Sulfurous ping-pong in the urinary tract
Swissmedic, the Swiss agency for therapeutic products, has approved Zevtera (ceftobiprole medocaril) for the treatment of complicated skin and soft tissue infections, including diabetic foot infections which have not spread to the bone. Ceftobiprole is licensed from and co-developed with Basilea Pharmaceutica Ltd. Janssen-Cilag will market ceftobiprole in Switzerland under the trade name Zevtera.
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Transfer of information is a basic property of biological systems. Common examples include transfer of genetic information or nerve impulses.
Transmission of signals occurs at an even more fundamental level between and within cells, including signaling molecules, which bear a phosphate or a sulfate group. The latter contain a sulfur atom. Since these processes are of supreme importance, they have been extensively studied and a number of mechanisms and related protein structures have been revealed. Thus, it is even more surprising that ETH Zurich researchers studying transfer processes among sulfurylated molecules discovered a protein, sulfotransferase, whose function is known but which exhibits a previously unknown structure. The group of Rudi Glockshuber recently published a paper about the protein, called ASST, in the scientific journal PNAS .
ETH Zurich researchers crossed the disulfide bridge
The discovery of the signal transfer mechanism happened accidentally, as is often the case in scientific research. The Glockshuber group studies protein folding mechanisms, where bonds between two sulfur atoms in a protein chain, disulfide bridges, play an important role. While examining gene data banks, the researchers stumbled upon an unusual gene combination present in strains of E. coli which cause urinary tract infections: two genes for the disulfide bond formation machinery were clustered with the gene for ASST.
Since bacteria often contain functionally-related genes close to each other, the researchers decided to use ASST to study disulfide bond formation.
Hence, they decided to elucidate the structure of ASST. This turned out to be a tantalizing task because this protein is large and present in only minute amounts in a bacterial compartment called periplasm. By growing large-scale bacterial cultures the scientists could obtain sufficient material for crystallographic studies. The crystals of ASST were analyzed at the Swiss Light Source at Paul Scherrer Institut in Villigen, Switzerland.
Two propellers building a cage
This analysis, down to 2 Angstrom resolution, revealed that ASST indeed contains an extremely short disulfide bond which can presumably only be formed by the action of the disulfide bond formation machinery genetically associated with ASST. This disulfide bridge is a prerequisite for proper folding of this protein and could also play a role in regulating its catalytic activity.
However, these features were almost outweighed by other unusual discoveries: the researchers found a previously never-observed protein structure to catalyze this process. This structure consists of two equal propeller-like parts which contain active sites in the center of the two propellers, built of beta-pleated sheets. Such a structure has never been observed for a sulfotransferase.
How does this two-propeller machine function? To answer this question, the scientists replaced individual amino acids, i.e. building blocks of the protein. In addition, they used molecules acting as sulfuryl-donors and repeated crystallographic analyses. Now they saw that five amino acids containing nitrogen are essential for the function of ASST. They built a reaction cage that accommodates both the donor and the acceptor of the sulfuryl group. Furthermore, during the transfer, the sulfuryl group is directly, covalently bound to a histidine side chain of ASST. Thus, the signal is first transferred from the donor to ASST and subsequently from ASST to the acceptor. Such a ping-pong mechanism is unique in the processes of sulfuryl transfer.
Point of vantage against the “bad” E. coli strains
A new structure, a new mechanism - this opens up medically relevant perspectives. Goran Malojèi?the first author of this study, explains several interesting points. Since ASST is not present in mammals, the protein could be a feasible target for antibacterial drugs. Furthermore, since ASST is present exclusively in E. coli strains causing urinary tract infections, a selective action against these bacteria would leave the other, useful bacteria intact.
In addition, Malojèi?ntends to collaborate with in-silico chemists, who use computers to design molecules, and develop inhibitors of ASST. He also plans to use ASST for the synthesis of novel molecules bearing sulfuryl groups.
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