Metal–sulfur compounds in general and iron–sulfur (Fe/S) clusters in particular are thought to be the earliest catalysts for the generation of biologically relevant molecules and thus have been implicated in the origin of life. Biological Fe/S clusters are among nature’s oldest cofactors, and their versatile chemical characteristics have allowed their widespread use in virtually all living organisms to execute a huge spectrum of biochemical and cell biological tasks. For instance, the accessibility of multiple redox states with potentials that can be tuned by the cluster structure and the protein environment gives Fe/S proteins enormous flexibility to mediate electron transport in diverse pathways, including those central to energy conversion. The chemical character of [4Fe–4S] clusters as a Lewis acid is utilized in enzyme catalysis for numerous metabolic reactions, while the combination of Lewis acidic and redox properties allow these clusters to be involved in direct redox catalysis of difficult chemical reactions. The lability of Fe/S clusters allows them to serve as sensors of environmental conditions such as oxygen concentrations and iron availability. Finally, the sulfur moiety can be re-used in a ‘suicidal’ disruption of the Fe/S cluster to generate the protein cofactors lipoic acid and biotin. Likely, additional general functions will be defined as more Fe/S proteins with novel properties are being discovered.
The most abundant Fe/S clusters are of the rhombic [2Fe–2S] and the cubic [4Fe–4S] type, but also [3Fe–4S] and [4Fe–3S] clusters have been described. Many proteins contain more than one of these cofactors, and more complex clusters frequently contain other metals such as molybdenum or nickel. The inventory of Fe/S proteins in archaea, bacteria and eukarya is rather different but there are a few examples that are present in more than one kingdom of life. Many of the bacterial and eukaryotic Fe/S proteins support central cellular pathways and hence are essential for viability. Important Fe/S proteins include bacterial nitrogenase which is crucial for the reduction of ambient nitrogen with crucial implications for plant growth and world nutrition. Various forms of archaeal and bacterial hydrogenases are important cellular energy devices and are being discussed for utilization in the bio-generation of hydrogen for energy production and other chemical purposes. Fe/S proteins involved in the intracellular energy conversion in the bacterial and mitochondrial membranes or in photosystem I of plastids belong to the earliest discovered and best studied members of this protein family. Regulatory proteins include sensors of oxygen (FNR) and Fe/S production (IscR) in bacteria, and the iron regulatory protein 1 (IRP1) in mammals.
In recent years several novel Fe/S proteins have been discovered with roles in various aspects of DNA synthesis and maintenance including replicative DNA polymerases, DNA helicases and DNA glycosylases. Another important function of these newly described Fe/S proteins is in various stages of protein translation. For instance, the archaeal and eukaryotic ATP binding cassette (ABC) protein Rli1/ABCE1 performs a critical task in ribosome assembly and function. Moreover, many Fe/S proteins are involved in diverse covalent tRNA modifications in both bacteria and eukaryotes. Finally, the large family of radical SAM-Fe/S proteins can perform an almost unlimited number of chemical conversions to catalyze chemically difficult reactions. Even this short selected list of important Fe/S proteins shows that there would be no life without this class of proteins.
The in vivo synthesis of Fe/S clusters and their insertion into the polypeptide chain has turned out to be a catalyzed rather than a spontaneous process. It may seem surprising that even the production of the simplest Fe/S cofactors, the [2Fe–2S] and [4Fe–4S] clusters, need complex proteinaceous machinery for their assembly. Depending on the cluster types and the organismic species several specialized or generic assembly systems have evolved. The NIF system for the maturation of the complex Fe/S clusters of nitrogenase has historically been the first example for which the need of catalysis has been recognized as a principle for Fe/S cluster assembly in vivo. The maturation of the various clusters of several classes of hydrogenases depends on specialized biogenesis systems including the HYD proteins. Bacteria ormitochondria and chloroplasts of eukaryotic cells employ the ISC and SUF systems for the generic synthesis of Fe/S proteins. These systems contain a number of related proteins for similar biogenesis steps. The CIA machinery in the cytosol of eukaryotic cells is essential for generating both cytosolic and nuclear Fe/S proteins. Each of these biosynthetic systems encompasses at least five and up to twenty different biogenesis factors impressively documenting the complexity to assemble Fe/S clusters in a living cell.
