Why do we die of a defect in molybdenum metabolism?

Abstract

The trace element molybdenum (Mo) is vital for humans. As catalytically active metal it is part of four enzymes. Oxidized Mo is taken up from our food as molybdate and bound to a chemical scaffold (pterin) thus becoming the molybdenum cofactor (Moco). Only in this form Mo can become biologically active. The biosynthesis of Moco is a multi-step process starting in the mitochondria and completed in the cytoplasm. A genetic defect in Moco biosynthesis leads to the activity loss of all four Mo-enzymes in humans with most dramatic effects through the loss of sulfite oxidase. The highly reactive sulfite accumulates and damages proteins and metabolites irreversibly. In newborns, neuronal cells react most sensitively to sulfite, and in most cases neurodegenerative symptoms (spasms, impairment of brain development) lead to the death of the little patients. Moco in its isolated form is too unstable to be injected into the newborns as therapeutic medication, but there is a therapy for patients with a mutation in the first step of Moco-biosynthesis. Those patients receive the missing biosynthesis intermediate cPMP by injection thus compensating for the genetic loss and permitting a normal child development. The medication was approved in 2021 in the USA and in 2022 in Europe.