Thio-molybdenum cofactor biosynthesis is a pathway that begins in the mitochondrial matrix and ends in the cytosol by which GTP becomes thio-molybdenum cofactor, the sulfo-form of molybdenum cofactor required by certain plant enzymes. First, the enzyme GTP 3',8-cyclase, located in the mitochondrial matrix, catalyzes the conversion of GTP, S-adenosylmethionine, and a reduced electron acceptor to 3′,8-cH2GTP, L-methionine, 5'-deoxyadenosine, an oxidized electron acceptor, and a hydrogen ion with the help of a [4Fe-4S] cluster cofactor. Second, cyclic pyranopterin monophosphate (cPMP) synthase catalyzes the conversion of 3′,8-cH2GTP to cPMP and pyrophosphate. Next, ABC transporter of the mitochondrion 3 (ATM3) exports cPMP from the mitochondrial matrix into the cytosol where it is acted upon by molybdopterin (MPT) synthase. MPT synthase is a heterotetramer composed of 2 large and 2 small subunits. The two small subunits are thiocarboxylated by molydopterin synthase sulfurtransferase, and each transfers a sulfur to cPMP to generate the dithiolene in molybdopterin and releasing hydrogen ion in the process. The following enzyme in the pathway, molybdenum insertase is a two-domain protein that catalyzes the fourth and fifth reactions. The smaller C-terminal Cnx1G domain functions as a molybdopterin molybdotransferase and activates molybdopterin for molybdenum insertion. The product of this reaction, molybdopterin adenine dinucleotide (MPT-AMP), is then transferred to the larger N-terminal Cnx1E domain which exhibits molybdopterin adenylyltransferase activity and inserts molybdenum into the dithiolene of molybdopterin, creating molybdenum cofactor (Moco). Molybdenum insertase requires a divalent cation (e.g. magnesium) as a cofactor. Lastly, molybdenum cofactor sulfurtransferase uses L-cysteine and a reduced electron acceptor to convert molybdenum cofactor into thio-molybdenum cofactor, producing L-alanine, oxidized electron acceptor, and water as byproducts. It requires pyridoxal 5'-phosphate as a cofactor.

Thio-Molybdenum Cofactor Biosynthesis References