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Chemistry of Biological Processes: An Introduction

Marc Fontecave

Chemistry of Biological Processes: An Introduction

Inaugural lecture delivered on Thursday 26 February 2009

Marc Fontecave
Traduction de Liz Libbrecht

Texte intégral

1Mr Administrator,
My dear colleagues,
Dear friends,
Ladies and gentlemen,

  • 1 F. Jacob (1998), Of Flies, Mice, and Men, Harvard University Press.

2In his book Of Flies, Mice, and Men1, the great French biologist François Jacob recalls that one day during a council of ministers General de Gaulle retorted to one of the members of the government: “There are three things in France that must not be touched: the Collège de France, the Pasteur Institute and the Eiffel Tower.” I am particularly glad, as I am sure you are, at least for the Collège de France, that the General’s recommendations have been respected, and it is with deep emotion and much pride that I would like to thank you, Mr Administrator and distinguished Professors, for welcoming me into this prestigious institution as the Chair of Chemistry of Biological Processes.

3Beyond these personal feelings, I would like to say just how much I perceive my presence here as an important sign of recognition for this great discipline, chemistry, all too often and unfairly discredited by public opinion and the media, and systematically placed behind its two big sisters, biology and physics, especially in our country. I will therefore use this opportunity to recall that while the science of the 20th century and early 21st century has seen disciplines becoming largely interdependent, chemistry has probably been the one that has most often and most profoundly multiplied its involvement in the others – the life and health sciences, the physical and material sciences, the engineering sciences, the earth and environmental sciences – all of which constantly draw on it.

Chemistry: molecules and language

4Chemistry has been so much in demand because it is first and foremost the science of the creation of molecules and materials on which everything else depends. As Marcelin Berthelot (1827-1907) said in 1860:

This creative faculty, similar to that of art itself, distinguishes it essentially from the natural and historical sciences.

5It is therefore chemistry that shapes the concrete world in which we live (medicines, cosmetics, polymers, plastics, glass, to cite but a few chemical components of our world). Our future will unfold around molecules and materials invented in chemistry laboratories, and there is an infinite number of resulting possible worlds, so great is the potential for the chemical transformation of matter and the transformation of societies by chemistry – fundamentally just like that of art, as Berthelot told us –, and so great is the potential practical utility underlying the fundamental questions raised by chemistry, the ultimate positive science. Chemistry is also the second largest industry in France after the automobile industry, with a turnover close to 100 billion Euros for over a thousand companies and 250,000 employees, ranking us second at European level and fifth worldwide.

Figure 1. Mendeleev’s periodic classification

Figure 1. Mendeleev’s periodic classification

6Chemistry is furthermore unique in that it has taken on a universal and fraternal language, practiced and understood throughout the world, which allows for an enlightening reading of the matter that constitutes us, surrounds us, and is possible. This language relies on an original alphabet, namely that of the wonderful periodic classification proposed in 1869 by Russian chemist Mendeleev (Figure 1). It also draws on names and representations of incredible beauty, and tells us, through a blend of scientific rigour and aesthetic dream, what we are and towards what we can go. It unifies the biological sciences and links them to the physical sciences, and if the living can be understood in rational terms, that is because, as we all too often forget, it is expressed in the language of chemistry.

Figure 2. Chemical structure of urea

Figure 2. Chemical structure of urea
  • 2 M. Fontecave, E. Mulliez and D. Logan (2002), “Deoxyribonucleotide Synthesis in Anaerobic Microorga (...)
  • 3 A. Sreekumar et alii (2009), “Metabolomic Profiles Delineate Potential Role for Sarcosine in Prosta (...)

7Is it not admirable that for human beings, whether from Madras, Shanghai or New York, the very simple set of signs in Figure 2 represents the same concrete reality, in this case that of urea? How can one not marvel at the form of this protein, the small sub-unit of the ribonucleotide reductase, the molecular heart that is absolutely crucial to life? In all living cells it is responsible for the transformation of ribonucleotides into deoxyribonucleotides, the four molecular bricks (called A, G, C and T) that combine to form a DNA chain and whose sequence constitutes the genetic message (Figure 3). Aren’t they romantic, these two DNA strands which, once formed, intertwine into this double helical molecular kiss which never ceases to give birth to life (Figure 4)! While this chemical representation is symbolic, is it not also profoundly meaningful in what it tells us about the molecular mechanisms underpinning the replication of the genetic heritage? Are these names of natural molecules, rebeccamycin, chlorophyll, adenosylcobalamin, not sweet to the ear, are they not so nicely suited to those chemical structures (Figure 5)? And this small molecule called sarcosine (Figure 5), whose importance in the development of prostate cancer2 was revealed in a recent article in Nature3, is it not admirably impertinent?

Figure 3. A molecular “heart”: the small ribonucleotide reductase sub-unit, the enzyme which catalyses the reduction of ribonucleotides into deoxyribonucleotides, the DNA precursors

Figure 3. A molecular “heart”: the small ribonucleotide reductase sub-unit, the enzyme which catalyses the reduction of ribonucleotides into deoxyribonucleotides, the DNA precursors

Ribonucleotides have one oxygen atom more than deoxyribonucleotides, oxygen being represented by a small circle. The DNA bases are A (adenine), G (guanine), C (cytosine), T (thymine). Those of RNA are A, G, C, U (uracil). Deoxyuridine (the deoxyribonucleotide carrying the U base) is not incorporated into DNA and is transformed beforehand into deoxythymidine (the deoxyribonucleotide carrying the T base) by another enzyme. PPO= pyrophosphate.

Figure 4. The molecular “kiss” of DNA’s double helix

Figure 4. The molecular “kiss” of DNA’s double helix

Figure 5. Chemical structures of small natural molecules

Figure 5. Chemical structures of small natural molecules

Chemistry: the molecular unity of life forms

8As I will be showing throughout this lecture, chemists have always been interested in the molecular nature of life. For ultimately what is a living cell if not a tiny drop, constituted and filled with thousands of molecules, of various shapes and sizes, exchanging energy and matter with the outside world? Tiny drops, certainly, but ones that have become visible, observable and tangible, as their molecular content has done, thanks to the most modern microscopy techniques, for example. What is life, if not this “informed” matter produced by communication between these molecules, through subtle interactions within networks that are indeed complex, but nevertheless easily described using the laws of physics and chemistry? What is life, finally, if not this matter “transformed” by a strongly interconnected dynamics of thousands of chemical reactions, admittedly with a kinetic efficiency and performance that laboratories cannot yet reach, but nevertheless chemical reactions? It is because chemistry is both a science of “informed” matter and one of “transformed” matter that chemists are entirely legitimate in participating in this great human project: understanding the living world.

