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:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Molybdenum Cofactor Biosynthesis|
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
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
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
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
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
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
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
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
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
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
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
Dahl13a: 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
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
Ding04: 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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