The importance of Fe/S cofactors and their biogenesis is most evident from more than ten known human diseases associated with genetic mutations in different biogenesis genes. Currently, all these disease-related genes encompass mitochondrial ISC assembly factors, but it seems safe to predict that the identification of disorders associated with CIA genes is only a matter of time. The mitochondrial Fe/S diseases affect numerous tissues and are typically associated with metabolic, neurological or hematological clinical phenotypes, often with fatal outcome. In contrast to the biochemical consequences elicited by the mutations, the clinical appearance of the affected patients cannot be predicted yet.
The broad spectrum of Fe/S protein functions, their importance for many cellular processes in virtually all living species, their complex biogenesis and, last but not the least, their disease relevance has attracted the interest of an increasing number of basic scientists and physicians from many areas of specialization. The current special issue of BBA-MCR aims to provide a general overview on the function of selected important Fe/S proteins, and how Fe/S proteins can be studied by biophysical techniques and structural analyses. In addition, many articles discuss the biogenesis of Fe/S proteins in bacteria and eukaryotes, and summarize the disease relevance of the process. We hope that this compendium of 21 articles from leading Fe/S laboratories will not only provide an excellent introduction into this fascinating class of proteins, but also be an inspiration for opening new avenues of future research.
Biographies
Roland Lill is a full Professor at the Institute of Zytobiologie, Philipps-Universität Marburg. Following his Diploma and PhD studies in Biochemistry at the University of Munich, he worked as postdoctoral fellow at University of California at Los Angeles on bacterial protein secretion. He then went back to Munich University to investigate mitochondrial protein import. After his appointment to a Professor for Cell Biology atMarburg University he focused on the elucidation of the components,mechanisms and disease relevance of iron–sulfur protein biogenesis and cellular iron regulation in eukaryotes. His research identified the biogenesis of cellular iron-sulfur proteins as the essential and minimal function of mitochondria. Roland Lill is amember of the LOEWE Center of Synthetic Microbiology, a former fellow of the Max-Planck Society, and an elected member of the German National Academy of Sciences Leopoldina and EMBO. He received several awards including the Gottfried-Wilhelm Leibniz Prize of Deutsche Forschungsgemeinschaft, the Feldberg Prize, and the Albrecht Kossel Prize. He serves on several editorial boards including EMBO Reports.
Joan B. Broderick is the Women in Science Distinguished Professor in the Department of Chemistry and Biochemistry at Montana State University. She is a graduate of Washington State University (B.S. Chemistry) and Northwestern University (Ph.D. Chemistry). She was an American Cancer Society postdoctoral fellow at MIT in the laboratory of JoAnne Stubbe, before beginning her first faculty position at Amherst College in 1993, where she began her efforts to elucidate the chemistry of pyruvate formate-lyase activating enzyme, an early representative of the radical SAM superfamily. She moved to Michigan State University in 1998 and then to Montana State University in 2005. Her current research is focused on mechanistic and spectroscopic studies of radical SAM enzymes, and the biogenesis of complex biological metal clusters. She has served as Chair of the Metals in Biology Gordon Research Conference and as co-Chair of the International Conference on Bioinorganic Chemistry. She has been on the editorial advisory boards of several journals, including Inorganic Chemistry, Journal of Biological Inorganic Chemistry, and Journal of Inorganic Biochemistry.
Dennis R. Dean is the Stroobants Professor of Biotechnology and a University Distinguished Professor within the Department of Biochemistry at Virginia Tech. He received a BA degree from Wabash College and was awarded a PhD in molecular biology from Purdue University where he was an NIH pre-doctoral fellow. He was an NIH post-doctoral Fellow at the University of Wisconsin working on the mechanism of the regulation of ribosome assembly and accumulation in bacteria. He was a staff scientist at the Kettering Research Laboratory prior to joining the Virginia Tech faculty. His current research interests include the chemical mechanism of biological nitrogen fixation and the biological assembly of iron–sulfur clusters. His laboratory discovered and elucidated the biochemical mechanism of cysteine desulfurases involved in iron–sulfur cluster assembly. Together with colleagues from the University of Georgia his group also advanced the concept of the involvement of molecular scaffolds in the assembly of simple and complex iron–sulfur clusters. He currently serves as the Vice President for Research at Virginia Tech and he is the executive director of the Fralin Life Science Institute.