Nature Structural & Molecular Biology pp 721 - 729

The bacteria causing tuberculosis produce a large number of molecules containing sulfur. Virulence of these bacteria correlates with the abundance of one group of such molecules, collectively called sulfolipid 1 (SL-1). A paper in the August issue of Nature Structural & Molecular Biology reports the identification and characterization of the enzyme that adds the sulfur to SL-1 precursor. These findings could facilitate the design of drugs that block the generation of SL-1 as a treatment for tuberculosis.

SL-1 molecules consist of lipids linked to a sugar core called trehalose. Addition of sulfur, in the form of the sulfate group, to trehalose occurs before SL-1 molecules are transported to the bacterial cell surface membrane. Bertozzi and colleagues determined the three-dimensional structure of the enzyme, a sulfotransferase, responsible for the addition of the sulfur group onto trehalose. They also identified the trehalose binding site and determined how the sulfotransferase specifically recognizes this sugar and modifies it at the correct location. These and other data suggest that the modification of trehalose is the first step in the synthesis of SL-1. The study therefore provides a framework for understanding the role of SL-1 in tuberculosis.

In the 1980s, there was a 98% chance of curing tuberculosis. This level of success required patients to take good quality antibiotics for six months. However, poor patient compliance with this regimen and the lack of medical supervision, especially in poorer countries, resulted in multi-drug resistant tuberculosis and a considerably lower cure rate (60-70%). The identification the sulfotransferases by Bertozzi and colleagues is expected to lead to the design of a new family of drugs that may decrease the virulence of the Mycobacterium tuberculosis and thereby increase the cure rate for tuberculosis.

Nature Structural & Molecular Biology pp 714 - 720

Every day our DNA is damaged by assaults from within and without. That's the bad news. The good news is that we have proteins that can fix or remove the damage. A paper in the August issue of Nature Structural & Molecular Biology now explains how one such protein executes this function.

SL-1 molecules consist of lipids linked to a sugar core called trehalose. Addition of sulfur, in the form of the sulfate group, to trehalose occurs before SL-1 molecules are transported to the bacterial cell surface membrane. Bertozzi and colleagues determined the three-dimensional structure of the enzyme, a sulfotransferase, responsible for the addition of the sulfur group onto trehalose. They also identified the trehalose binding site and determined how the sulfotransferase specifically recognizes this sugar and modifies it at the correct location. These and other data suggest that the modification of trehalose is the first step in the synthesis of SL-1. The study therefore provides a framework for understanding the role of SL-1 in tuberculosis.

O⁶-alkylguanine-DNA alkyltransferase (AGT) is a DNA repair protein that can directly reverse damage at the O⁶-position of guanine in DNA. Damage at this position is mutagenic and forms the basis of anti-cancer chemotherapies that involve DNA methylation and chloroethylation that result in cytotoxicity. Therefore increased levels of AGT in tumor cells confer resistance to these agents and inhibitors of AGT are currently in clinical trials as anticancer therapeutics.

To understand more about how this protein recognizes and repairs the damaged DNA and to aid in the design of new inhibitors, Tainer and co-workers (The Scripps Research Institute) solved the structures of AGT bound to different DNAs. They find that the protein binds to DNA in a new way and that this type of binding may promote flipping of the mutated base and thus facilitate DNA repair. On the basis of these findings it may be possible to design new AGT inhibitors and thus improve the clinical efficacy of the chemotherapeutic agents.