Mass. General study may lead to better treatment of rare but devastating human genetic disorder
A study conducted in C. elegans nematode roundworms may lead to improved treatment of a rare human genetic disorder that causes severe neurological symptoms leading to death in early childhood. In their report published in Nature Chemical Biology, two Massachusetts General Hospital (MGH) investigators describe finding that C. elegans can acquire the molybdenum cofactor (Moco) – a molecule essential to the function of essential enzymes – by consuming E.coli bacteria, the first evidence that Moco can be transferred between species. The investigators also identified the metabolic pathway that is responsible for the symptoms observed in Moco deficiency.
“Until now, Moco was thought to be too unstable to be trafficked between cells and tissues, much less between organisms separated by a billion years of evolution,” says lead author Kurt Warnhoff, PhD, MGH Molecular Biology. “But we found the interaction between these species to be quite robust. Bacteria isolated from rotting fruit – a typical C. elegans habitat – were able to supply Moco to the nematodes. This ability of C. elegans to extract Moco from its microbiome is intriguing and offers hope that we might be able to exploit similar systems to deliver mature Moco to patients with Moco deficiency.”
Many reactions essential to life require the action of enzymes, several of which, in turn, require molecules called cofactors or coenzymes to function correctly. One such coenzyme, Moco, is required for the incorporation of the element molybdenum into several important enzymes. In humans, genetic mutations in Moco-synthesizing enzymes cause Moco deficiency. Affected infants develop seizures, deterioration of brain tissue, developmental delay and usually die within the first few months of life. Moco deficiency is estimated to affect 1 in 100,000 to 200,000 births.
Healthy animals from C. elegans to humans can synthesize Moco within their bodies. In mutant C. elegans that cannot synthesize Moco, normal development halts and the animals die unless fed a bacterial diet featuring the coenzyme, paralleling the effects of Moco deficiency in humans. Using C. elegans genetics to investigate how Moco deficiency leads to death, Warnhoff and senior author Gary Ruvkun, PhD, also of MGH Molecular Biology, identified the pathway that normally breaks down the sulfur-containing amino acids methionine and cysteine as the culprit. A byproduct of that breakdown is the release of sulfite, a toxin used as a preservative in many foods, and the researchers found that lack of Moco inactivates the SUOX enzyme that normally detoxifies sulfite, leading to death of the nematodes.
Says Ruvkun, a professor of Genetics at Harvard Medical School, “These molecular insights offer potential therapeutic avenues for treating Moco deficiency. Limiting exposure to sulfur-containing compounds and inactivating the enzymes that generate sulfite might alleviate the physiologic defects and resultant death that are inevitable in human Moco deficiency.”
Finding that simply ingesting Moco-producing E.coli was sufficient to support the growth and development of Moco-deficient C. elegans suggests that the coenzyme might function as a vitamin. The researchers found that around two-thirds of bacterial genomes synthesize Moco, indicating that the nematodes could depend on bacteria to supply this essential cofactor most of the time. Now Warnhoff and Ruvkun and working to discern how C. elegans determines when to synthesize Moco within its body and when to ingest as a “dietary supplement,” from the bacteria it consumes.
The study was supported by National Institutes of Health grant 5R01 GM044619-26 and Damon Runyon Fellowship grant DRG-2293-16.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $925 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2018 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of “America’s Best Hospitals.”
Terri Ogan Janos