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MetaCyc Pathway: molybdenum cofactor biosynthesis
Traceable author statement to experimental supportInferred from experiment

Enzyme View:

Pathway diagram: molybdenum cofactor biosynthesis

This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: moco biosynthesis, molybdopterin biosynthesis

Superclasses: BiosynthesisCofactors, Prosthetic Groups, Electron Carriers BiosynthesisMolybdenum Cofactor Biosynthesis

Some taxa known to possess this pathway include : Arabidopsis thaliana col, Escherichia coli K-12 substr. MG1655, Homo sapiens, Staphylococcus aureus aureus N315, Thermus thermophilus HB8

Expected Taxonomic Range: Archaea, Bacteria , Eukaryota

General Background

The transition element molybdenum (Mo) has been long known as an essential micronutrient across the kingdoms of plants, animals, fungi and bacteria. However, molybdate itself is catalytically inactive and, with the exception of bacterial nitrogenase, needs to be activated through complexation by a special cofactor. There are several molybdenum cofactors, including molybdopterin (MPT), guanylyl molybdenum cofactor (MGD), cytidylyl molybdenum cofactor, or others [Rajagopalan92].

The chemical nature and biosynthesis of molybdenum cofactors have been investigated in detail in bacteria [Wuebbens95, Pitterle93a, Pitterle93, Rajagopalan92, SantamariaArauj04] and plants [Schwarz06, Mendel06, Mendel02, Mendel05, Mendel97]. All of the different cofactors are synthesized from molybdopterin (MPT). The variability of the molybdenum cofactors found in bacteria is achieved by the attachment of GMP, AMP, IMP, or CMP to the phosphate group of MPT.

The MPT structure is conserved in all organisms and it has been demonstrated that its biosynthesis is preserved in bacteria and plants alike. It is produced from GTP via cyclic pyranopterin phosphate (precursor Z) in two steps catalyzed by cyclic pyranopterin monophosphate synthase and molybdopterin synthase [Hoff95].

About This Pathway

The small subunits of MPT synthases from different organisms (such as the bacterial MoaD protein) contain a double glycine motif at the C terminus. The free carboxylate group of the terminal glycine is activated by an accessory protein ( MoeB in bacteria, MOCS3 in humans and Cnx5 in plants) to a carboxy-adenylate form, which is then sulfurylated by the action of two sulfurtransferase, one of which is a rhodanese, resulting in a thiocarboxylate. Each small subunit in the complex donates the sulfur atom of the thiocarboxylate to cyclic pyranopterin phosphate, resulting in formation of molybdopterin [Gutzke01].

The insertion of Mo into molybdopterin, forming the biologically active prosthetic group, is catalyzed in eukaryotes by a multifunctional two-domain protein. The protein first activates molybdopterin to molybdopterin adenine dinucleotide [Llamas04, Schwarz97, Schwarz01, Kuper03, Kuper00] and then inserts molybdate into the cofactor in a step that involves AMP cleavage [Llamas06, Llamas04]. In a somewhat analogous manner, in Escherichia coli the MoeA protein mediates ligation of Mo to molybdopterin while the MogA protein enhances this process in an ATP-dependent manner [Nichols07].

The insertion of Mo coincides with the release of copper bound to the molybdopterin dithiolate sulfur [Kuper04] which seems to play a more stabilizing role of MPT-AMP than being actively involved in Mo insertion [Llamas06].

The main differences between the prokaryotic and eukaryotic pathways are at the enzyme level. Some of the eukaryotic enzymes are fusion proteins with two functional domains, each catalyzing a different step in the pathway, while the bacterial proteins are single domain enzymes and catalyze only a single step.

Unification Links: EcoCyc:PWY-6823

Created 20-Jun-2011 by Caspi R, SRI International
Revised 23-Sep-2011 by Caspi R, SRI International


Gutzke01: Gutzke G, Fischer B, Mendel RR, Schwarz G (2001). "Thiocarboxylation of molybdopterin synthase provides evidence for the mechanism of dithiolene formation in metal-binding pterins." J Biol Chem 276(39);36268-74. PMID: 11459846

Hoff95: Hoff T, Schnorr KM, Meyer C, Caboche M (1995). "Isolation of two Arabidopsis cDNAs involved in early steps of molybdenum cofactor biosynthesis by functional complementation of Escherichia coli mutants." J Biol Chem 270(11);6100-7. PMID: 7890743

Kuper00: Kuper J, Palmer T, Mendel RR, Schwarz G (2000). "Mutations in the molybdenum cofactor biosynthetic protein Cnx1G from Arabidopsis thaliana define functions for molybdopterin binding, molybdenum insertion, and molybdenum cofactor stabilization." Proc Natl Acad Sci U S A 97(12);6475-80. PMID: 10823911

