1 / 12

Molybdenum in Action

Molybdenum in Action. Naomi Bryner. Overview. General molybdenum importance Enzymes that use Moco 3 families Biosynthetic pathway Genes involved Deficiency Current Literature. Molybdenum. Nitrogenase Fix N 2 (g) In bacteria Molybdopterin Cofactor for Mo Can be W instead

espen
Download Presentation

Molybdenum in Action

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Molybdenum in Action Naomi Bryner

  2. Overview • General molybdenum importance • Enzymes that use Moco • 3 families • Biosynthetic pathway • Genes involved • Deficiency • Current Literature

  3. Molybdenum • Nitrogenase • Fix N2(g) • In bacteria • Molybdopterin • Cofactor for Mo • Can beW instead • Same group

  4. 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

  5. Enzyme families that use Moco • Sulfite oxidase • DMSO reductase • Xanthine oxidase • Catalyzes oxygen atom transfer • Distorted trigonal prismatic coordination • Bacteria, Archaea • Rhodobactersphaeroides • DMSO reductase, biotin-S-oxide reductase, trimethylamine-N-oxide reductase, nitrate reductase, formate dehydrogenase, polysulfide reductase, arsenite oxidase, formylmethanofuran dehydrogenase

  6. Enzyme families that use Moco • Sulfite oxidase • DMSO reductase • Xanthine oxidase • Catalyzes oxidative hydroxylation • Distorted square-pyramidal coordination • All domains • Desulfovibriogigas • 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)-hydroxycarboxylateoxidoreductase

  7. Biosynthetic Pathway • MOCS1 • On c-some 6 • MOCS1A • MOCS1AB/MOCS1B • Separated by 15 nt cPMP = ‘precursor Z’ • MOCS2 • On c-some 5 • MOCS2A • MOCS2B

  8. Biosynthetic Pathway • MOCS3 • On c-some 20 • Mutations = OK MPT  no Mo! • Gephyrin (GPHN) • On c-some 16 • 3’ side first • 5’ side second

  9. 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

  10. 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

  11. 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

  12. 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.; SerapKalkanoglu, 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.

More Related