9What their research has fundamentally revealed is the wonderful chemical unity of life forms. The same essential molecules and macromolecules are found, in relatively limited numbers, in all living beings, whether bacteria, mammals or plants, and the diversity of life forms does not so much result from chemical diversity as from a complex combinatorics in the use of this finite collection of molecules. It is precisely this finitude that allows chemistry to play a major role in the exploration of the living. Through the admittedly reduced but relevant prism of its molecular content, and using the language and representations of chemistry, the understanding of life then becomes an achievable objective.

10I would like to illustrate this capacity of life forms to use a small number of chemical bricks to extraordinarily economically build a palace, as well as this permanence of chemical solutions throughout the ages and the diverse organisms, using the example of anaerobic ribonucleotide reductase. This is an enzyme that Peter Reichard and I discovered at the Biochemistry Department of the Karolinska Institute in Stockholm, where I lived for a period of time with my family in the 1980s, and then intermittently in the 1990s. This fascinating enzyme was then studied in Grenoble for many years. I would like to take advantage of this tribune to thank two of my most important colleagues in this unique adventure: Étienne Mulliez, Senior Researcher at the CNRS, and Sandrine Ollagnier-de-Choudens who, in an exceptional thesis, contributed to revealing many secrets of this system of rare complexity, and with whom I subsequently shared many projects and still do.

  • 4 M. Fontecave, R. Eliasson and P. Reichard (1989), “Oxygen-Sensitive Ribonucleoside Triphosphate Red (...)

11For this story to be understandable, I should recall a relatively unknown profound biological reality, which is that the DNA biosynthesis in our own cells cannot occur without the oxygen we breathe. This DNA/oxygen synthesis link is explained by the fact that the synthesis reaction of DNA precursors, the deoxyribonucleotides that I have already mentioned (Figure 3), involves a very specific oxidation (which there is no need to explain here) of ribonucleotide reductase by the oxygen in the air, as Peter Reichard showed in the 1970s. In 1987-1988, Peter and I began to consider the then original and unexplored question of the synthesis of the same deoxyribonucleotides but this time in anaerobic microorganisms, that is, those that proliferate without any oxygen. This led me to discover and isolate a new ribonucleotide reductase in the early 1990s. In 2009, 20 years later, a lot still needs to be done to shed light on the complex chemical functioning of this enzyme, which functions without any oxygen, through the formation and transfer of very reactive though extraordinarily well controlled free radicals4.

  • 5 M. Fontecave et alii (1989), op. cit.

12In particular, something incredible happens which we have been trying to understand for years. This enzyme, which is comprised of hundreds of amino acids and therefore thousands of hydrogen atoms, is only functional – and the DNA synthesis is therefore only effective – if just one of its amino acids, a glycine hidden within the protein, has lost a hydrogen atom through a selective radical mechanism5. This illustrates the fantastic power of chemistry: a seemingly minor event, the flutter of a butterfly wing, the uprooting of a hydrogen atom of the protein, triggers a biological tsunami, a crucial process: the synthesis of DNA precursors. What is life contingent on? On one more or one less hydrogen atom! More importantly still, the chemistry we discovered 20 years ago is in fact highly universal: this is what genomes are showing us today. Jean Weissenbach, the 2008 CNRS gold medallist, recently told me that close to 5,000 genes found in all living organisms, and not only anaerobes, present the chemical features of our ribonucleotide reductase. And it is gradually being confirmed that hundreds of metabolic pathways, of reactions of biosynthesis of essential cofactors, of antibiotics and vitamins, of reactions of modification of transfer RNA and of DNA repair, etc., use the same radical mechanism. This discovery has therefore brought to light an endless wealth of incredibly interesting reactions and enzymes from a chemical perspective and with potential applications, and puts us in an ideal position to study them, which we are currently doing.

  • 6 F. Jacob (1976), The Logic of Life. A History of Heredity, New York, Vintage Books.

13This illustrates the relevance of the molecular approach I was advocating earlier: discovering and understanding a new chemical reaction of life forms can suddenly allow for hundreds of others to be understood. François Jacob expressed this beautifully in his book The Logic of Life6. When a well-controlled chemical solution has been found for a given application, it is an economic type of logic that consists in exploiting it to the full in all possible applications, before inventing a new one – which is much harder.

14Ultimately, chemistry is what we share in common with all living beings in the universe, it is what brings us together: the same genes, the same chemical components. It is what prevents us from seeing our neighbour, whether she or he is white, brown or black, as being different from ourselves. It links us to the Earth that we come from, since we are but the chemical product of transformations undergone by the nutrients provided by the Earth, where we end up, giving back to it all the carbon and other chemical elements constituting us, for another cycle of life. In this cycle there are no longer life forms, complexity, or diversity: there are our molecules, cold and eternal, at last revealing so evidently our profound chemical identity, this soul of the invisible, the unchanging and the eternal.

15Chemistry, finally, is what links us to our ancestors, the first living beings to have appeared 3.5 billion years ago. If life is possible, it is because it discovered chemical solutions to light the flame and keep it going. And as I have just mentioned, many of these primitive mechanisms have been maintained throughout time, though they have admittedly gradually improved. Chemistry is therefore what allows us to ask the fundamental question: “how did it all begin”? Lastly, it is the molecular unity of the living since its origins that allows us to think of ourselves in eternal terms, to see a chemical and eternal fate for human beings.

Vitalism and reductionism

16The history of relations between chemists and life forms, which I would like to cover quickly now, is essentially that of the sometimes violent debate between, to simplify, vitalists and reductionists.

17Vitalism is the belief in the existence, within living organisms, of a “vital force” that is different and superior to physical forces, and the only one able to explain the order of life forms, the belief in a strength which opposes death. As French physiologist Marie François Xavier Bichat (1771-1802) wrote at the end of the 18th century:

The science of organized bodies should be treated in a manner quite different from those which have unorganized bodies for objects. [...] Natural philosophy, chemistry, are connected, because the same laws regulate their phenomena; but a vast interval separates them from the science of organized bodies, because a wide difference exists between their laws and those of life.

