Unstable enzyme underlies inherited ALS.

In March, researchers announced they had pinpointed the faulty gene in the familial form of amyotrophic lateral sclerosis (ALS), often called Lou Gehrig's disease (SN: 3/6/93, p. 148). Mistakes in that gene's sequence lead to alterations in an enzyme called superoxide dismutase. Typically, this enzyme becomes active when two identical "subunits" link up (as shown) to form a "dimer" and disarm potentially harmful oxygen free radicals by converting them to hydrogen peroxide or molecular oxygen.

Using X-ray crystallography and computer graphics techniques, John A. Tainer and his colleagues at the Scripps Research Institute in La Jolla, Calif., found that enzyme alterations (the most common in red; others, in gold) do not affect the sites (orange and blue) where this chemical conversion occurs. Instead the alterations weaken the dimer linkage, causing it to fall apart easily. Thus the enzyme scavenges fewer free radicals, says Teepu Siddique of Northwestern University Medical School in Chicago.

He and his colleagues measured the enzyme's activity in the red blood cells of 15 ALS patients from seven families inherited ALS. The enzyme worked between one-third and one-half as well as normal, they and collaborators from several institutions, including Scripps, report in the Aug. 20 SCIENCE.

"Now we know this disease is caused by free radicals," Siddique says. These results strongly suggest that therapy involving this enzyme or some surrogate compound (not simple antioxidants such as vitamins) may help slow both the inherited and noninherited forms of the illness.