Kuper03: Kuper J, Winking J, Hecht HJ, Mendel RR, Schwarz G (2003). "The active site of the molybdenum cofactor biosynthetic protein domain Cnx1G." Arch Biochem Biophys 411(1);36-46. PMID: 12590921

Kuper04: Kuper J, Llamas A, Hecht HJ, Mendel RR, Schwarz G (2004). "Structure of the molybdopterin-bound Cnx1G domain links molybdenum and copper metabolism." Nature 430(7001);803-6. PMID: 15306815

Llamas04: Llamas A, Mendel RR, Schwarz G (2004). "Synthesis of adenylated molybdopterin: an essential step for molybdenum insertion." J Biol Chem 279(53);55241-6. PMID: 15504727

Llamas06: Llamas A, Otte T, Multhaup G, Mendel RR, Schwarz G (2006). "The Mechanism of nucleotide-assisted molybdenum insertion into molybdopterin. A novel route toward metal cofactor assembly." J Biol Chem 281(27);18343-50. PMID: 16636046

Mendel02: Mendel RR, Hansch R (2002). "Molybdoenzymes and molybdenum cofactor in plants." J Exp Bot 53(375);1689-98. PMID: 12147719

Mendel05: Mendel RR (2005). "Molybdenum: biological activity and metabolism." Dalton Trans (21);3404-9. PMID: 16234918

Mendel06: Mendel RR, Bittner F (2006). "Cell biology of molybdenum." Biochim Biophys Acta 1763(7);621-35. PMID: 16784786

Mendel97: Mendel RR (1997). "Molybdenum cofactor of higher plants: biosynthesis and molecular biology." Planta 203(4);399-405. PMID: 9421926

Nichols07: Nichols JD, Xiang S, Schindelin H, Rajagopalan KV (2007). "Mutational analysis of Escherichia coli MoeA: two functional activities map to the active site cleft." Biochemistry 46(1);78-86. PMID: 17198377

Pitterle93: Pitterle DM, Rajagopalan KV (1993). "The biosynthesis of molybdopterin in Escherichia coli. Purification and characterization of the converting factor." J Biol Chem 268(18);13499-505. PMID: 8514782

Pitterle93a: Pitterle DM, Johnson JL, Rajagopalan KV (1993). "In vitro synthesis of molybdopterin from precursor Z using purified converting factor. Role of protein-bound sulfur in formation of the dithiolene." J Biol Chem 268(18);13506-9. PMID: 8514783

Rajagopalan92: Rajagopalan KV, Johnson JL (1992). "The pterin molybdenum cofactors." J Biol Chem 267(15);10199-202. PMID: 1587808

SantamariaArauj04: Santamaria-Araujo JA, Fischer B, Otte T, Nimtz M, Mendel RR, Wray V, Schwarz G (2004). "The tetrahydropyranopterin structure of the sulfur-free and metal-free molybdenum cofactor precursor." J Biol Chem 279(16);15994-9. PMID: 14761975

Schwarz01: Schwarz G, Schrader N, Mendel RR, Hecht HJ, Schindelin H (2001). "Crystal structures of human gephyrin and plant Cnx1 G domains: comparative analysis and functional implications." J Mol Biol 312(2);405-18. PMID: 11554796

Schwarz06: Schwarz G, Mendel RR (2006). "Molybdenum cofactor biosynthesis and molybdenum enzymes." Annu Rev Plant Biol 57;623-47. PMID: 16669776

Schwarz97: Schwarz G, Boxer DH, Mendel RR (1997). "Molybdenum cofactor biosynthesis. The plant protein Cnx1 binds molybdopterin with high affinity." J Biol Chem 272(43);26811-4. PMID: 9341109

Wuebbens95: Wuebbens MM, Rajagopalan KV (1995). "Investigation of the early steps of molybdopterin biosynthesis in Escherichia coli through the use of in vivo labeling studies." J Biol Chem 270(3);1082-7. PMID: 7836363

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Agar00: Agar JN, Krebs C, Frazzon J, Huynh BH, Dean DR, Johnson MK (2000). "IscU as a scaffold for iron-sulfur cluster biosynthesis: sequential assembly of [2Fe-2S] and [4Fe-4S] clusters in IscU." Biochemistry 39(27);7856-62. PMID: 10891064

Amy81: Amy NK (1981). "Identification of the molybdenum cofactor in chlorate-resistant mutants of Escherichia coli." J Bacteriol 148(1);274-82. PMID: 7026535

An12: An X, Xiong W, Yang Y, Li F, Zhou X, Wang Z, Deng Z, Liang J (2012). "A novel target of IscS in Escherichia coli: participating in DNA phosphorothioation." PLoS One 7(12);e51265. PMID: 23240007

