Non-canonical metabolites: friends and foes
(2026)
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- Abstract
- Living cells rely on a highly interconnected network of enzyme-catalyzed chemical reactions. However, the pool of cellular metabolites extends beyond the textbook described reactions. These non-canonical metabolites can represent a threat to metabolic integrity but can also be part of undiscovered pathway. We discovered a rescue metabolite that functions as a “guardian angel” for an enzyme operating in a hostile environment. Catel-Manzke syndrome is caused by mutations in the gene TGDS, which belongs to a metabolic pathway considered extinct in humans. We demonstrate that the TGDS product, UDP-4-keto-6-deoxyglucose, is required to maintain the activity of UDP-xylose synthase 1 (UXS1). Cell-based and in vitro studies demonstrated that this metabolite regenerates the NAD⁺ cofactor of UXS1 within the catalytic pocket, a mechanism that has not been described previously. The dependence on TGDS arises from the particular localization of UXS1 in the ER and Golgi apparatus where NAD⁺ is scarce. At the organismal level, the loss of UXS1 is associated with defects in bone formation. UDP-xylose is an essential nucleotide sugar in glycosaminoglycan biosynthesis that are involved in bone development. Biochemical analysis of TGDS deficiency in mice and humans’ samples show that the absence of the enzyme-rescue metabolite is the cause of Catel-Manzke syndrome. This work demonstrates that metabolites not accounted for in canonical metabolic pathways can play central roles in both physiology and disease.
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Citations
Jacobs, J. (2026). Non-canonical metabolites: friends and foes. https://hdl.handle.net/2078.5/273830