocarditis, toxic shock syndrome and pneumonia [1]. The IDH activation drives the flow of carbon through the TCA cycle inducing a decrease in the intracellular level of isocitrate and an increase in the level of α-ketoglutarate thereby regulating redox status in the bacteria which is a vital factor in the virulence of S. aureus [10]. These features are best explained through docking of substrate to its 3D structure of the enzyme and correlating with its kinetics [10, 11]. The best predicted model with least DOPE (discrete optimized protein energy) score was selected for further investigation
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