18This “vital force” served for over a century to effortlessly explain the formation – using food substances – and the transformation of complex chemical compounds in living organisms. There currently exist more or less subtle forms, whether political or unconscious, of resurging vitalism. This is in large part due to the comeback of anti-scientific religious fundamentalism throughout the world, including in the most developed countries like the United States but also in Europe. I see this vitalism in the most extreme forms of environmental activism, which lead citizens to believe that the truth is found only in nature and that the danger lies essentially with human beings, who invent. Finally, it also exists among us, when the enthusiasm generated by so-called post-genomic approaches to biology translates into a new faith in the models produced by these approaches, based on massive quantities of data, because these models are mathematical and therefore irrefutable, and lead to the so-called “systems biology”, which no one can escape today.

19“Reductionists” are those who, on the contrary, refuse to see anything else in life forms than the expression of the laws of physics and chemistry. These include 19th century Justus von Liebig and Marcelin Berthelot and, more recently for instance, the great American chemist Georges Whitesides (2007 Priestley medallist), who summed it up as follows: “The nature of the cell is an entirely molecular problem”. As you will have gathered, I too have believed for a long time in this idea of the living world’s nature being profoundly molecular, which warrants dedicating one’s existence to exploring this complex and mysterious biological chemistry.

20Let us not hide from ourselves the fact that this approach necessitates tremendous intellectual and practical rigour, as it requires the chemist to be multicultural. Unfortunately, in today’s France, in light of politicians’ increasingly utilitarian view of science, of our archaic university education, of the rigidity of the structure of our research organizations, and finally of our companies’ conservatism, and despite current discourse (there has never been so much talk of this famous “chemistry-biology interface”), the gap separating chemistry and biology is in my view far from being filled.

21And yet what a joy for chemists, as I have experienced firsthand, to be faced with these questions on life forms and what they imply in terms of worlds yet to discover. It is no longer a question of being double or triple but multiple and thereby universal, for as the philosopher Michel Serres put it in his wonderful contribution to questions surrounding education, Le Tiers-Instruit:

  • 7 M. Serres (1991), Le Tiers-Instruit, Paris, François Bourin.

The body crossing through admittedly learns a second world, the one towards which it is headed, where another language is spoken, but it especially initiates itself to the third, through which it transits7.

22It is in this world, at the interface, at the upsetting and hostile threshold between disciplines, that we must invest to understand life forms, and through which we will travel in my next lectures since, again as Michel Serres put it:

No learning can avoid journeying.

A brief history of biological chemistry

23Where does this science come from? What are its concepts and methods? I thought a brief journey in time, sweeping over the last few centuries, might provide you with some elements to answer these questions. From the 18th to the early 19th century, chemists’ activity was limited to the analysis and characterization of the different molecular constituents of life forms. The carbon compounds from both animal and plant organisms were called “organic substances”, and were clearly differentiated from inorganic chemical substances, that is, those that do not contain carbon. At the time, synthesizing them in a laboratory was considered impossible, as only the vital force was thought to explain their biosynthesis and transformations. This concept was eventually called into question in 1828 by a German chemist called Frederick Wöhler (1800-1882). To obtain ammonium isocyanate, he heated a mix of silver isocyanate and ammonium chloride, and discovered that the product was urea, known since 1773 as an organic residue excreted in mammals’ urine, whose chemical formula we all saw a few minutes ago (Figure 6A). Wöhler then wrote to his master Berzelius:

I must inform you that I am able to obtain urea without an animal or human kidney.

24In 1837 Justus Von Liebig (1830-1873), a German chemist who made major contributions to biological chemistry, wrote:

The extraordinary and inexplicable production of urea without the help of vital functions, which we owe to Wöhler, must be considered as one of the discoveries with which a new era of science is beginning.

25This is when biological chemistry truly started, as from the second half of the 19th century this finding encouraged many researchers to attempt the synthesis of molecules of life and to envisage the unity of the organic and inorganic worlds, of the world of the living and of that of objects. Marcelin Berthelot can be said to have been the first to conceptualize this unity, thanks to his exceptional experimental skills, by successfully producing in vitro a whole series of organic compounds using inorganic precursors, carbon, hydrogen, oxygen, etc., on the one hand and, on the other, by combating vitalism, with a great sense of controversy.

Figure 6. A: Urea synthesis by F. Whöler (1828); B: acetic acid synthesis by H. Kolbe (1845)

Figure 6. A: Urea synthesis by F. Whöler (1828); B: acetic acid synthesis by H. Kolbe (1845)
  • 8 S. L. Miller (1953), “A Production of Amino Acids under Possible Primitive Earth Conditions”, Scien (...)

26I would also like to pay tribute to the German Hermann Kolbe (1818-1884), who in 1845 carried out the first organic compound synthesis, involving the formation of carbon-carbon and carbon-hydrogen bonds, using inorganic compounds. With elemental carbon and hydrogen, water as a source of oxygen, and the help of a little iron sulphide and chlorine, he successfully produced acetic acid, a natural product known at the time as a component of vinegar (Figure 6B). This magnificent synthesis offers a superb illustration – and one of the very first – of the fundamental hypothesis underpinning “prebiotic” chemistry, which is that life was able to appear following the accumulation of more or less complex organic molecules, formed with mineral components and simple forms of carbon. Much later, in an article for the journal Science in 19538, American chemist Stanley Miller (1930-2007) reported a landmark experiment. He demonstrated that under certain conditions of temperature (reactional environment at boiling point) and irradiation (triggered by electric arcs) mimicking to some extent the extreme conditions of the prebiotic Earth, a mixture of water, hydrogen, methane and ammonia did lead to the formation, in small quantities, of a whole series of “biological” compounds: acids, amino acids, sugars, etc. Even though the conditions used could objectively be criticised – mainly because at the origin of life the atmosphere was probably much more oxidizing –, and even if Miller’s hypothesis of a prebiotic soup in which the first living cell supposedly came to life is probably not valid, to the young student that I was in the 1970s this experiment was a real shock. It had its role to play in my decision, when choosing a thesis topic, to go into the field of biological chemistry.

