 General molybdenum importance  Enzymes that use Moco › 3 families  Biosynthetic pathway › Genes involved  Deficiency  Current Literature

 Nitrogenase › Fix N 2 (g) › In bacteria  Molybdopterin › Cofactor for Mo › Can be W instead  Same group

 Sulfite oxidase  DMSO reductase  Xanthine oxidase  Catalyzes oxygen atom transfer  Square pyramidal coordination  Eukarya  Rat liver  Sulfite oxidase, nitrate reductase

 Sulfite oxidase  DMSO reductase  Xanthine oxidase  Catalyzes oxygen atom transfer  Distorted trigonal prismatic coordination  Bacteria, Archaea  Rhodobacter sphaeroides  DMSO reductase, biotin-S- oxide reductase, trimethylamine-N-oxide reductase, nitrate reductase, formate dehydrogenase, polysulfide reductase, arsenite oxidase, formylmethanofuran dehydrogenase

 Sulfite oxidase  DMSO reductase  Xanthine oxidase  Catalyzes oxidative hydroxylation  Distorted square- pyramidal coordination  All domains  Desulfovibrio gigas  Xanthine oxidase, xanthine dehydrogenase, aldehyde oxidase, aldehyde oxidoreductase, formate dehydrogenase, CO dehydrogenase, quinolone-2- oxidoreductase, isoquinoline 1- oxidoreductase, quinoline-4- carboxylate-2-oxidoreductase, quinaldine-4-oxidoreductase, quinaldic acid 4-oxidoreductase, nicotinic acid hydroxylase, 6- hydroxynicotinate hydroxylase, (2R)- hydroxycarboxylate oxidoreductase

 MOCS1 › On c-some 6  MOCS1A  MOCS1AB/MOCS1B  Separated by 15 nt cPMP = ‘precursor Z’  MOCS2 › On c-some 5  MOCS2A  MOCS2B

 MOCS3 › On c-some 20 › Mutations = OK MPT  no Mo!  Gephyrin (GPHN) › On c-some 16 › 3’ side first › 5’ side second

 Lost activity › Sulfite oxidase › Aldehyde oxidase › Xanthine oxidoreductase  Disease causing mutations › MOCS1, MOCS2, GPHN  Autosomal recessive  Type A › First step in pathway blocked (no cPMP)  Type B › Second step in pathway blocked (no MPT)  Result › Sulfite accumulation › Can cross BBB

 2013 Journal of Medicinal Chemistry - Synthesis of cyclic pyranopterin monophosphate, a biosynthetic intermediate in the molybdenum cofactor pathway › Synthesis of cPMP for general Moco production › In vitro comparison with bacterial cPMP › Equally effective  2009 Nucleosides, Nucleotides, and Nucleic Acids – A Turkish case with molybdenum cofactor deficiency › Sequenced patient’s Moco coding regions › Sequenced family (mother, father, siblings) › Family heterozygous, patient homozygous

 2012 Inorganic Chemistry - Substrate and metal control of barrier heights for oxo transfer to Mo and W bis- dithioline sites › DMSO reductase kinetics with altered ligands › Studying Me-oxo transfers will help find rate-determining step › Transition step 2 is limiting, depends on substrate and metal  2008 Journal of Inorganic Biochemistry – Synthesis, electrochemistry, geometric and electronic structure of oxo-molybdenum compounds involved in an oxygen atom transferring system › Sulfite oxidase electronic structure with OPMe 3 ligand › Redox potential was separated [375 mV from Mo(V)  Mo(IV)] › This ligand could allow for atom transfer reaction investigation

 Santamaria-Araujo, J.; Wray, V.; Schwarz, G. Structure and stability of the molybdenum cofactor intermediate cyclic pyranopterin monophosphate. Journal of Biological Inorganic Chemistry, 2012, 17,  Clinch, K.; Watt, D.; Dixon, R.; Baars, S.; Gainsford, G.; Tiwari, A.; Schwarz, G.; Saotome, Y.; Storek, M.; Belaidi, A.; Santamaria-Araujo, J. Synthesis of cyclic pyranopterin monophosphate, a biosynthetic intermediate in the molybdenum cofactor pathway. Journal of Medicinal Chemistry, 2013, 56,  Hille, R. The mononuclear molybdenum enzymes. Chemical Reviews, 1996, 96,  Tenderholt, A.; Hodgson, K.; Hedman, B.; Holm, R.; Solomon, E. Substrate and metal control of barrier heights for oxo transfer to Mo and W bis-dithioline sites. Inorganic Chemistry, 2012, 51,  Ichicda, K.; Ibrahim Aydin, H.; Hosoyamada, M.; Serap Kalkanoglu, H.; Dursun, A.; Ohno, I.; Coskun, T.; Tokatli, A.; Shibasaki, T.; Hosoya, T. A Turkish case with molybdenum cofactor deficiency. Nucleosides, Nucleotides, and Nucleic Acids, 2006, 25,  Reiss, J.; Johnson, J. Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, MOCS3, and GEPH. Human Mutation, 2003, 21,  Reiss, J. Genetics of molybdenum cofactor deficiency. Human Genetics, 2000, 106,  Schwarz, G. Molybdenum cofactor biosynthesis and deficiency. Cellular and Molecular Life Sciences, 2005, 62,  Sengar, R.; Nemykin, V.; Basu, P. Synthesis, electrochemistry, geometric and electronic structure of oxo-molybdenum compounds involved in an oxygen atom transferring system. Journal of Inorganic Biochemistry, 2008, 102 (4),