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The Biosynthesis of the Molybdenum Cofactor in Escherichia Coli and Its Connection to Fes Cluster Assembly and the Thiolation of Trna

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The Biosynthesis of the Molybdenum Cofactor in Escherichia Coli and Its Connection to Fes Cluster Assembly and the Thiolation of Trna Hindawi Publishing Corporation Advances in Biology Volume 2014, Article ID 808569, 21 pages http://dx.doi.org/10.1155/2014/808569 Review Article The Biosynthesis of the Molybdenum Cofactor in Escherichia coli and Its Connection to FeS Cluster Assembly and the Thiolation of tRNA Silke Leimkühler Department of Molecular Enzymology, Institute of Biochemistry and Biology, University of Potsdam, Karl-Liebknecht-Straße 24-25, 14476 Potsdam, Germany Correspondence should be addressed to Silke Leimkuhler;¨ [email protected] Received 16 January 2014; Accepted 28 March 2014; Published 29 April 2014 Academic Editor: Paul Rosch¨ Copyright © 2014 Silke Leimkuhler.¨ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The thiolation of biomolecules is a complex process that involves the activation of sulfur. The L-cysteine desulfurase IscS is the main sulfur mobilizing protein in Escherichia coli that provides the sulfur from L-cysteine to several important biomolecules in the cell such as iron sulfur (FeS) clusters, molybdopterin (MPT), thiamine, and thionucleosides of tRNA. Various proteins mediate the transfer of sulfur from IscS to various biomolecules using different interaction partners. A direct connection between the sulfur- containing molecules FeS clusters, thiolated tRNA, and the molybdenum cofactor (Moco) has been identified. The first step of Moco biosynthesis involves the conversion of 5 GTP to cyclic pyranopterin monophosphate (cPMP), a reaction catalyzed by a FeS cluster containing protein. Formed cPMP is further converted to MPT by insertion of two sulfur atoms. The sulfur for this reaction is provided by the L-cysteine desulfurase IscS in addition to the involvement of the TusA protein. TusA is also involved in the sulfur transfer for the thiolation of tRNA. This review will describe the biosynthesis of Moco in E. coli in detail and dissects the sulfur transfer pathways for Moco and tRNA and their connection to FeS cluster biosynthesis. 1. An Introduction to the Importance of fundamental since the reactions include the catalysis of key Molybdenum and Molybdoenzymes in steps in carbon, nitrogen, and sulfur metabolism. Bacteria There are two distinct types of molybdoenzymes: molyb- denum nitrogenase has a unique molybdenum-iron-sulfur Molybdenum is the only second row transition metal essen- cluster, the [Fe4S3]-(bridging-S)3-[MoFe3S3] center called tial for biological systems, which is biologically available as FeMoco [4]. Nitrogenase catalyzes the reduction of atmo- molybdate ion [1]. Molybdenum has a chemical versatility spheric dinitrogen to ammonia. All other molybdoenzymes that is useful to biological systems: it is redox-active under contain the molybdenum cofactor (Moco). In Moco the physiological conditions (ranging between the oxidation molybdenum atom is coordinated to a dithiolene group on states VI and IV); since the V oxidation state is also accessible, the 6-alkyl side chain of a pterin called molybdopterin (MPT) the metal can act as transducer between obligatory two- [3, 5]. The chemical nature of Moco has been determined electron and one-electron oxidation-reduction systems and byRajagopalanandcoworkersin1982[5]. They postulated it can exist over a wide range of redox potentials [2, 3]. a structure of the cofactor consisting of a pterin deriva- The metal forms the active site of molybdoenzymes, which tive, with the pterin ring substituted at position 6 with a execute key transformations in the metabolism of nitrogen, phosphorylated dihydroxybutyl side chain containing a cis- sulfur, and carbon compounds [3]. The catalyzed reactions dithiolene bond (Figure 1). The sulfur atoms of the dithiolene are in most cases oxo-transfer reactions; for example, the group were proposed to coordinate the molybdenum atom, hydroxylationofcarboncentersandthephysiologicalroleare with a stoichiometry of one MPT per Mo. Moco is present 2 Advances in Biology O O Mo − S O O H N S HN 2− OPO3 N O H2N N H Molybdenum cofactor (Moco) Mo-MPT O − − OH OH O O O H H S H Mo O H H P P O N N NH2 S Mo O O OH S O O O O O H O Cys N S H Guanine NH HN Cytosine N S S N HN O/S H O O O O O O 2− S O N N O P P H H OPO3 Mo H2N H N O O S − − H H H2N N H X O O OH OH H N S HN Guanine O O O O O O N N O P P H H H2N H − − H H O O OH OH Xanthine oxidase family Sulfite oxidase family DMSO reductase family Sulfurated MCD di-oxo Moco bis-MGD Aldehyde oxidoreductase Sulfite oxidase (YedY) TMAO reductase A (TorA) (PaoABC) TMAO reductase Z (TorZ) Xanthine dehydrogenase DMSO reductase (DmsABC) (XdhABC, XdhD) Nitrate reductase A (NarGHI) Nitrate reductase Z (NarZYV) Peripl. Nitrate reductase (NapA) Biotin sulfoxide reductase (BisC) Formate dehydrogenase N (FdnGHI) Formate dehydrogenase O (FdoGHI) Formate dehydrogenase H (FdhF) Figure 1: The different structures of Moco in E. coli. The basic form of Moco is a 5,6,7,8-tetrahydropyranopterin with a unique