14 years ago, the world was shaken up by two devastating terrorist attacks on US soil. First was, 9/11 attack on world trade centre which was followed by the postal deliveries of lethal bioweapon, Anthrax. Anthrax is an infectious disease caused by Bacillus anthracis and apart form being bioweapon, anthrax is major cause of global burden of livestock infections as well as a latest form of contagion in injectional heroin users in Europe.
One of the ways to go about fighting anthrax is to understand the mechanism of virulence of the bacteria and identify the factors responsible for it. As metalloproteins play a major role in virulence of bacteria, bacterial genes involved in metal homeostasis have been broadly demonstrated to be key virulence determinants. Bacillus anthracis expresses a putative metal import system, MntBCA, which belongs to the large family of ATP Binding Cassette (ABC) transporters and is essential for it’s virulence. Deletion of MntA, the systems substrate binding protein, yields a completely non-virulent strain. Various trace metals imported by ABC transporters such as Fe, Zn, Mn are essential to bacterial virulence and pathogenesis.
Which of these metals is involved in virulence of anthrax?
The answer to this question can be found by determining the binding affinity of various metals to the baMntA ( the system’s high affinity substrate binding protein). In a recent article in Metallomics, Oded Lewinson et al. elucidate the first structure-function analysis of baMntA. They determined its metal binding specificity and affinities by Isothermal Titration Calorimetry (ITC) and Identified residues that participate in metal coordination.
A series of ITC experiments revealed that-
- MntA does not bind to Fe2/3+ (contrast to inference from growth complementation studies).
- Rather , MntA binds a variety of metal ions, including Mn2+, Zn 2+, Cd2+, CO2+ and Ni2+.
- Binding of Zn 2+ and CO2+ have a pronounced thermo-stabilising effect on MntA, with Mn2+ having a milder effect.
- Thermodynamic stability of MntA, metal binding and release experiments suggest that Mn2+ is the metal that is likely transported by MntBCA and is therefore the limiting factor for virulence of Bacillus anthracis.
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