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Bioinorganic chemistry
Bioinorganic chemistry New vistas in bioinorganic chemistry Editorial overview Catherine L Drennan and William B Tolman Current Opinion in Chemical Biology 2007, 11:113–114 Available online 19th March 2007 1367-5931/$ – see front matter # 2007 Elsevier Ltd. All rights reserved. DOI 10.1016/j.cbpa.2007.02.040
Catherine L Drennan Building 16 Room 573a, Massachusetts Institute of Technology, Cambridge, MA 02139, USA e-mail: [email protected]
Catherine L Drennan received her PhD in Biological Chemistry from the University of Michigan in 1995, studying with Professor Martha L Ludwig. She completed postdoctoral studies at the California Institute of Technology with Professor Douglas C Rees. Currently, she is an Associate Professor of Chemistry and Howard Hughes Medical Institute Professor. William B Tolman Department of Chemistry & Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street SE, Minneapolis, MN 55455, USA e-mail: [email protected]
William B Tolman is a Distinguished McKnight University and Lee Irvin Smith Professor of Chemistry. He received his PhD from the University of California, Berkeley, in 1987 and was a postdoctoral fellow in the laboratory of SJ Lippard at MIT before beginning his independent career at the University of Minnesota in 1990.
Encompassing the varied and disparate roles of metal ions in biology, the field of bioinorganic chemistry has reached a certain level of maturity, as indicated, for example, by the publication of a number of comprehensive textbooks on the subject in recent years. Yet research at the frontier continues to reveal fundamentally new principles, as exemplified by the provocative ideas about how metalloenzymes work, how metal ion concentrations in cells are controlled, how metalloprotein active sites are constructed and how complexes of metal ions might be applied as drugs or diagnostic agents. Recent results of such research are summarized in this issue of Current Opinion of Chemical Biology, which covers a wide swath of the vibrant and interdisciplinary bioinorganic chemistry area. The field of bioinorganic chemistry includes topics ranging from the study of naturally occurring metals in biology, to the use of metals as pharmaceuticals, to the applications of metals for studying biological systems. The review by Cohen provides an update for those interested in the ‘metals in medicine’ area. It describes recent advances in metal-based imaging agents and metalcontaining or metal-inspired therapeutics. It is clear from this review that the field of metal-based pharmaceuticals, termed ‘metallopharmaceuticals’, is alive and well. Also appropriate for the metals in medicine community is the review by Fahrni. Here, synchrotron X-ray fluorescence microscopy (SXRF), used for quantitative mapping of elemental distributions, is described. This technique can be applied, for instance, to study whether a metal-based therapeutic has reached its target location in the cell. Toxic heavy metals or trace elements can also be tracked with this technique, providing insight into the relationship between metal accumulation and disease. A particular problem related to metal ion homeostasis and its impact on disease is discussed in the article by Donnelly, Xiao and Wedd. A variety of neurodegenerative diseases have been linked to improper control of metal ion concentrations in cells, a notable example being the role of copper ions in the onset of Alzheimer’s Disease (AD). Interesting links have been discovered between copper ion homeostasis, associated levels of oxidative stress, and the protein aggregation/amyloid plaque formation associated with AD. These relationships, as well as those involving copper and other neurodegenerative diseases, are only just beginning to be understood at the molecular level. Such understanding will undoubtedly help in the development of new therapeutic approaches that target copper ion levels, transport and redox behavior. Modern theoretical approaches towards understanding difficult electronic structural issues in bioinorganic chemistry are highlighted in the contribution
www.sciencedirect.com
Current Opinion in Chemical Biology 2007, 11:113–114
114 Bioinorganic chemistry
