Scientists have come a step closer to designing a new kind of drug that could stop certain virulent bacterial infections in their tracks. By deciphering the structure of a particular bacterial enzyme that modifies its own chromosome chemistry and function, the researchers hope to expose an opening that future medicine could exploit. Their research will be published in today’s issue of the journal Cell.
“The enzyme, called ‘Dam,’ is found in bacteria and not their hosts, so that gives us a target unique to the pathogens,” says Stan Hattman, professor emeritus of biology at the University of Rochester, and a co-author of the study. “This could give us an alternative weapon against infections that are resistant to current antibiotics. Since higher organisms don’t have Dam, a drug that exploits this difference should affect the bacteria without interfering with important biological processes in humans. When I started studying the Dam methyltransferase more than 30 years ago, I never in my wildest dreams imagined that it could lead to something of potential medical importance.”
“For the first time, using the 3-D crystal structure, we have been able to see the specific Dam structure in action,” says Xiaodong Cheng, professor of biochemistry at Emory University School of Medicine and principal author of the research. Using this information it should be possible to design a drug to inhibit the enzyme’s chemical reaction.
Scientists have known for many years that Dam (DNA adenine methyltransferase) plays a role in regulating gene expression in many bacteria. Each time the bacteria reproduce, Dam modifies the A (adenine) nucleotide in the DNA sequence GATC through a chemical reaction known as methylation. All biological methylation reactions involve the transfer of a methyl group from a small molecule, S-adenosyl-methionine (AdoMet or SAM). The process is used to tag a variety of macromolecules, including DNA, and it is important in cellular processes such as regulating gene expression, DNA replication and repair. In humans DNA methylation is carried out by other methyltransferases, and it occurs on the C (cytosine) rather than A (adenine) nucleotide.
Recently scientists have discovered a new role for Dam methylation; viz, it is essential for regulating the expression of genes responsible for bacterial virulence. When the Dam gene is rendered defective through mutation, bacteria lose their disease-causing potency. The Dam enzyme begins by randomly binding to DNA. Then gliding along the molecule (like fingers sliding down a guitar neck searching for the right chord) it examines groups of base pairs as it goes. Each time it finds the sequence GATC it stops and methylates the A nucleotide, transferring a methyl group from a small molecule, S-adenosyl-methionine. Dam must move quickly because if the bacteria reproduce with the wrong methylation pattern, gene expression may be incomplete and the bacteria will lose their virulence.
Hattman and Cheng plan to continue their research to screen for compounds that might inhibit the Dam enzyme.