Objective
A.GENERAL BACKGROUND
A1: Why a COST Action on this topic
The subject of bioinorganic enzymology, the chemistry of metalloenzymes and closely related areas dealing with metalloprotein functions, constitutes a broad interdisciplinary research field, representing an intellectually attractive and experimentally demanding frontier in modern chemical and biological sciences. Its scope is enormous, ranging from the enzymology of a wide series of important and often vital life processes to molecular biology, biotechnology, chemical synthesis and catalysis, clinical medicine, pharmacology and environmental sciences.
Metalloproteins are natural products that in essence are highly elaborated metal complexes where the ligand is a structured polypeptide chain. The resulting complexes may contain one or more metal ions and are optimally conditioned by protein structure and environment to the accomplishment of evolutionary directed functions. It is estimated that more than 30% of all purified proteins and about 50% of all deposited three-dimensional protein structures contain one or more metal ions as essential prosthetic group. From a practical point of view it is convenient to classify protein-bound metal ions into five basic types:
(a)Structural, contributing to protein tertiary and/or quaternary structure;
(b)Storage, for uptake, binding and release of metals in soluble form;
(c)Electron transfer, for uptake, release and storage of electrons;
(d)Dioxygen binding, for coordination and release of atmospheric oxygen;
(e)Catalytic, to perform enzymatic reactions on substrates (an extensive class subdivided according to the type of reaction catalysed).
The functions inherently associated with (b)-(d) can be considered as variants of catalytic functions in a broad sense, since they are performed with highly efficient mechanisms, which are typical of enzymatic reactions.
The structural and electronic properties of biological metal centres are often modulated from those of small molecules containing the same metal ion. Understanding these differences is essential for understanding function, and for this reason the contribution of synthetic and biomimetic chemistry is extremely important for the progress of this field. The ultimate goal of biological inorganic chemistry research is definition of function in terms of structure. The various disciplines embodied in the subject make major contributions to this goal; for instance, enzymology determines kinetic and equilibrium parameters characterising protein activity; spectroscopy defines electronic structure and stereochemical parameters; molecular biology perturbs structure and observes the effect on reactivity and conformation; synthetic chemistry assembles minimal site characteristics and determines intrinsic structural, electronic and reactivity properties.
The key importance of the interdisciplinary field centred on metalloprotein functions and reactions has been previously recognised within COST Actions D1 (Coordination Chemistry in the Context of Biological and Environmental Studies) and D7 (Molecular Recognition Chemistry), and subsequently within COST Action D8 (Metals in Medicine), with participation of many working groups. There are presently about 30 laboratories organised in four working groups (0010, 0015, 0021, 0022) within the COST D8 programme which carry out research on various aspects of metalloprotein function and biomimetic inorganic chemistry. This justifies the launch of a new COST action on "Metalloenzymes and Chemical Biomimetics", with the objective to coordinate future efforts by the participating groups and, possibly, new research teams working in this area on topics of timely and relevant interest.
A2:Status of the research in the field
The field of bioinorganic enzymology is at a favourable stage of development. An increasing number of the basic types of metal coordination units, together with overall protein structure, have been defined by crystallographic methods at atomic resolution. Several key metal enzymes for essential life processes of different organisms have been structurally characterised. These are often astonishingly complex molecules, such as cytochrome c oxidase, nitrogenase, ribonucleotide reductase, sulfite reductase and ceruloplasmin. NMR technologies have also considerably progressed in the three-dimensional structural determination in solution of paramagnetic metalloproteins of small to moderate size. Paramagnetic contributions to chemical shifts and nuclear relaxation contain structural information on the metal active site environment that can be used also when the complete structural determination of the protein is impossible to achieve. The increased knowledge of structural details brings an obvious advancement in the assessment of mechanistic details of protein function, since these can be approached at the molecular level. Thus, research can now focus more intensely on learning how function relates to structure.
A strong contribution to the latter issue is increasingly coming from the synthetic studies dealing with active site analogues of metalloenzymes. The wide-spread use of low-temperature spectroscopic and kinetic techniques, and the spectacular synthesis of metal complexes with sophisticated, biomimetic ligand molecules have often allowed to trap and characterise key intermediates in reactions and processes that have important but often elusive counterparts in the biological world. Examples are, inter alia, the dioxygen adducts of multinuclear iron and copper complexes, which are relevant to biological oxygen transport and activation by a number of proteins and enzymes, and the dinitrogen adducts of metal clusters related to nitrogenase.
