Molybdenum in ActionNaomi Bryner

Overview General molybdenum importance Enzymes that use Moco

› 3 families Biosynthetic pathway

› Genes involved Deficiency Current Literature

Molybdenum Nitrogenase

› Fix N2(g)› In bacteria

Molybdopterin› Cofactor for Mo› Can be W instead

Same group

Enzyme families that use Moco Sulfite oxidase

DMSO reductase

Xanthine oxidase

Catalyzes oxygen atom transfer

Square pyramidal coordination

Eukarya Rat liver

Sulfite oxidase, nitrate reductase

Enzyme families that use Moco 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

Enzyme families that use Moco 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

Biosynthetic Pathway MOCS1

› On c-some 6 MOCS1A MOCS1AB/MOCS1B Separated by 15 nt

cPMP = ‘precursor Z’ MOCS2

› On c-some 5 MOCS2A MOCS2B

Biosynthetic Pathway MOCS3

› On c-some 20› Mutations = OK

MPT no Mo! Gephyrin (GPHN)

› On c-some 16› 3’ side first › 5’ side second

Moco Deficiency 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

Current Lit - Medicinal 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

Current Lit - Computational 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 OPMe3 ligand› Redox potential was separated [375 mV from Mo(V)Mo(IV)]› This ligand could allow for atom transfer reaction investigation

References 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, 113-122.

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, 1730-1738.

Hille, R. The mononuclear molybdenum enzymes. Chemical Reviews, 1996, 96, 2757-2816. 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, 3436-3442.

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, 1087-1091.

Reiss, J.; Johnson, J. Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, MOCS3, and GEPH. Human Mutation, 2003, 21, 569-576.

Reiss, J. Genetics of molybdenum cofactor deficiency. Human Genetics, 2000, 106, 157-163. Schwarz, G. Molybdenum cofactor biosynthesis and deficiency. Cellular and Molecular Life

Sciences, 2005, 62, 2792-2810.9 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), 748-756.