Eukaryotic molybdopterin synthase, like the Escherichia coli MoaD-MoaE counterpart, is a heterotetramer that is composed of two subunits: MOCS2A and MOCS2B. MOCS2B is the catalytic subunit of the molybdopterin synthase complex (MOCS2), a complex that catalyses the conversion of precursor Z into molybdopterin. MOC2SB acts by mediating the incorporation of two sulfur atoms from thiocarboxylated MOCS2A (the small MOCS2 subunit which functions as a sulfur carrier) into precursor Z to generate a dithiolene group [, , , ].Mutations in human MOCS2B gene cause Molybdenum cofactor deficiency type B (MOCOD type B), an autosomal recessive disease which leads to the pleiotropic loss of all molybdoenzyme activities and is characterised by severe neurological damage, neonatal seizures and early childhood death [].
The majority of molybdenum-containing enzymes utilise a molybdenum cofactor (MoCF or Moco) consisting of a Mo atom coordinated via a cis-dithiolene moiety to molybdopterin (MPT). MoCF is ubiquitous in nature, and the pathway for MoCF biosynthesis is conserved in all three domains of life. MoCF-containing enzymes function as oxidoreductases in carbon, nitrogen, and sulphur metabolism [, ]. In Escherichia coli, biosynthesis of MoCF is a three stage process. It begins with the MoaA and MoaC conversion of GTP to the meta-stable pterin intermediate precursor Z. The second stage involves MPT synthase (MoaD and MoaE), which converts precursor Z to MPT; MoeB is involved in the recycling of MPT synthase. The final step in MoCF synthesis is the attachment of mononuclear Mo to MPT, a process that requires MoeA and which is enhanced by MogA in an Mg2 ATP-dependent manner []. MoCF is the active co-factor in eukaryotic and some prokaryotic molybdo-enzymes, but the majorityof bacterial enzymes requiring MoCF, need a modification of MTP for it to be active; MobA is involved in the attachment of a nucleotide monophosphate to MPT resulting in the MGD co-factor, the active co-factor for most prokaryotic molybdo-enzymes. Bacterial two-hybrid studies have revealed the close interactions between MoeA, MogA, and MobA in the synthesis of MoCF []. Moreover the close functional association of MoeA and MogA in the synthesis of MoCF is supported by fact that the known eukaryotic homologues to MoeA and MogA exist as fusion proteins: CNX1 () of Arabidopsis thaliana (Mouse-ear cress), mammalian Gephryin (e.g. ) and Drosophila melanogaster (Fruit fly) Cinnamon () [].This entry represents MoaA (also known as GTP 3',8-cyclase), which belongs to a family of enzymes involved in the synthesis of metallo-cofactors (). Each subunit of the MoaA dimer is comprised of an N-terminal SAM domain () that contains the [4Fe-4S]cluster typical for this family of enzymes, as well as an additional [4Fe-4S]cluster in the C-terminal domain that is unique to MoaA proteins []. The unique Fe site of the C-terminal [4Fe-4S]cluster is thought to be involved in the binding and activation of 5'-GTP.Mutations in the human MoCF biosynthesis proteins MOCS1, MOCS2 or GEPH cause MoCF Deficiency type A (MOCOD), causing the loss of activity of MoCF-containing enzymes, resulting in neurological abnormalities and death [].