The significance of the metal-centred chemistry performed by metalloenzymes is not limited to the biological environment. It has a strong impact on the medical sciences (e.g. generation of oxygen radicals, production and reactions of nitric oxide), pharmacological sciences (e.g. enzyme inhibition, protein receptors, metal toxicity), and environmental sciences (e.g. nitrogen and sulphur cycles, soil and water detoxification). But the capacity of metalloenzymes to carry out efficiently energetically difficult chemistry in mild conditions is attracting ever more attention from chemical industries, under the pressure to develop environmentally safe processes.
A3:Relationship with other European Programmes
Several conference series, both on a worldwide international scale, with visible European participation, and on a European level have been set up since the early 80's to encourage scientific exchange in the field of bioinorganic chemistry and specifically on metalloenzymes and chemical models.
These are:
(i)Biannual "International Conferences on Bioinorganic Chemistry (ICBIC)", held in Florence (1983), Algarve (1985), Leiden (1987), Cambridge, USA (1989), Oxford (1991), San Diego (1993), L_beck (1995), Yokohama (1997), Minneapolis (1999), with average participation of now 800 - 900 scientists;
(ii)Biannual "European Bioinorganic Chemistry Conferences (EUROBIC)", held in Newcastle (1992), Florence (1994), Noordwijkerhout (1996), Sevilla (1998) and to be held in Toulouse (2000), with an average participation of 350 - 400 scientists;
(iii)"International Symposium on Applied Bioinorganic Chemistry (ISABC)", with the 5th Conference organised for the first time in Europe (in April 1999, Corfu, Greece), following conferences in China (2), Australia, and South Africa;
(iv)"European Research Conferences (EURESCO)", held in different places, among others in Albufeira, Portugal (1994), San Miniato, Italy (1995), Tomar, Portugal (1997 and 1999);
(v)Various other national or bi- and trilateral conferences on this theme.
There have been various attempts on the national level to strengthen bioinorganic chemistry in Europe, e.g. through the establishment of the Royal Society of Chemistry (UK) Discussion Group "Inorganic Biochemistry" (about 350 members) or a very successful "Schwerpunktsprogramm Bioanorganische Chemie" of the Deutsche Forschungsgemeinschaft (DFG).
B.OBJECTIVES OF THE ACTION AND SCIENTIFIC CONTENT
B1:Main objective
The main objective of the Action is an increase of the knowledge of the chemistry of metal sites in proteins to strengthen their application to chemical, biotechnological, pharmacological and environmental sciences.
This COST Action will coordinate new joint research efforts and strengthen existing ones in the interdisciplinary field dealing with metalloenzymes, metalloproteins and their chemical models. Promotion of more intensive scientific exchange between individual groups, particularly those with complementary expertise, will be beneficial for European research and lead to a stronger impact of this research in a rapidly growing field. It is expected that the proposed Action will be attractive also for industrial research groups interested in biotechnological applications of metalloenzyme chemistry or new catalytic systems.
While the detailed scientific programme will depend on the projects submitted, there is a will to encourage participation in certain priority areas, which appear to be of particular importance for the progress of the field. These priority areas are outlined in the following sub-topics, which report proposed research activities, by a number of potential participants to this Action (listed in the Annex).
B2:Sub-Topics
(a)Structural, mechanistic and spectroscopic studies of metalloenzymes
Enzymes of several types will be the targets of this investigation. One main group is that of copper enzymes involved in oxidative functions: tyrosinase, catechol oxidase, ascorbate oxidase, laccase, and ceruloplasmin. All these use dioxygen but act in different ways on the substrates, which can undergo monooxygenation, dehydrogenation, or one-electron oxidation to radical species. These differences arise from the structural characteristics of the metal active site and the mode of binding of both dioxygen and the substrate to the enzyme. A second group is that of the enzymes containing molybdenum and tungsten as metal cofactors. Some of them also include a pterin cofactor, i.e. aldehyde oxidoreductase, formate dehydrogenase, and nitrate reductase, while others feature novel heterometal clusters containing molybdenum and other metals. Another group is that of heme containing enzymes belonging mostly to the family of peroxidases, but also containing e.g. myoglobin mutants with peroxidase activity and heme-peptide complexes derived from controlled digestion of cytochrome c ("microperoxidases"). For many enzyme systems the study will concentrate on the search of appropriate inhibitors. Inhibitor studies can give structural information, e.g. on the active site accessibility and characteristics, and can be extremely important to find new molecules of interest for pharmaceutical and therapeutic applications.
