Molybdenum cofactor biosynthesis and deficiency

Abstract

The molybdenum cofactor (Moco) forms the active site of all molybdenum (Mo) enzymes, except nitrogenase. Mo enzymes catalyze important redox reactions in global metabolic cycles. Moco consists of Mo covalently bound to one or two dithiolates attached to a unique tricyclic pterin moiety commonly referred to as molybdopterin (MPT). Moco is synthesized by an ancient and conserved biosynthetic pathway that can be divided into four steps, according to the biosynthetic intermediates precursor Z (cyclic pyranopterin monophosphate), MPT and adenylated MPT. In a fifth step modifications such as attachment of nucleotides, sulfuration or bond formation between Mo and the protein result in different catalytic Mo centers. A defect in any of the steps of Moco biosynthesis results in the pleiotropic loss of all Mo enzyme activities. Human Moco deficiency is a hereditary metabolic disorder characterized by severe neurodegeneration resulting in early childhood death. Recently, a first substitution therapy was established.

Arabidopsis Molybdopterin Biosynthesis Protein Cnx5 Collaborates with the Ubiquitin-like Protein Urm11 in the Thio-modification of tRNA

“…The MoeB-catalyzed formation of thiocarboxylate at the C-terminal glycine of MoaD is necessary to transfer the sulfur atom to the cyclic pyranopterin monophosphate to form molybdopterin (MPT), which is the precursor of MoCo (15,16). Similar MoCo biosynthetic pathways have been identified in plants and animals (13,(17)(18)(19). In plants, Cnx (cofactor for nitrate reductase and xanthine dehydrogenase) proteins have been shown to participate in multistep reactions (17).…”

Protein Radical Formation Resulting from Eosinophil Peroxidase-catalyzed Oxidation of Sulfite

“…The toxic potential of bisulfite is most clearly indicated by the loss of sulfite oxidase, the molybdenum-containing enzyme that oxidizes sulfite to sulfate (SO 4 2Ϫ ) (51). In fact, in humans, the loss of sulfite oxidase is fatal in infancy or early childhood (52). It is noteworthy that in cases of sulfite oxidase deficiency, the concentration of sulfite in plasma is abnormal (10 M to ϳ2 mM) (5,53).…”

Molybdenum cofactor-dependent resistance to N-hydroxylated base analogs in Escherichia coli is independent of MobA function

“…MoCo biosynthesis proceeds in a number of discrete steps [see 34 or 35 for reviews]. The final product in E. coli is MGD (Molybdopterin Guanine Dinucleotide), in which molybdopterin is connected by dinucleotide linkage to a GMP residue [34,35]. With few exceptions (see below), the known E. coli molybdoenzymes use this MGD form of MoCo.…”