Molybdenum cofactor biosynthesis in plants and humans

The transition element molybdenum (Mo) needs to be complexed by a special cofactor in order to gain catalytic activity. With the exception of bacterial Mo-nitrogenase, where Mo is a constituent of the FeMo-cofactor, Mo is bound to a pterin, thus forming the molybdenum cofactor Moco, which in different variants is the active compound at the catalytic site of all other Mo-containing enzymes. The biosynthesis of Moco involves the complex interaction of six proteins and is a process of four steps, which also requires reducing equivalents, iron, ATP and probably copper. After its synthesis, Moco is distributed to the apoproteins of Mo-enzymes by Moco–carrier/binding proteins that also participate in Moco-insertion into the cognate apoproteins. A deficiency in the biosynthesis of Moco has lethal consequences for the respective organisms. In humans, Moco deficiency is a severe inherited inborn error in metabolism resulting in severe neurodegeneration in newborns and causing early childhood death. Due to our better understanding of the chemistry of Moco synthesis, a first therapy has been brought to the clinic.

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► Biosynthesis of the pterin-based molybdenum cofactor involves four steps.
► Six proteins catalyze pyranopterin synthesis, sulfur transfer and metal insertion.
► Iron, S-adenosyl methionine, ATP, cysteine and probably copper are needed.
► Moco is distributed by specific carrier/binding proteins to apo-enzymes.
► Moco deficiency is a severe neurodegenerative disorder; a first therapy is available.