27Surprisingly, with Pasteur (1822-1895) came the revival of vitalism, which resulted in serious controversies with Berthelot. Pasteur’s vitalist stance is explained both by his discovery of molecular dissymmetry and by the science of fermentation. I will discuss only the second one here. By studying fermentations, Pasteur demonstrated that these processes, known since Antiquity, which transform organic solutions into alcoholic or acidic substances, as with the manufacturing of beer or cider or the transformation of wine into vinegar, are the work of a living microorganism, the ferment. As with molecular dissymmetry, Pasteur thus saw fermentation as a work of life that reinforced the hypothesis of an unknown original force, which specifically introduces these chemical properties into life forms.

28The vitalism-reductionism opposition, captured in the Berthelot-Pasteur controversy, was resolved in the first half of the 20th century as a result of two great discoveries. First, the discovery of enzymes explained, amongst other things, molecular dissymmetry and fermentation, paving the way for the chemistry of transformed living matter. Second, the discovery of DNA’s double helix later on afforded an understanding of the mechanisms of cellular replication and heredity mechanisms, paving the way for the chemistry of informed living matter.

29The revolution came from the work of German chemist Edouard Büchner (1860-1917), the 1907 Nobel Prize Laureate for chemistry. By grinding a dried yeast cake in a mortar with sand, Büchner observed that the yeast juice, once completely rid of all living cells through filtering, could still cause the fermentation of glucose into alcohol and carbon dioxide, thus disqualifying the vitalist theory of fermentation. He concluded:

This demonstrates that the fermentation process does not require so complicated an apparatus as is represented by the living cell.

30The conclusion is therefore clear. Living beings possess very particular molecules, since then called “enzymes”, which afford them a formidable power of chemical transformation of living matter. These enzymes which, let us not forget, are no more than proteins have the unique ability to greatly accelerate (by factors that can sometimes reach 1019) all of a cell’s chemical reactions and orient them with extreme precision and surprising selectivity. I will come back to this point in more detail a bit later. This property, enzymatic catalysis, is certainly one of the great chemical secrets of life. Following the dogma “one reaction, one enzyme”, a fantastic field of research thus opened up to the chemist, who became a biochemist and focused not only on the identification of molecules of life but also on the way they are transformed by fascinating catalytic reactions within the cell.

  • 9 J. D. Watson and F. H. C. Crick (1953), “Molecular Structure of Nucleic Acids: A Structure for Deox (...)

31The second great discovery was that of the structure of DNA. On 25 April 1953, an article in the famous scientific journal Nature described for the first time the structure of the DNA molecule (deoxyribonucleic acid)9. The authors of this two-page letter were American biologist Jim Watson (24) and British physicist Francis Crick (36). Their model, as I have already mentioned, provides a wonderful explanation of how the DNA contained in all living beings’ cells can be identically duplicated, allowing a mother cell to turn into two daughter cells with the same genetic makeup. This discovery offered a brilliant illustration of the power of the reductionist approach which, in this precise case, went from the isolation of the biological molecule, by Friedrich Miescher in 1868, to its chemical and structural characterization, which then provided the key to understanding its mechanism of physiological action.

32DNA, with two molecules (the two strains) which communicate in a highly specific way through weak non-covalent interactions and which mutually inform each other (Figure 3), is also a fine biological example of this so-called supramolecular chemistry, whose concepts were very important to understanding life forms in particular and were later formalized by Jean-Marie Lehn, the 1987 Nobel Prize Laureate for chemistry. Let me use this opportunity today, dear Jean Marie, to pay you a tribute and thank you for your contribution which, like that of Jacques Livage whom I would also like to thank, played a determining role in my nomination as professor at the Collège de France. Once again I would like to stress how proud I, your colleague, am to be here, today.

Bio-inorganic chemistry: living … mineral

33I would like to end this brief history of biological chemistry by very quickly completing it with its mineral chapter, written much later. In my opinion, one of the great revelations of the analysis of the living world in the last forty years relates to the importance of the role played by metallic ions. Long seen as essentially “organic” and therefore “bio-organic”, the chemistry of life forms reveals a metallic facet with a complex relief and thereby also becomes “bio-inorganic”. This is the domain that I have been continuously and passionately exploring with my laboratory for the past thirty years, and I would like to convince you of the importance of this science, in a few words.

34This history can be traced back to the German chemist Ernst Felix Emmanuel Hoppe-Seyler (1825-1895) who, at the end of the 19th century, demonstrated the presence of iron in haemoglobin and its role in the transportation of the oxygen in the air. French biochemist Gabriel Bertrand (1867-1962), who was Chair of Biological Chemistry at the Sorbonne in 1905, was one of the first to suggest that metal could act as a catalyst in enzymes, after studying the oxidation reactions catalyzed by a copper enzyme, laccase. It was first in the years from 1920 to 1940, with a Russian chemist named David Keilin (1887-1963), and then in the mid-1960s with Helmut Beinert (1913-2007), a German physicist who emigrated to the United States during the Second World War and recently passed away, that we understood that the complex chemistry of breathing depends on metalloenzymatic systems like cytochrome oxidase, which contains iron and copper. Helmut Beinert was also the one to discover, in 1960, a new class of metal centres, small “stones” called “iron-sulphur clusters”, exclusively constituted of iron and sulphur atoms and therefore purely inorganic, endowed with unique chemical properties and which, attached to proteins, play major roles in biology. We have been working on the latter components for many years in my laboratory and are still very actively doing so.

35There is no life without metals. The syntheses that led to the first elaborate molecules of life presumably occurred on the reactive surface of solid metallic sulphurs, iron and nickel. Between this genesis, several billion years ago, and now, nothing has changed: almost all the major functions of life are carried out by metalloproteins and metalloenzymes, therefore requiring the presence of one or several sodium, calcium, zinc, iron or copper atoms. The most beautiful illustration of this profound reality probably lies within the chemical cycle, both virtuous and ecological – a model of sustainable and mutually supportive development as well as a system of fascinating structural and functional complexity – which unites human beings with nature and the sun (Figure 7). Without magnesium, calcium and manganese, which constitute the crucial elements of plant and algae photosynthesis, there would be neither oxygen nor the organic matter which provides us with energy. And it is thanks to the iron and copper in our oxidases that, through breathing, we are able to use this resource to our own benefit, while also giving back to nature the carbon dioxide it needs.

