InterPro domain: IPR013483

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 [ 1 , 2 ].

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 [ 3 ]. MoCF is the active co-factor in eukaryotic and some prokaryotic molybdo-enzymes, but the majority of 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 [ 4 ]. 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 ( Q39054 ) of Arabidopsis thaliana (Mouse-ear cress), mammalian Gephryin (e.g. Q9NQX3 ) and Drosophila melanogaster (Fruit fly) Cinnamon ( P39205 ) [ 5 ].

This entry represents the MoaA protein (molybdenum cofactor biosynthesis protein A), also known as cyclic pyranopterin monophosphate synthase or GTP 3',8-cyclase.

MoaA is a member of the wider S-adenosylmethionine(SAM)-dependent enzyme family which catalyze the formation of protein and/or substrate radicals by reductive cleavage of SAM via a [4Fe-4S] cluster. Monomeric and homodimeric forms of MoaA have been observed in vivo , and it is not clear what the physiologically relevant form of the enzyme is [ 6 ]. The core of each monomer consists of an incomplete TIM barrel, formed by the N-terminal region of the protein, containing a [4Fe-4S] cluster. The C-terminal region of the protein, which also contains a [4Fe-4S] cluster consists of a beta-sheet covering the lateral opening of the barrel, an extended loop and three alpha helices. The N-terminal [4Fe-4S] cluster is coordinated with 3 cysteines and an exchangeable SAM molecule, while the C-terminal [4Fe-4S], also coordinated with 3 cysteines, is the binding and activation site for GTP [ 7 ].

1. Cell biology of molybdenum. Biochim. Biophys. Acta 1763, 621-35
2. Molybdenum and tungsten in biology. Trends Biochem. Sci. 27, 360-7
3. Mutational analysis of Escherichia coli MoeA: two functional activities map to the active site cleft. Biochemistry 46, 78-86
4. In vivo interactions between gene products involved in the final stages of molybdenum cofactor biosynthesis in Escherichia coli. J. Biol. Chem. 277, 48199-204
5. Molybdenum co-factor biosynthesis: the Arabidopsis thaliana cDNA cnx1 encodes a multifunctional two-domain protein homologous to a mammalian neuroprotein, the insect protein Cinnamon and three Escherichia coli proteins. Plant J. 8, 751-62
6. Crystal structure of the S-adenosylmethionine-dependent enzyme MoaA and its implications for molybdenum cofactor deficiency in humans. Proc. Natl. Acad. Sci. U.S.A. 101, 12870-5
7. Binding of 5'-GTP to the C-terminal FeS cluster of the radical S-adenosylmethionine enzyme MoaA provides insights into its mechanism. Proc. Natl. Acad. Sci. U.S.A. 103, 6829-34