Anderson00: Anderson LA, McNairn E, Lubke T, Pau RN, Boxer DH, Leubke T (2000). "ModE-dependent molybdate regulation of the molybdenum cofactor operon moa in Escherichia coli." J Bacteriol 182(24);7035-43. PMID: 11092866

Arifuzzaman06: Arifuzzaman M, Maeda M, Itoh A, Nishikata K, Takita C, Saito R, Ara T, Nakahigashi K, Huang HC, Hirai A, Tsuzuki K, Nakamura S, Altaf-Ul-Amin M, Oshima T, Baba T, Yamamoto N, Kawamura T, Ioka-Nakamichi T, Kitagawa M, Tomita M, Kanaya S, Wada C, Mori H (2006). "Large-scale identification of protein-protein interaction of Escherichia coli K-12." Genome Res 16(5);686-91. PMID: 16606699

Bebien02: Bebien M, Kirsch J, Mejean V, Vermeglio A (2002). "Involvement of a putative molybdenum enzyme in the reduction of selenate by Escherichia coli." Microbiology 148(Pt 12);3865-72. PMID: 12480890

Beisel12: Beisel CL, Updegrove TB, Janson BJ, Storz G (2012). "Multiple factors dictate target selection by Hfq-binding small RNAs." EMBO J 31(8);1961-74. PMID: 22388518

Bevers08: Bevers LE, Hagedoorn PL, Santamaria-Araujo JA, Magalon A, Hagen WR, Schwarz G (2008). "Function of MoaB proteins in the biosynthesis of the molybdenum and tungsten cofactors." Biochemistry 47(3);949-56. PMID: 18154309

Bolstad10: Bolstad HM, Wood MJ (2010). "An in vivo method for characterization of protein interactions within sulfur trafficking systems of E. coli." J Proteome Res 9(12);6740-51. PMID: 20936830

Burgis03: Burgis NE, Brucker JJ, Cunningham RP (2003). "Repair system for noncanonical purines in Escherichia coli." J Bacteriol 185(10);3101-10. PMID: 12730170

Butland05: Butland G, Peregrin-Alvarez JM, Li J, Yang W, Yang X, Canadien V, Starostine A, Richards D, Beattie B, Krogan N, Davey M, Parkinson J, Greenblatt J, Emili A (2005). "Interaction network containing conserved and essential protein complexes in Escherichia coli." Nature 433(7025);531-7. PMID: 15690043

CuppVickery03: Cupp-Vickery JR, Urbina H, Vickery LE (2003). "Crystal structure of IscS, a cysteine desulfurase from Escherichia coli." J Mol Biol 330(5);1049-59. PMID: 12860127

Dahl11: Dahl JU, Urban A, Bolte A, Sriyabhaya P, Donahue JL, Nimtz M, Larson TJ, Leimkuhler S (2011). "The identification of a novel protein involved in molybdenum cofactor biosynthesis in Escherichia coli." J Biol Chem 286(41);35801-12. PMID: 21856748

Dahl13: Dahl JU, Radon C, Buhning M, Nimtz M, Leichert LI, Denis Y, Jourlin-Castelli C, Iobbi-Nivol C, Mejean V, Leimkuhler S (2013). "The sulfur carrier protein TusA has a pleiotropic role in Escherichia coli that also affects molybdenum cofactor biosynthesis." J Biol Chem 288(8);5426-42. PMID: 23281480

Dai12: Dai Y, Outten FW (2012). "The E. coli SufS-SufE sulfur transfer system is more resistant to oxidative stress than IscS-IscU." FEBS Lett 586(22);4016-22. PMID: 23068614

DavidWatine01: David-Watine B (2001). "The human gephyrin (GPHN) gene: structure, chromosome localization and expression in non-neuronal cells." Gene 271(2);239-45. PMID: 11418245

delCampilloCamp82: del Campillo-Campbell A, Campbell A (1982). "Molybdenum cofactor requirement for biotin sulfoxide reduction in Escherichia coli." J Bacteriol 1982;149(2);469-78. PMID: 6460021

DiazMejia09: Diaz-Mejia JJ, Babu M, Emili A (2009). "Computational and experimental approaches to chart the Escherichia coli cell-envelope-associated proteome and interactome." FEMS Microbiol Rev 33(1);66-97. PMID: 19054114

Ding04b: Ding H, Clark RJ, Ding B (2004). "IscA mediates iron delivery for assembly of iron-sulfur clusters in IscU under the limited accessible free iron conditions." J Biol Chem 279(36);37499-504. PMID: 15247288

Ding05: Ding H, Harrison K, Lu J (2005). "Thioredoxin reductase system mediates iron binding in IscA and iron delivery for the iron-sulfur cluster assembly in IscU." J Biol Chem 280(34);30432-7. PMID: 15985427

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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