Molybdenum in Human Health and Disease

Abstract

Molybdenum is an essential trace element and crucial for the survival of animals. Four mammalian Mo-dependent enzymes are known, all of them harboring a pterin-based molybdenum cofactor (Moco) in their active site. In these enzymes, molybdenum catalyzes oxygen transfer reactions from or to substrates using water as oxygen donor or acceptor. Molybdenum shuttles between two oxidation states, Mo(IV) and Mo(VI). Following substrate reduction or oxidation, electrons are subsequently shuttled by either inter- or intra-molecular electron transfer chains involving prosthetic groups such as heme or iron-sulfur clusters. In all organisms studied so far, Moco is synthesized by a highly conserved multi-step biosynthetic pathway. A deficiency in the biosynthesis of Moco results in a pleitropic loss of all four human Mo-enzyme activities and in most cases in early childhood death. In this review we first introduce general aspects of molybdenum biochemistry before we focus on the functions and deficiencies of two Mo-enzymes, xanthine dehydrogenase and sulfite oxidase, caused either by deficiency of the apo-protein or a pleiotropic loss of Moco due to a genetic defect in its biosynthesis. The underlying molecular basis of Moco deficiency, possible treatment options and links to other diseases, such as neuropsychiatric disorders, will be discussed.

S-sulfocysteine/NMDA receptor–dependent signaling underlies neurodegeneration in molybdenum cofactor deficiency

“…Under oxygenated conditions such as in serum and plasma, cysteine is converted to its oxidized cystine form, while cellular reducing conditions favor the presence of the reduced cysteine form. We probed cystine and cysteine reaction with sulfite and found a cystine-and sulfite-dependent formation of SSC in a stoichiometric manner, while cysteine was not able to form SSC with sulfite (Supplemental Figure 2A), which supports the proposed extracellular scavenging function of cysteine (10). Likewise, the addition of sulfite to neuronal culture medium resulted in a dosedependent formation of SSC, which reached saturation as a result of a limited cystine concentration in the medium (Supplemental Figure 2B).…”

“…Patients with MoCD harbor mutations in the genes encoding the enzymes molybdenum cofactor synthesis 1 (MOCS1), MOCS2, or gephyrin (GPHN) that are required for molybdenum cofactor (Moco) biogenesis (4,10), a pathway that is highly conserved throughout evolution. MoCD leads to the loss of activity of 4 molybdenum enzymes in humans (11) including sulfite oxidase (SO).…”

“…MoCD leads to the loss of activity of 4 molybdenum enzymes in humans (11) including sulfite oxidase (SO). SO is a mitochondrial enzyme (12) that catalyzes the oxidation of toxic sulfite, generated from cysteine metabolism, to sulfate (10). The latter is required for multiple biochemical reactions including the sulfation of several substrates important for brain development (13,14).…”

“…The latter is required for multiple biochemical reactions including the sulfation of several substrates important for brain development (13,14). MoCD has a clinical presentation similar to that of SO deficiency (SOD) disorder (15), implicating sulfite toxicity as the major pathomechanism in both diseases (10). Patients with MoCD have high levels of sulfite in their urine, which is accompanied by elevated urinary levels of taurine and thiosulfate, while their plasma cystine level is depleted (10,16).…”

“…Patients with MoCD have high levels of sulfite in their urine, which is accompanied by elevated urinary levels of taurine and thiosulfate, while their plasma cystine level is depleted (10,16). In addition, S-sulfocysteine (SSC), a secondary sulfurcontaining metabolite, accumulates in the urine and plasma of MoCD patients and is used for MoCD diagnostics (10,17).…”