from Kirchner, Wennmohs, Ye and Neese. Synthetic molecules that contain ligand radicals coordinated to metal ions are important models for metalloprotein active sites and can exhibit unique catalytic reactivity. The authors explain that an adequate description of the electronic structures of such species requires proper application of multiconfigurational ab initio methods because of the multiple possible spin states that can arise from the complicated interactions between the unpaired electrons on the metal ion and the ligated organic radical. How such ab initio methods have been combined with QM/MM approaches to understand the properties of (heme)Fe=O species and their reactivity in enzymes is also discussed. Finally, the recent use of first-principles molecular dynamics simulations to delve into complicated bioinorganic reaction mechanisms is described, as illustrated by recent insights into the controversial mechanism for N2 reduction by the Fe–Mo cofactor of nitrogenase. The binding and activation of dioxygen by copper proteins is crucial in numerous biological contexts (e.g. C–H bond hydroxylations), and has stimulated intense efforts to understand mechanistic details of such processes. The powerful use of 18O-isotope effects to reveal the nature of oxygenated intermediates and the pathways of their reactions in copper enzymes is described in the article by Roth. Important insights into the mechanisms traversed by superoxide dismutase, amine oxidases, dopamine b-monooxygenase (DbM), and peptidylglycine a-hydroxylating monooxygenase (PHM), as well as synthetic copper model systems, have been obtained through experimental measurement of kinetic and thermodynamic 18O-isotope effects and analysis by theory. Mechanisms of dioxygen activation are further discussed in the provocative article by Bollinger and Krebs. The prevailing view for how metalloenzymes accomplish difficult hydrocarbon oxidations posits a high oxidation state metal–oxenoid intermediate (e.g. FeIV=O) as being responsible for attacking the substrate C–H bond. An alternative pathway has gained a foothold recently, wherein the scission of the dioxygen O–O bond is suggested to occur after the C–H bond is attacked. Thus, evidence has accumulated in support of the notion that a metal–superoxide is the key oxidant in DbM, PHM and the nonheme iron enzymes isopenicillin-N-synthase and myo-inositol oxygenase. This intriguing hypothesis has broad implications for our understanding of biological oxidation catalysis, and will stimulate extensive experimental and theoretical efforts to evaluate its validity and generality.
Current Opinion in Chemical Biology 2007, 11:113–114
One of the fastest growing areas in the field of bioinorganic chemistry is the study of cellular metal regulation and metallocluster assembly. The in vivo assembly of iron–sulfur clusters was one of the first systems to be studied in depth, whereas studies of how other metalloclusters are assembled in vivo are still in their infancy. In this issue, Leach and Zamble report on the current knowledge of how [NiFe] and [FeFe] clusters of hydrogenases are assembled. This is a rapidly advancing field, with new enzymes and chemistries involved in the process regularly being unveiled. Both [NiFe] and [FeFe] cofactors are quite complex, composed of both metals and organic molecules such as CN and CO. Alone, the process of making CN for the [NiFe] cluster requires two dedicated proteins and two ATP-dependent steps. For decades, scientists have been fascinated with the amazing chemistry catalyzed by complex metalloclusters, such as the Hcluster of hydrogenase or the C- or A-clusters of carbon monoxide dehydrogenase/acetyl-CoA synthase, but now scientists can be further captivated by the intriguing chemistry behind the biosynthesis of Nature’s most interesting cofactors. Zinc is a commonly used metal throughout biology, although in many cases its function is structural (as in zinc-fingers) rather than catalytic. One of the more interesting catalytic roles of zinc is that of zinc-promoted alkyl transfer reactions. This chemistry is used by medically important enzymes ranging from methionine synthases to betaine-homocysteine methyltransferases to protein farnesyl transferases. Whereas protein farnesyl transferases have emerged as promising targets for combating various forms of cancer, studies of methionine synthases and betaine-homocysteine methyltransferases have increased as evidence linking substrate homocysteine concentration and vascular diseases continues to grow. In the past few years, a great deal of new information about the nature of the zinc active sites in these enzymes has become available, providing new mechanistic ideas and explanations, as summarized in the review by PennerHahn. Taken together, this collection of reviews touches on a wide range of topics in the bioinorganic area. We see the diversity of approach that makes this field strong, from synthetic work to spectroscopic techniques, from modern theoretical approaches to wet-lab enzymology. We are grateful to these authors for contributing their timely prospectives on some of the more exciting recent advances at the interface of biology and inorganic chemistry.