Figure 7. Plants’ photosystem contains magnesium, manganese and calcium, which allow for the oxidation of water into oxygen and for it to recover its electrons to reduce carbon dioxide in carbonaceous molecules (sugars, etc.)

Figure 7. Plants’ photosystem contains magnesium, manganese and calcium, which allow for the oxidation of water into oxygen and for it to recover its electrons to reduce carbon dioxide in carbonaceous molecules (sugars, etc.)

The cytochrome oxidase, which contributes to breathing, contains the iron and copper owing to which the reduction of oxygen to four electrons can be catalyzed into the water needed for the “combustion” of nutrients. This combustion produces the energy we consume to live and gives back to nature the water and carbon dioxide on which it depends.

36The reason for all this is simple. Life depends on living organisms’ ability to use their environment’s chemical potential efficiently. This potential comes from the sun, for energy, as well as a relatively limited number of generally small molecules with great chemical inertia – wells of chemical potential in a sense – that have accumulated at the surface of the Earth: water, oxygen, carbon dioxide, nitrogen, etc. To be used, they must be activated, which requires profound electronic modifications that are only possible with metallic ions. The metalloenzymes in charge of these activations – proteases, monooxygenases, hydrogenases, oxidases, photosystem – are truly extraordinary and their action mechanisms very subtle. Some of them have been studied in my laboratory for years now, never ceasing to defy and amaze us at the same time. This core question of the activation of small molecules will form one of the main angles from which I will discuss the chemistry of life forms in my lectures at the Collège de France.

Chemistry of life forms: perspectives

The general context

37I would like to spend the last part of this lecture briefly discussing some foreseeable and desirable developments in biological chemistry. As both a scientist and a world citizen, I cannot propose such reflection without taking into account the general context in which this discipline can thrive, and two major aspects of which I will now point out. At the turn of the 21st century we find ourselves, with science in general and chemistry in particular, caught at the centre of profound contradictions. On the one hand, the highly advanced state of knowledge, its more or less rapid translation into innovative technology and the growing needs for new, cheaper and better performing objects, link scientific activity with humanity’s economic and social development more than ever before. On the other hand, the warped and darkened image of a science and its applications that can contribute to reinforcing inequalities on a global scale and introducing new dangers, is fuelling citizens’ anxieties, the youth’s growing lack of interest in research careers, the fortune of Nostradamuses of all sorts whose fame is proportional to the size of the disaster announced, and finally the inertia of economic and political actors, supported by a precautionary principles that leads people to believe that such a thing as zero risk exists. Scientists owe it to themselves to demystify science and rigorously challenge it. But if we want to avoid being overwhelmed by all the different forms of conservatism, we must urgently get involved more pedagogically and passionately in our laboratories, our companies, our polling booths, newspapers and television, and our primary and secondary schools, in order to say and repeat that there is no future without science, no progress without fundamental research.

38Chemistry is at the heart of this debate, insofar as it constantly and to an extent irreversibly introduces, in our environment and in all living organisms – human beings, plants and bacteria –, new molecules and new materials which can not only lead to toxic processes but also transform life forms themselves, lastingly. This was illustrated by the example of antibiotics which, while they revolutionized medicine in the 20th century, simultaneously led to the transformation of pathogenic bacterial strains into more resistant and virulent ones. Another example is the current development of nanotechnologies, which has already translated into the arrival, in our homes, cars and work places, of radically new chemical objects, carbon nanotubes or metallic nanoparticles. These objects can provide very interesting solutions to technological and environmental challenges like the conversion of solar energy, medicine, industrial catalysis, and the purification of water, but we still know nothing about their potential toxicity.

39The second important aspect of the general context is the growing awareness, belated but real nevertheless, that during the century to come societies will be confronted first with a considerable increase in the global population which will reach 9 to 10 billion inhabitants by 2050, and therefore with unprecedented energy consumption, and second with the gradual and irreversible disappearance of traditional non-renewable energy sources: fuel, gas and then coal.

40To respond both to citizens’ questions about science and technology and to demographic and energy trends, a new age of humanity must be invented right from today. Building a sustainable society, in which human beings will satisfy their needs but at last without jeopardizing the fate of future generations, as Henri Leridon defined it in his inaugural lecture, constitutes a tremendous scientific and technological challenge. Researchers will be called upon to find completely innovative, clean, economic, efficient and above all sustainable strategies for the production of fuels, electricity, chemical products and materials.

“Green” chemistry: toxicology, (bio)catalysis, “bio-inspired” catalysis

41Chemistry will evidently play a major role in the development of this new science. A so-called “green” chemistry therefore needs to be created. It will reflect in new synthesis processes its concern for the potential toxicity of solvents, products and reagents to be taken into account, for products from renewable sources to be used, and for waste and the related energy spending to be limited.

42The chemistry of life forms obviously has its role to play in this respect. One of the first domains to urgently develop is toxicology and eco-toxicology, for society as a whole is expressing a strong need for specialists and a sound science in these areas. Understanding the impact of a chemical product on complex living organisms on a molecular scale presents a fascinating challenge for chemists, who must apply themselves to establishing this chemical structure/toxicity relationship. This will allow us not only to avoid introducing toxic substances into our environment but also to validate, in favourable cases, the use of new compounds, which has become more and more difficult. This subject is sufficiently important to warrant being addressed during the lectures and seminars that will be given within the framework of this Chair of Chemistry of Biological Processes.

43Another domain is that of catalysis which, as I have already mentioned, through its ability to accelerate, orient and optimize chemical reactions can make them cleaner and more economical as regards materials, energy and waste.

Figure 8. The RimO metalloprotein catalyzes the selective thiomethylation of an aspartic acid within protein S12, one of the components of the ribosome

Figure 8. The RimO metalloprotein catalyzes the selective thiomethylation of an aspartic acid within protein S12, one of the components of the ribosome
  • 10 M. Fontecave, E. Mulliez and M. Atta (2008), “New Light on Methylthiolation Reactions”, Chemistry  (...)
  • 11 C. Mathevon, F. Pierrel, J.-L. Oddou, R. Garcia-Serres, G. Blondin, J.-M. Latour, S. Ménage, S. Gam (...)