(b)Synthetic studies of mononuclear and polynuclear metal complexes with biomimetic ligands as active site models and biomimetic catalysts
The main focus in this topic are transition metal complexes with polydentate ligands that feature structural or functional aspects of metalloenzyme chemistry. The emphasis is on iron (both heme and non-heme), copper, molybdenum and manganese centres, mononuclear or multinuclear, involved in redox processes and particularly in oxidative catalysis. This is a rapidly expanding field, because in the last few years many structural details of metalloenzymes responsible for the above activities have become available. The attempt to reproduce the active site details of the enzymes is often a synthetic challenge. However, the synthetic approach offers a unique opportunity to understand how structure is related to function, because it enables to establish the effect of modulation of metal site properties and activities upon slight variations in coordination geometry, ligand nature and characteristics, charge effects, solubility etc. This information is of extreme importance for the prospect to obtain new, efficient and chemically stable metal catalysts for a variety of synthetic, biomimetic and even industrial applications.
Another issue that will be addressed in this sub-topic is that of inhibition of metalloenzymes by molecules like hydroxamic acids. The study of the adducts formed by these molecules with biomimetic metal complexes and the mechanism of inhibition will enable the establishment of the mode of interaction with the metal centres and assess the contribution of protein structure, which is not clear in many cases. It is expected that the information from these studies will establish parameters for the rational design of in vivo inhibitors.
(c)Structural and spectroscopic studies on electron transfer proteins
The targets of these studies will be mostly a range of non-heme iron containing proteins and several cytochromes. The first group contains proteins with dinuclear centres of rubredoxin type and proteins with ferredoxin centres in association with other non-heme sites, some of them with novel coordination units. Most of these proteins have been over-expressed and mutants are available to facilitate the spectroscopic studies. The cytochromes will be from different origins and include, besides common monoheme proteins, the more complex di-heme association of cytochrome c peroxidase and nitrite reductase (cd1). The kinetics and thermodynamics of functional modulation of the heme centres will flank the structural and spectroscopic studies on these proteins.
The important issue of protein-protein association will also be a main target, since this can give insight into the physiological performance of electron transfer proteins. This problem will be addressed considering, for instance, the complexes of cytochrome c peroxidase with monoheme cytocromes and pseudoazurin, those of cytochrome cd1 with monoheme cytochromes, and aldehyde oxidoreductase with flavoproteins.
(d)Characterisation and biological role of metal-protein interactions
Metal-binding proteins are able to bind a variety of essential, toxic and pharmacologically active metal ions. Therefore, they play important roles in the understanding of the physiological mechanisms regulating the flow of metals through the organism in health and diseases, of the molecular pathway of metal ions in the biosynthesis and degradation of metalloenzymes, and in metal toxicity. The targets of these studies are the characterisation of several important metal-binding proteins and their role in the interactions with metals such as zinc, cadmium and copper in the development of diseases, the relationships between cadmium toxicity and renal effects, Wilson diseases and other diseases in relation with copper toxicity. In addition, interactions between DNA, metal-binding proteins and radicals will be considered. Furthermore, emphasis will also be put on selenoproteins such as selenoprotein P and glutathion peroxidases.
(e)Small molecules activation at biological and biomimetic metal centres
This topic is strictly related to (a) and (b) inasmuch as many of the enzyme systems and biomimetic complexes which are under study involve the binding and activation of small molecules like dioxygen or peroxide in their functional or catalytic activities. The focus will be on the kinetics, thermodynamics and spectroscopy of metal-dioxygen and metal-peroxide complexes, generally through studies at the low or very low temperatures necessary to stabilise these usually elusive species. The most important advancement in this field would be the characterisation of the ternary complexes resulting from the association between a metal-dioxygen adduct and a substrate, since the specificity of enzyme action and the type of substrate transformation often depends on the characteristics of this interaction.
Among other small molecules, which are worth investigating, nitric oxide and related NxOy species are of extreme interest in human physiology and medicine. Biological metal centres are primary targets of their reactivity but the current knowledge of the mechanisms and the products of this interaction is extremely scarce.
C.ORGANISATION MANAGEMENT AND RESPONSIBILITIES
C1:Management
The objectives described under section B2 are a selection of very important sub-topics which are already stimulated in several European member countries and which are very promising for coordination at the European level.
C2:Responsibilities
The Management Committee has responsibilities for:
(1)Drawing up the inventory during the first year, organisation of workshops and start of the activity; existing contacts will be used which should greatly facilitate this task;
(2)Coordination of the joint activities with other COST Actions; joint meetings are likely to result from this activity;
(3)Explore the possibilities for wider participation and exchange of information with EU-specific programmes, ESF, etc;
(4)Planning the intermediate report, the final report and the concluding symposium.