www.sciencedirect.com
Catherine L Drennan Building 16 Room 573a, Massachusetts Institute of Technology, Cambridge, MA 02139, USA e-mail: [email protected]
Catherine L Drennan received her PhD in Biological Chemistry from the University of Michigan in 1995, studying with Professor Martha L Ludwig. She completed postdoctoral studies at the California Institute of Technology with Professor Douglas C Rees. Currently, she is an Associate Professor of Chemistry and Howard Hughes Medical Institute Professor. William B Tolman Department of Chemistry & Center for Metals in Biocatalysis, University of Minnesota, 207 Pleasant Street SE, Minneapolis, MN 55455, USA e-mail: [email protected]
William B Tolman is a Distinguished McKnight University and Lee Irvin Smith Professor of Chemistry. He received his PhD from the University of California, Berkeley, in 1987 and was a postdoctoral fellow in the laboratory of SJ Lippard at MIT before beginning his independent career at the University of Minnesota in 1990.
Encompassing the varied and disparate roles of metal ions in biology, the field of bioinorganic chemistry has reached a certain level of maturity, as indicated, for example, by the publication of a number of comprehensive textbooks on the subject in recent years. Yet research at the frontier continues to reveal fundamentally new principles, as exemplified by the provocative ideas about how metalloenzymes work, how metal ion concentrations in cells are controlled, how metalloprotein active sites are constructed and how complexes of metal ions might be applied as drugs or diagnostic agents. Recent results of such research are summarized in this issue of Current Opinion of Chemical Biology, which covers a wide swath of the vibrant and interdisciplinary bioinorganic chemistry area. The field of bioinorganic chemistry includes topics ranging from the study of naturally occurring metals in biology, to the use of metals as pharmaceuticals, to the applications of metals for studying biological systems. The review by Cohen provides an update for those interested in the ‘metals in medicine’ area. It describes recent advances in metal-based imaging agents and metalcontaining or metal-inspired therapeutics. It is clear from this review that the field of metal-based pharmaceuticals, termed ‘metallopharmaceuticals’, is alive and well. Also appropriate for the metals in medicine community is the review by Fahrni. Here, synchrotron X-ray fluorescence microscopy (SXRF), used for quantitative mapping of elemental distributions, is described. This technique can be applied, for instance, to study whether a metal-based therapeutic has reached its target location in the cell. Toxic heavy metals or trace elements can also be tracked with this technique, providing insight into the relationship between metal accumulation and disease. A particular problem related to metal ion homeostasis and its impact on disease is discussed in the article by Donnelly, Xiao and Wedd. A variety of neurodegenerative diseases have been linked to improper control of metal ion concentrations in cells, a notable example being the role of copper ions in the onset of Alzheimer’s Disease (AD). Interesting links have been discovered between copper ion homeostasis, associated levels of oxidative stress, and the protein aggregation/amyloid plaque formation associated with AD. These relationships, as well as those involving copper and other neurodegenerative diseases, are only just beginning to be understood at the molecular level. Such understanding will undoubtedly help in the development of new therapeutic approaches that target copper ion levels, transport and redox behavior. Modern theoretical approaches towards understanding difficult electronic structural issues in bioinorganic chemistry are highlighted in the contribution
www.sciencedirect.com
Current Opinion in Chemical Biology 2007, 11:113–114
114 Bioinorganic chemistry
