Mapping metabolic coevolution identifies c11orf54 as the missing pentose pathway decarboxylase.

Metabolic networks and enzyme-molecule connections are still being elucidated. Here, through systematic analysis of gene loss and gain across the eukaryotic tree, mapped onto metabolic networks, we build a coevolutionary framework of human metabolism. Using this information, we identify unmapped genes in metabolic pathways, leading to the discovery of C11orf54 as the long-missing decarboxylase of the glucuronate/pentose pathway. These findings provide insights into an alternative route for sugar conversion in humans and other metazoans and its connection to L-ascorbate (vitamin C) biosynthesis. More broadly, our approach offers a framework for mapping missing enzymes across species.