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Hypothesis: Entatic Versus Ecstatic States in Metalloproteins Delft University of Technology Hypothesis: entatic versus ecstatic states in metalloproteins Hagen, Fred DOI 10.1039/C9MT00208A Publication date 2019 Document Version Final published version Published in Metallomics: integrated biometal science Citation (APA) Hagen, F. (2019). Hypothesis: entatic versus ecstatic states in metalloproteins. Metallomics: integrated biometal science, 11(11), 1768-1778. https://doi.org/10.1039/C9MT00208A Important note To cite this publication, please use the final published version (if applicable). Please check the document version above. Copyright Other than for strictly personal use, it is not permitted to download, forward or distribute the text or part of it, without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license such as Creative Commons. Takedown policy Please contact us and provide details if you believe this document breaches copyrights. We will remove access to the work immediately and investigate your claim. This work is downloaded from Delft University of Technology. For technical reasons the number of authors shown on this cover page is limited to a maximum of 10. Metallomics View Article Online PERSPECTIVE View Journal Hypothesis: entatic versus ecstatic states in metalloproteins Cite this: DOI: 10.1039/c9mt00208a Wilfred R. Hagen Over half a century ago the hypothesis was put forth that redox-active metal ions and multidentate protein ligands may combine to form a local state of entasis: an irregular symmetry intermediate between those dictated by coordination chemistry for the two redox states involved. Such an Received 19th August 2019, energetically poised domain would be at the basis of high activity (notably electron-transfer rates) in Accepted 3rd October 2019 biological systems. Today the concept of the entatic state has become textbook material. Based on EPR DOI: 10.1039/c9mt00208a spectroscopic data it is proposed here that poised, entatic states may only be of marginal existence; rather the occurrence of relatively wide distributions of coordination geometries (or: ecstatic states) rsc.li/metallomics afford a stochastic tuning of structure towards low-energy unimolecular transition states. Creative Commons Attribution 3.0 Unported Licence. Null hypothesis: entatic states the existence in the enzyme of an area with energy, closer to that of a unimolecular transition state than to that of a conventional, in proteins, in particular stable molecule, thereby constituting an energetically poised in electron-transfer metalloproteins domain’’ (their italicization). The key motive that inspired them to the formulation of this hypothesis was a number of perceived In 1968 F. A. Cotton communicated a seminal paper by B. L. peculiarities in the optical and EPR spectroscopic properties of Vallee and R. J. P. Williams to the Proceedings of the National metalloproteins when compared to synthetic metal complexes, Academy of Sciences of the USA entitled ‘‘Metalloenzymes: the pointing to unusual environments in the former. Fig. 1 gives a 1 This article is licensed under a entatic nature of their active sites’’. The authors proposed that schematic representation of what became over time the most ‘‘Enzymatic catalysis...would be facilitated by a state of entasis: well-known instance of an entatic state. Clearly the most conspicuous case was the biological ‘‘blue copper’’ centers with their extremely high absorption in the Open Access Article. Published on 09 October 2019. Downloaded 11/11/2019 9:03:27 AM. Delft University of Technology, Department of Biotechnology, Van der Maasweg 9, 2629HZ Delft, The Netherlands. E-mail: [email protected]; Tel: +31 152785051 visible spectrum combined with their unprecedentedly small parallel hyperfine splitting from the copper nucleus in the EPR spectrum. A second case brought forward, that of the non-heme Fred Hagen received his PhD in iron proteins with their g values without parallel amongst Biochemistry from the University synthetic mononuclear octahedral iron complexes, was later of Amsterdam in 1982. After de facto falsified when the structure and exchange coupling of a post-doc in the Biophysics iron–sulfur clusters was established.2 The third case in point, Research Division of the Univer- the observation of shoulders in the optical spectra of sity of Michigan he returned to Co(II)-substituted Zn enzymes, which were not observed in the Netherlands in 1984 to the simple high-spin Co(II) compounds of regular symmetry, was Biochemistry Department of perhaps the least convincing argument. Indeed, it has never Wageningen University where he been repeated in the ensuing discussion on entatic states up to built a research group on complex this date. Taken together, of the three spectroscopic cases that metalloenzymes. In 1995 he incited the formulation of the entatic-state hypothesis, only the became full professor of Physical blue-copper case has stood the test of time. Wilfred R. Hagen Chemistry in Nijmegen and in The original hypothesis speaks of ‘enzyme’, and not of electron- 1998 also