44In order to show the extreme selectivity of enzymes, I would like to take a few minutes to share with you the fundamental questions that Hamid Atta and I are asking ourselves about two particularly interesting systems recently identified in our laboratory and that we call RimO and MiaE (Figures 8 and 9). The ribosome, which is responsible for synthesizing proteins, is one of the biggest and most important machineries of the cell. The protein S12 of the small ribosomal sub-unit, which is a real hodgepodge of proteins and nucleic acids, contains an amino acid, an aspartate, which has undergone a remarkable chemical transformation (Figure 8). This transformation is catalyzed by the RimO metalloenzyme10. Through what magical reconnaissance mechanism is RimO able to identify the point of transformation lost among a gigantic mass of atoms? Through what subtle control is it maintained asleep as long as the target is not reached, thus avoiding irreversible waste and deterioration? Finally, through what chemical reactivity, still currently unknown and never seen before in synthetic chemistry, is a C-H bond transformed into a C-S bond in just one step? We are also asking ourselves these questions surrounding the incredible selectivity of enzymes in relation to the incorporation, catalyzed by the metalloenzyme MiaE, of a single oxygen atom on a particular carbon of one of the nucleobases of a transfer RNA, a biological macromolecule that possesses hundreds of carbon atoms likely to be oxidized11 (Figure 9).

Figure 9. The MiaE metalloprotein catalyses the selective oxidation of a nucleobase of a transfer RNA

Figure 9. The MiaE metalloprotein catalyses the selective oxidation of a nucleobase of a transfer RNA

45Discovering new enzymes and understanding their functioning will therefore provide us with original and practical solutions for the chemical transformation of matter, for example by making it possible to use whole micro-organisms or enzymes as catalysts in industrial and biotechnological processes, to recover methane and hydrocarbons, to break down plant cell walls and transform cellulose into biofuel, to retrieve and use carbon dioxide, to produce high value added key intermediaries in the synthesis of a medicine, and so on. Biotechnological synthesis processes accounted for 5% of the chemical industry’s market in 2003. They should account for approximately 30% of production in 2020 and become a dominant technology in the future. For example, the company BASF produces 1,000 tons of vitamin B2 a year, mainly used in animal feed, through a biotechnological process that uses a filamentous fungus. This single-stage manufacturing system has replaced the eight-stage chemical process, thereby cutting production costs by 40%, decreasing CO2 by 30% and reducing waste by 95%.

46Another approach to the invention of new catalysts is that of “biomimetic” or “bio-inspired” chemistry, which we practice in our laboratory, as it is practised in many other laboratories throughout the world. The aim for chemists is to identify an interesting biological reaction, to characterize as comprehensively as possible the enzyme responsible for this transformation and more particularly its active site, which is the tiny part of the enzyme where the reaction takes place, and finally to synthesize an original molecule. This chemical model reproduces as accurately as possible the structure and reactivity of this active site. Very far from recreating life, without trying to play God, and without wanting to achieve in a few weeks what the living world took billions of years to develop, chemists are forever humbly amazed by the possibility of chemically synthesizing a piece of natural biocatalyst.

Figure 10. Hydrogen combustion produces energy and water

Figure 10. Hydrogen combustion produces energy and water

Figure 11. An example of “bio-inspired” chemistry

Figure 11. An example of “bio-inspired” chemistry

The preparation of metallic complexes mimicking the active site, made of nickel and iron, hydrogenases and their coupling to nanostructure materials leads to original and cheap catalysts for the production of hydrogen.

  • 12 J. Rifkin (2002), The Hydrogen Economy. The Creation of the World-Wide Energy Web and the Redistrib (...)
  • 13 S. Canaguier, V. Artero and M. Fontecave (2008), “Mimicking NiFe Hydrogenases: Nickel-Based Electro (...)
  • 14 A. Le Goff, V. Artero, P. Tran Dinh, N. Guillet, R. Métayé, A. Fihri, S. Palacin and M. Fontecave ( (...)

47To illustrate this approach, I would like to say a few words about research that recently began in my laboratory, aimed at finding new catalysts for the production and use of hydrogen, one of the energy vectors of the future. This is a fascinating adventure for me, firstly because it relates to the issue of energy, which is humanity’s big challenge for the 21st century. As the carbon era is slowly but surely reaching an end, and as it is now within our reach to transform into fuel water and sunlight, inexhaustible sources of energy, I dream, along with economist Jeremy Rifkin in his book The Hydrogen Economy12, of a world where each human being could be both the producer and consumer of his or her own energy, in a decentralized and autonomous way. This adventure is also fascinating because it raises fundamental questions for chemistry, as a large share of the solutions will come from chemists’ inventiveness. Finally, it is so because I share this project with a particularly brilliant and creative young researcher at the CEA, Vincent Artero. I would like to take this opportunity to thank him for the quality of the personal and professional relationship we have had for several years now. Hydrogen is a particularly interesting combustible given the large quantity of energy released by its combustion (almost three times more than oil per unit of mass) and because, unlike oil, this combustion produces no CO2, only water (Figure 10). Obviously this fuel presents a number of major drawbacks, otherwise our cars would have been running on hydrogen for a long time. The first is that its combustion, in what we call fuel cells or hydrogen fuel cells, requires catalysts made of platinum, a metal that is too expensive and in minute quantities at the Earth’s surface. Another problem is that hydrogen does not exist in its useful form H2 and must be produced, for example, using hydrocarbons or better still water, through energy-intensive processes or processes also requiring catalysts made with precious metals. Once again, life forms can provide us with the solution: a particularly attractive and fascinating chemical solution, since organisms like cyanobacteria or microalgae have found a way to use manganese, nickel and iron within extraordinary enzymes to produce hydrogen exclusively using water and the sun – the same sun which, in a day, provides the Earth with the amount of energy consumed annually by the world population and that will continue to do so for several billion years. Understanding the aspects of this extremely complex chemistry and drawing inspiration from it to invent original and cheap catalysts to replace platinum in the future are already major research themes virtually everywhere in the world. With Vincent at the helm, we were for instance very recently able to show, in the laboratory, that it is possible on an atomic scale to mimic the active site of hydrogenases, the metalloenzymes that catalyze the transformation of water into hydrogen (Figure 11). Their active site contains not platinum but nickel and iron atoms. The chemical models based on these non-precious metals which can be invented, using a bio-inspired approach, constitute effective catalysts for the production of hydrogen13. Nanotechnologies’ contributions can prove to be valuable, as shown by our most recent work in collaboration with Serge Palacin’s team at Saclay, which was patented a few weeks ago: nickel complexes grafted onto carbon nanotubes provide cheap electrode materials which present remarkable catalytic properties that are close to those of platinum14. I feel compelled to conclude this section with a quote from The Mysterious Island, written in 1874 by Jules Verne, a visionary and profound optimist, as we all should be. In reply to Pencroff who asks “And what will they burn instead of coal?”, Cyrus Smith says:

Water! […] Yes, my friends, I believe that water will one day be employed as fuel,
that hydrogen and oxygen which constitute it, used singly or together, will
furnish an inexhaustible source of heat and light, of an intensity of which
coal is not capable. […] There is, therefore, nothing to fear.

The molecules of life

48I have not spoken yet about that which, without a doubt, will remain one of the missions of biological chemistry: the identification of the molecules of life and their physiological role. As I have said, this is a task that began over 200 years ago. The means now available to do so, thanks to the hundreds of accessible genomes, are unprecedented.

49The first largely unexplored universe is that of small biological molecules. We often forget that life forms do not just consist of proteins, nucleic acids, lipids, polysaccharides, etc. They also depend on small molecules whose architectural complexity is generally not found in compounds synthesized by chemists, and which are important actors of cellular life: vitamins, neurotransmitters, hormones, cofactors, etc. Living organisms, particularly plants and bacteria, constitute immense molecular mines and their exploitation should open up to new horizons, particularly with regard to medicines and therapies. Between 1983 and 2005, a third of the thousand or so new molecules approved by the FDA (Food and Drug Administration) were constituted of natural products, derived components or components inspired by natural products. This number increases by approximately 60% if we only consider anti-cancer medicines.

50The other inventory of biological molecules to draw up is that of proteins – let us call it the proteome –, particularly because of their importance as potential targets for new medicines. We can now theoretically obtain the proteic product of any gene, in an abundant and pure form, and determine its structural and functional properties. Theoretically only, as in reality, in contradiction with the dogma “one gene, one protein”, we now know that just one gene can code for several different proteins through diverse and controlled processes of gene translation and post-translational modification, so that the number of proteins to characterize by far exceeds the number of genes in a genome. Furthermore, for obvious reasons, the most stable and abundant proteins are the ones that have until now been successfully isolated and characterized and the work that remains to be done concerns a large share of weakly expressed, unstable and insoluble proteins that are difficult to clone or express recombinantly, and are refractory to crystallization, such as membrane proteins. Finally, most proteins do not function in isolation in the cell but rather as elements of multiprotein complexes within which protein-protein interaction and post-translational modifications optimise and modulate the activity of each of the molecular components. The analysis of the structure and function of these complex systems and their in vitro replication in test tubes therefore represent a new, difficult yet inspiring challenge for chemists.

51The obvious applications of this protein chemistry first relate to the health field. Biology and its medical applications were the great scientific adventure of the 20th century. The result is extraordinary, as shown by the amazing and ongoing increase in life expectancy, particularly in developed countries. Chemistry has played a major role in this progress. Research on new medicines will without any doubt remain a crucial activity of the chemistry of life forms in the fields of infectious diseases, the main neurodegenerative or cardiovascular diseases, and cancer. A medicine is most often a small molecule, whether natural or synthetic, capable on selectively fixing itself on a biological macromolecule (protein, nucleic acid) and modulating its activity. The fixing of a small molecule onto a protein, through subtle interactions – as in the case of the rare crystallographic structures of structurally characterized complexes between a membrane receptor and a ligand, or in the more frequent case of an enzyme in interaction with a specific inhibitor –, is one of the most fundamental molecular processes in biology. The rational discovery of such protein ligands by chemists continues to be a fascinating yet extremely difficult problem, as we still do not have a reliable “recipe” for finding the molecule which specifically fixes itself on a protein, whose sequence and structure we know. Acquiring this knowledge remains one of the main missions of modern biological chemistry. To conclude on this subject, I would like to state my conviction that, despite regular announcements of the imminent arrival of gene and cell therapies, which constitute fascinating perspectives, medicine will for a long time and by far remain molecular – synthesis or natural molecules, small molecules or biological macromolecules – and advances in medicine and health are still greatly indebted to chemistry.

52Many other questions surrounding the biological chemistry of today and tomorrow could have been discussed during this lecture. I have in mind the power of synthesis chemistry in the development, for instance, of drug targeting agents to steer active molecules through the maze of tissues and cells to selectively deposit them on the right therapeutic target, or of new life imaging and diagnostic tools, radioactive or fluorescent tracers, molecular probes and markers. I also have in mind this fascinating question of the chemistry of the brain: if thinking is a matter of molecules, will we know one day how these molecules, neuromediators and protein receptors, interacted to produce My Funny Valentine in Chet Baker’s somewhat disturbed brain? Finally, chemists’ greatest dream is without a doubt the artificial production of living matter, capable of reproducing itself. Despite the important ethical issues raised by such research, chemists must continue down the path opened by Stanley Miller in 1953, towards a clearer understanding of the molecular scenario of the appearance of life on Earth. I do not have enough time to talk about all this today. I do however have the wonderful fortune of having this time ahead of me, these years of reflection, research and teaching that you, Mr Administrator and Distinguished Professors, have granted me.