Progress reports will also be provided by each respective participant in the projects in their own countries within the framework of existing programmes.
C3:Evaluation of Progress
The progress of the programme will be monitored by means of brief annual reports from each of the participating scientists. These will describe the results of research obtained through concerted action. The Management Committee will prepare a milestone report after 2 years of joint activities. The report will be presented to the COST Technical Committee for Chemistry for their review and to the COST Senior Officials Committee for information. A final report will be published to inform non-participating scientists and research workers interested in the results about the scientific achievements of the Action. It is expected that some review by participants, which describe the progress made and state of the field, will be published in International Journals. To conclude the COST Action, a symposium will be held after 5 years. It will be accessible to other scientists.
D.TIMETABLE
The programme will cover five years and consist of four stages:
Stage 1:After the first meeting of the Management Committee a detailed inventory of ongoing research and existing plans of the participating groups to begin joint projects will be made. This will result in a discussion document to allow further planning.
Stage 2:It will be evident which projects are closely related and would benefit from joint activities. Researchers (and co-workers) will set-up (and continue) joint collaborative projects and exchange their recent research results. It may be appropriate to explore wider collaboration with other European countries during this stage.
Stage 3:An intermediate progress report will be prepared after two years for review by the COST Technical Committee for Chemistry and for information to the COST Senior Officials Committee.
Stage 4:This final phase will begin after four years and will involve the evaluation of the results obtained. It may include the organisation of a symposium for all the participants and co-workers. The final report will be submitted to the COST Technical Committee for Chemistry for scientific assessment and after to the COST Senior Officials Committee.
In summary the total timetable can be represented as follows:
-Start 1st year
-Formation of projects 1st and 2nd year
-Workshop of group leaders end of 1st year and each year later on
-Overview available; start meetings; continue meetings on subtopics end of 2nd year
-Start exploration of wider participation 3rd and 4th year
-Intermediate Progress Report available for Technical Committee and CSO end 2nd year
-Start evaluation of results continuously each year after 1st year at the yearly workshop
-Concluding Symposium end of 5th year.
E.DURATION OF THE ACTION
The Action will last for five years.
F.ECONOMIC DIMENSION OF THE ACTION
It is to be expected that many teams in the four working groups presently in the COST D8 Action and the group previously in COST D7 Action will transfer into the new COST Action, following some regrouping and extension by additional laboratories. It is estimated that a total of 40 laboratories will eventually be involved in the Action.
Based on experience in the COST D8 programme, it is estimated that the economic dimension of the Action (initial estimate of total costs = personnel + operational + running + Commission costs) will be EUR 100 million.
The total human efforts in the Action "Metalloenzymes and Chemical Biomimetics" as described in this document, amounts to 800 man-years (160 researchers during 5 years), being equivalent to EUR 80 million.
F1.Personnel costs
Estimates of personnel costs (research and administration) will depend on the rates applicable to various EU countries (total estimate EUR 80 million).
In detail, the estimates of personnel costs (research and administration) within the sub-topics of the project are as follows:
Sub-topic (a): in about 5 countries a total of 160 man-years, totalling EUR 16 million
Sub-topic (b): in about 7 countries a total of 200 man-years, totalling EUR 20 million
Sub-topic (c): in about 4 countries a total of 140 man-years, totalling EUR 14 million
Sub-topic (d): in about 5 countries a total of 160 man-years, totalling EUR 16 million
Sub-topic (e): in about 4 countries a total of 140 man-years, totalling EUR 14 million.
F2.Operational and running costs
The estimate of the total operational and running costs including costs of instruments and materials is EUR 20 million.
F3.Coordination costs
The costs for coordination to be covered by the COST budget are estimated to be EUR 80 000 per year, giving a total of EUR 400 000 for 5 years of the Action (0,4%).
G.DISSEMINATION OF SCIENTIFIC RESULTS
All publications arising from research carried out under COST Action D21 will credit COST support and the Management Committee will encourage and promote all co-authored papers. Results of research carried out by the working groups under COST Action D21 will be submitted to international scientific journals and reviews.
Joint meetings among different working groups in COST Action D21 and with working groups from other COST Actions, particularly with those of COST Actions D8, D18 and D20 will be organised in such a way as to best promote interdisciplinary communication.
The Management Committee (MC), in conjunction with the working groups (WG) of the Action, will meet every year with the main aim of presenting results to the MC as a whole and, where possible, the MC will invite potential users and interested parties to this meeting.
The Management Committee will, during the first year of the Action, also set up a work-plan for interdisciplinary events for the dissemination of results of the Action COST D21.
Fields of science (EuroSciVoc)
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Italy
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