dithiolene group coordinating the molybdenum atom, named Mo-MPT. Mo-MPT (shown in the tri-oxo structure [25]) can be further modified and in E. coli three different molybdenum-containing enzyme families exist classified according to their coordination at the molybdenum atom: the xanthine oxidase, sulfite oxidase, and DMSO reductase families. In E. coli, the xanthine oxidase family contains the sulfurated MCD cofactor. The sulfite oxidase family is characterized by a di-oxo Moco with an additional protein ligand, which usually is a cysteine. The DMSO reductase family contains two MGDs ligated to one molybdenum atom with additional ligands being an O/S and a sixth ligand X, which can be a serine, a cysteine, a selenocysteine, an aspartate or a hydroxide, and/or water molecule. The characterized molybdoenzymes in E. coli are shown in blue for each family. in more than fifty enzymes in bacteria, including nitrate with one MPT equivalent coordinated to the molybdenum reductases, sulfite dehydrogenase, xanthine oxidoreductase, atom,oneoxo-group,onesulfido-group,andonehydroxo- aldehyde oxidoreductase, DMSO reductase, formate dehy- group [3](Figure 1). The sulfido-group is cyanide labile [8– drogenase, CO dehydrogenase, and various other enzymes 10], and removal of the sulfido group results in formation of [3]. In the redox reactions catalyzed by molybdoenzymes an inactive desulfo-enzyme, with an oxygen ligand replacing electron transfer is mediated by additional redox centers the sulfur at the Mo active site [10]. The enzymes of this present in the protein or on other protein domains, like FeS family are involved in two-electron transfer hydroxylation centers, cytochromes, or FAD/FMN cofactors [6]. During and oxo-transfer reactions with water as the source of oxygen these redox reactions, the molybdenum atom can exist in [7, 11]. Among the members of the XO family in E. coli are the various oxidation states and couple oxide or proton transfer xanthine dehydrogenase XdhABC, the periplasmic aldehyde with electron transfer [2]. oxidoreductase PaoABC, and the so far uncharacterized The different enzymes contain different forms of Moco xanthine dehydrogenase homologue XdhD (Figure 1, Table 1) and were historically categorized into three families based on [6, 12]. the ligands at the molybdenum atom, which are characteristic Enzymes of the SO family coordinate a single equivalent VI for each family (Figure 1): the xanthine oxidase (XO) family, ofthepterincofactorwithanMPT-Mo O2 core in its the sulfite oxidase (SO) family, and the dimethyl sulfoxide oxidized state and usually an additional cysteine ligand which (DMSO) reductase family [3, 7]. The XO family is charac- is provided by the polypeptide [3]. Members of this family VI terized by an MPT-Mo OS(OH) core in the oxidized state, catalyzethetransferofanoxygenatomeithertoorfrom Advances in Biology 3 Table 1: Overview on the E. coli molybdoenzymes and the involved atom. This sulfur is mobilized from L-cysteine in the cell, chaperones required for maturation/cofactor insertion. by a general pathway which links Moco biosynthesis to the synthesis of other sulfur-containing biomolecules like FeS Subunits Chaperone Moco Mo-enzyme cluster assembly and the thiolation of tRNA. Additionally, FeS DMSO reductase family cluster containing proteins are required for the biosynthesis Nitrate reductase A NarGHI NarJ bis-MGD of the first intermediate in Moco biosynthesis. Thus, we will Nitrate reductase Z NarZYV NarW bis-MGD dissect the sulfur transfer pathway for the biosynthesis of Peripl. nitrate reductase NapABCGH NapD bis-MGD Moco and FeS clusters and their connection to the thiolation oftRNAinthesecondpartofthereview.Thebiosynthesis TMAO reductase A TorAC TorD bis-MGD of the molybdenum cofactor in eukaryotes has been addi- TMAO reductase Z TorZY ? bis-MGD tionally studied and is also highly conserved. Since there DMSO reductase DmsABC DmsD bis-MGD arenumerousreviewsavailableintheliteraturedescribing Formate dehydrogenase N FdnGHI FdhD bis-MGD Moco biosynthesis in humans and plants [17–20], we focus Formate dehydrogenase O FdoGHI FdhD bis-MGD only on the biosynthesis in bacteria and the newly discovered Formate dehydrogenase H FdhF FdhD bis-MGD connection to other biosynthetic pathways. Biotin sulfoxide reductase BisC — bis-MGD Selenate reductase YnfEFGH DmsD bis-MGD 2. The Biosynthesis of the Molybdenum ? YdhYVWXUT ? ? Cofactor in E. coli ? YdeP ? ? Using a combination of biochemical, genetic, and structural Xanthine oxidase family approaches, Moco biosynthesis has been extensively stud- Aldehyde oxidoreductase PaoABC PaoD MCD ied for decades. In all bacteria Moco is synthesized by a Xanthine dehydrogenase XdhABC YqeB MCD conserved biosynthetic pathway that can be divided into ? XdhD (YgfM) YqeB ? four steps, according to the stable biosynthetic interme- Sulfite oxidase family diates which can be isolated and were intensively studied Sulfite oxidase YedYZ — Mo-MPT in Escherichia coli (Figure 2)[21]: the synthesis of cyclic pyranopterin monophosphate (cPMP) [22], conversion of YcbX — ? ? cPMP into MPT by introduction of two sulfur atoms [23], ? YiiM — ? and insertion of molybdate to form Moco [24].
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