When cells fail to properly dress their proteins in carbohydrates, the results can be devastating—a category of rare genetic disorders called congenital disorders of glycosylation, or CDGs, that are treatable but still incurable. Now researchers at Hiroshima University have discovered that the molecular machinery responsible for this essential process is far more resilient and universal than scientists previously understood.
The key player is dolichol, a lipid molecule that acts as a carrier during protein glycosylation—the process of adding carbohydrates to proteins, a modification vital for countless protein functions throughout the body. For decades, scientists believed dolichol was made through a single, straightforward step: the reduction of a precursor molecule called polyprenol. But that simple story changed when research in 2024 revealed a completely different three-step "detour" pathway operating in humans, one controlled by a gene called DHRSX. The question that immediately followed was whether this newly discovered route was unique to humans or shared across other forms of life.
Kouichi Funato, a professor at Hiroshima University's Graduate School of Integrated Sciences for Life, led a team that set out to answer this question using budding yeast, a favorite model organism for cellular research. Since genes matching DHRSX hadn't been identified in yeast, it was genuinely unknown whether the detour pathway represented a universal strategy or a human-specific quirk. The researchers systematically examined 13 genes belonging to a family called the short-chain dehydrogenase/reductase superfamily—the same family DHRSX belongs to. Two genes stood out: TDA5 and ENV9, with TDA5 showing the strongest connection to dolichol biosynthesis.
What they found was striking. TDA5 performs the exact same function in yeast that DHRSX performs in humans—and it operates independently from DFG10, the gene responsible for the traditional single-step pathway. Rather than working in a rigid sequence, TDA5 and DFG10 appear to work in parallel, offering cells multiple simultaneous routes to produce dolichol. Their results, published in the Proceedings of the National Academy of Sciences, demonstrate that the three-step detour pathway is evolutionarily conserved, meaning it's a fundamental biological system shared across eukaryotes, not a human invention.
But the discovery gets more intriguing. When the researchers deleted both TDA5 and DFG10 simultaneously in yeast—knocking out both known pathways—they expected dolichol production to stop entirely. It didn't. Instead, cells continued manufacturing dolichol at reduced but measurable levels. This unexpected resilience suggests the existence of a third, completely independent "backup pathway" that remains mysterious. "Even when TDA5 and DFG10 were both knocked out simultaneously, dolichol did not completely disappear," Funato explains. "This suggests the possibility that cells retain a 'backup pathway' separate from the three-step detour pathway."
The implications ripple outward. Cells appear to have evolved redundant safeguards around dolichol production—because the stakes of failure are simply too high. Understanding this fuller picture of dolichol biosynthesis could eventually illuminate how defects lead to congenital disorders of glycosylation and guide new therapeutic approaches. For now, Funato's team is focused on identifying the mysterious backup pathway's components. "Our goal is to elucidate the complete picture of dolichol biosynthesis," he says, "and lay the groundwork for explaining how abnormalities in glycan modification lead to cellular dysfunction and disease."