of Bioinorganic transfer proteins. In the mind of the authors the entatic-state Chemistry in Wageningen. In 2000 he moved to Delft as professor concept was applicable to all active centers including catalytic of Enzymology. In 2017 he became emeritus and since then he can metal sites, catalytic radical sites, and catalytic sites formed by be found full time in the lab building novel EPR spectrometers and amino-acids without or with additional non-metal prosthetic applying them to problems in bioinorganic chemistry. groups or cofactors [1]. It is informative to briefly consider the This journal is © The Royal Society of Chemistry 2019 Metallomics View Article Online Perspective Metallomics The situation is similar for enzymes with active sites made of amino-acid side chains only. Vallee’s and Williams above cited original assertion that looking for an entatic state in a protein without a metal had not been feasible, returned in a statement by Williams at a 1971 Cold Spring Harbour Symposium on Quantitative Biology as ‘‘It is not clear whether or not similar discussion is suitable in the case of enzymes which do not contain metals’’.7 However, at the 1976 Solvay meeting Williams proposed that ‘‘a peculiar interaction’’ between a glutamate and a tryptophane in lysozyme, and also ‘‘a peptide bond that is distorted into a form close to the transitions state of the trypsin reaction’’ in trypsin inhibitor, are manifestations of entatic states.3 Subsequenly, in his 1995 review he draws the specific example of an entatic state in a serine protease in the absence of substrate in which the serine –OH group is activated by a set of hydrogen bonds afforded by the overall protein structure.4 And this is where the thread appears to be running out. Once more, no studies have appeared on non-metal Fig. 1 A schematic representation of a typical case of entasis in a enzymes in which the concept of the entatic state has been metalloprotein. Depending on its redox state a transition ion has prefer- ence for a particular coordination geometry in small model complexes. explored experimentally or computationally. Equally, the original In this example the metal ion is in a tetrahedron when reduced and in invitation to apply the concept to catalytic sites formed by amino- a planar structure when oxidized. Binding of the complex to a macro- acids with additional non-metal prosthetic groups or cofactors molecular structure (in this case a protein) creates a strained, or entatic Creative Commons Attribution 3.0 Unported Licence. appears to have never been picked up. state with a geometry that is intermediate between tetrahedral and planar. And so we are bound to stick to the metalloproteins as The extra energy input required to create this local strain in both redox states is mandatorily more than compensated for by (a distribution of) putative test systems. However, here a clear-cut distinction has conformational changes in the rest of the protein here symbolized by the been made from the onset between metalloenzymes and electron- action of a set of cogs. Note the impossibility, under this description, for a transferring metalloproteins. For the latter the entatic-state coordination complex to be in an entatic state in the absence of a discussion is, and indeed always has been, cast in terms of a macromolecular ligand. structural and/or electronic configuration that is somewhere intermediate between respective coordination chemical dictates development over time of the application of the entatic-state for the two redox states involved. In other words, the two This article is licensed under a concept to these different classes of proteins. Vallee and structures have been ‘deformed’, each in a different way, by Williams note that ‘‘Metalloenzymes would seem exceptionally strain imposition of the coordinating protein, in order to well suited for the examination of the physicochemical basis of minimize reorganization energy associated with the redox enzymatic properties, for the physical and chemical charac- event. To apply this concept to a description of the workings Open Access Article. Published on 09 October 2019. Downloaded 11/11/2019 9:03:27 AM. teristics of certain metals constitute intrinsic probes of their of a metalloenzyme active site in not trivial. Whether or not the protein environments.’’ On the contrary, they decide that, by catalysis is a redox reaction, there is always the substrate 1968, with the class of nonmetallo-enzymes ‘‘it has not been looming around the corner. Vallee and Williams originally tried feasible to examine the possibility that enzymes might be to resolve this problem by explicitly excluding the substrate poised for catalytic action in the absence of substrate, i.e., are from participation: ‘‘The ideas here suggested rest upon the in an entatic state’’.1 From a view to the literature on entatic properties of the enzyme itself and are not intended to bear states it transpires that the validity of these two statements has upon the role of substrate; hence, they make no contribution to not been affected over the last five decades.
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