The revised three-step detour pathway in dolichol biosynthesis is evolutionarily conserved in budding yeast.

Abstract

The identification of <i>SRD5A3</i>, a causative gene for congenital disorders of glycosylation (CDGs), together with its yeast ortholog <i>DFG10</i>, established the prevailing model that dolichol is synthesized from polyprenol in a single step. Subsequently, a recent discovery of DHRSX in CDG patients revised this view and led to the proposal of a three-step detour pathway for dolichol biosynthesis. However, it remains unclear whether this pathway represents a conserved mechanism or reflects evolutionary diversity in eukaryotes. Here, we identified <i>TDA5</i> as a yeast ortholog of <i>DHRSX</i>. Deletion of <i>TDA5</i> caused glycosylation defects, reduced dolichol levels, and accumulated polyprenol. All these phenotypes were rescued by expression of <i>DHRSX</i>, but not by <i>DFG10</i> or <i>SRD5A3</i>. These findings show that Tda5 serves the same function as DHRSX in yeast, thereby demonstrating conservation of the three-step detour pathway in yeast and supporting a broader eukaryotic framework for dolichol biosynthesis.