from Kirchner, Wennmohs, Ye and Neese. Synthetic molecules that contain ligand radicals coordinated to metal ions are important models for metalloprotein active sites and can exhibit unique catalytic reactivity. The authors explain that an adequate description of the electronic structures of such species requires proper application of multiconfigurational ab initio methods because of the multiple possible spin states that can arise from the complicated interactions between the unpaired electrons on the metal ion and the ligated organic radical. How such ab initio methods have been combined with QM/MM approaches to understand the properties of (heme)Fe=O species and their reactivity in enzymes is also discussed. Finally, the recent use of first-principles molecular dynamics simulations to delve into complicated bioinorganic reaction mechanisms is described, as illustrated by recent insights into the controversial mechanism for N2 reduction by the Fe–Mo cofactor of nitrogenase. The binding and activation of dioxygen by copper proteins is crucial in numerous biological contexts (e.g. C–H bond hydroxylations), and has stimulated intense efforts to understand mechanistic details of such processes. The powerful use of 18O-isotope effects to reveal the nature of oxygenated intermediates and the pathways of their reactions in copper enzymes is described in the article by Roth. Important insights into the mechanisms traversed by superoxide dismutase, amine oxidases, dopamine b-monooxygenase (DbM), and peptidylglycine a-hydroxylating monooxygenase (PHM), as well as synthetic copper model systems, have been obtained through experimental measurement of kinetic and thermodynamic 18O-isotope effects and analysis by theory. Mechanisms of dioxygen activation are further discussed in the provocative article by Bollinger and Krebs. The prevailing view for how metalloenzymes accomplish difficult hydrocarbon oxidations posits a high oxidation state metal–oxenoid intermediate (e.g. FeIV=O) as being responsible for attacking the substrate C–H bond. An alternative pathway has gained a foothold recently, wherein the scission of the dioxygen O–O bond is suggested to occur after the C–H bond is attacked. Thus, evidence has accumulated in support of the notion that a metal–superoxide is the key oxidant in DbM, PHM and the nonheme iron enzymes isopenicillin-N-synthase and myo-inositol oxygenase. This intriguing hypothesis has broad implications for our understanding of biological oxidation catalysis, and will stimulate extensive experimental and theoretical efforts to evaluate its validity and generality.
Current Opinion in Chemical Biology 2007, 11:113–114
One of the fastest growing areas in the field of bioinorganic chemistry is the study of cellular metal regulation and metallocluster assembly. The in vivo assembly of iron–sulfur clusters was one of the first systems to be studied in depth, whereas studies of how other metalloclusters are assembled in vivo are still in their infancy. In this issue, Leach and Zamble report on the current knowledge of how [NiFe] and [FeFe] clusters of hydrogenases are assembled. This is a rapidly advancing field, with new enzymes and chemistries involved in the process regularly being unveiled. Both [NiFe] and [FeFe] cofactors are quite complex, composed of both metals and organic molecules such as CN and CO. Alone, the process of making CN for the [NiFe] cluster requires two dedicated proteins and two ATP-dependent steps. For decades, scientists have been fascinated with the amazing chemistry catalyzed by complex metalloclusters, such as the Hcluster of hydrogenase or the C- or A-clusters of carbon monoxide dehydrogenase/acetyl-CoA synthase, but now scientists can be further captivated by the intriguing chemistry behind the biosynthesis of Nature’s most interesting cofactors. Zinc is a commonly used metal throughout biology, although in many cases its function is structural (as in zinc-fingers) rather than catalytic. One of the more interesting catalytic roles of zinc is that of zinc-promoted alkyl transfer reactions. This chemistry is used by medically important enzymes ranging from methionine synthases to betaine-homocysteine methyltransferases to protein farnesyl transferases. Whereas protein farnesyl transferases have emerged as promising targets for combating various forms of cancer, studies of methionine synthases and betaine-homocysteine methyltransferases have increased as evidence linking substrate homocysteine concentration and vascular diseases continues to grow. In the past few years, a great deal of new information about the nature of the zinc active sites in these enzymes has become available, providing new mechanistic ideas and explanations, as summarized in the review by PennerHahn. Taken together, this collection of reviews touches on a wide range of topics in the bioinorganic area. We see the diversity of approach that makes this field strong, from synthetic work to spectroscopic techniques, from modern theoretical approaches to wet-lab enzymology. We are grateful to these authors for contributing their timely prospectives on some of the more exciting recent advances at the interface of biology and inorganic chemistry.
www.sciencedirect.com