53Here am I, reaching the end of this first lecture. I must conclude. As I said, what matters is the journey. Mine was the fortune, at the start of my career, of having met two exceptional scientists who enriched me and helped me both at home and abroad. One was the French chemist Daniel Mansuy, a member of the Académie des sciences, one of the pioneers of this bio-inorganic chemistry that I have discussed at length. He was my PhD supervisor and was able, at the time, to turn off the deafening sirens of rugby, music and politics in me, at least enough to allow me to hear those of science more clearly. Dear Daniel, allow me to publicly thank you for your teaching, your support later on, and your friendship. The other exceptional scientist was Swedish biologist Peter Reichard, a professor at the Karolinska Institute in Stockholm, now retired, who was tremendously open to the language and methods of chemistry, and with whom I shared the unforgettable emotions arising from the observation of ribonucleotide reductase activity that is not dependent on oxygen during the summer of 1988. Mine was also the fortune of having journeyed with enthusiastic, generous and intelligent colleagues. I have mentioned some of them, and while I cannot name them all I would like to add to the list: Stéphane Ménage, who is taking over as head of the Laboratory of Chemistry and Biology of Metals, the fruit of my 20 years of scientific research and policy in Grenoble; Hamid Atta, with whom I continue to share my passion for iron-sulphur proteins and Morocco; and Vincent Nivière, for the years of flavin reductase and superoxide reductase that we spent together. Lastly, I had the fortune of being recruited at a very young age to be a professor at one of the best universities in France, the Joseph Fourier university, of having received the support of the CNRS from the very first day, and finally of having wandered for ten years through the CEA, a remarkable and relatively little known research organization.

54No journey is possible without a sailboat that can weather all storms. I have had this sailboat for the last 30 years: my wife Sylvie and my children, Julie, Claire and Thomas, and as of recently my grandson Antoine. I would like to thank them for their patience and unwavering support. Finally, I keep in mind my parents, always attentive and proud but who have still not understood what I do. Don’t tell them that I’m a chemist, they think I’m a biologist, or perhaps it’s the other way round. I invite them, as I invite you all of course, to pursue this dialogue here at the Collège de France.


1 F. Jacob (1998), Of Flies, Mice, and Men, Harvard University Press.

2 M. Fontecave, E. Mulliez and D. Logan (2002), “Deoxyribonucleotide Synthesis in Anaerobic Microorganisms: the Class III Ribonucleotide Reductase”, Progress in Nucleic Acid Research and Molecular Biology, 72, 95-127, doi: 10.1016/S0079-6603(02)72068-0.

3 A. Sreekumar et alii (2009), “Metabolomic Profiles Delineate Potential Role for Sarcosine in Prostate Cancer Progression”, Nature, 457, 910-914, doi: 10.1038/nature07762.

4 M. Fontecave, R. Eliasson and P. Reichard (1989), “Oxygen-Sensitive Ribonucleoside Triphosphate Reductase in Anaerobic E. Coli”, Proc. Natl. Acad. Sci. USA, 86, 2147-2151.
et alii (2002), op. cit.

5 M. Fontecave et alii (1989), op. cit.

6 F. Jacob (1976), The Logic of Life. A History of Heredity, New York, Vintage Books.

7 M. Serres (1991), Le Tiers-Instruit, Paris, François Bourin.

8 S. L. Miller (1953), “A Production of Amino Acids under Possible Primitive Earth Conditions”, Science, 117 (3046), 528-529, doi: 10.1126/science.117.3046.528.

9 J. D. Watson and F. H. C. Crick (1953), “Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid”, Nature, 171 (4356), 737-738, doi: 10.1038/171737a0.

10 M. Fontecave, E. Mulliez and M. Atta (2008), “New Light on Methylthiolation Reactions”, Chemistry & Biology, 15 (3), 209-210, doi: 10.1016/j.chembiol.2008.02.011.

11 C. Mathevon, F. Pierrel, J.-L. Oddou, R. Garcia-Serres, G. Blondin, J.-M. Latour, S. Ménage, S. Gambarelli, M. Fontecave and M. Atta (2007), “The tRNA-Modifying MiaE Protein from Salmonella Typhimurium is a Non Heme Diiron Monooxygenase”, Proc. Natl. Acad. Sci., 104, 13 295-13 300.

12 J. Rifkin (2002), The Hydrogen Economy. The Creation of the World-Wide Energy Web and the Redistribution of Power on Earth, Jeremy P. Tarcher.

13 S. Canaguier, V. Artero and M. Fontecave (2008), “Mimicking NiFe Hydrogenases: Nickel-Based Electrocatalysts for Hydrogen Production”, J. Chem. Soc., Dalton Trans., 315-325.

14 A. Le Goff, V. Artero, P. Tran Dinh, N. Guillet, R. Métayé, A. Fihri, S. Palacin and M. Fontecave (2009), “From Hydrogenases to Noble Metal-Free Catalytic Nanomaterials for H2 Production and Uptake”, Science, 326 (5958), 1384-1387, doi: 10.1126/science.1179773.

Table des illustrations

Titre Figure 1. Mendeleev’s periodic classification
Fichier image/png, 190k
Titre Figure 2. Chemical structure of urea
Fichier image/jpeg, 16k
Titre Figure 3. A molecular “heart”: the small ribonucleotide reductase sub-unit, the enzyme which catalyses the reduction of ribonucleotides into deoxyribonucleotides, the DNA precursors
Légende Ribonucleotides have one oxygen atom more than deoxyribonucleotides, oxygen being represented by a small circle. The DNA bases are A (adenine), G (guanine), C (cytosine), T (thymine). Those of RNA are A, G, C, U (uracil). Deoxyuridine (the deoxyribonucleotide carrying the U base) is not incorporated into DNA and is transformed beforehand into deoxythymidine (the deoxyribonucleotide carrying the T base) by another enzyme. PPO= pyrophosphate.
Fichier image/png, 210k
Titre Figure 4. The molecular “kiss” of DNA’s double helix
Fichier image/png, 261k
Titre Figure 5. Chemical structures of small natural molecules
Fichier image/png, 76k
Titre Figure 6. A: Urea synthesis by F. Whöler (1828); B: acetic acid synthesis by H. Kolbe (1845)
Fichier image/png, 39k
Titre Figure 7. Plants’ photosystem contains magnesium, manganese and calcium, which allow for the oxidation of water into oxygen and for it to recover its electrons to reduce carbon dioxide in carbonaceous molecules (sugars, etc.)
Légende The cytochrome oxidase, which contributes to breathing, contains the iron and copper owing to which the reduction of oxygen to four electrons can be catalyzed into the water needed for the “combustion” of nutrients. This combustion produces the energy we consume to live and gives back to nature the water and carbon dioxide on which it depends.
Fichier image/png, 35k
Titre Figure 8. The RimO metalloprotein catalyzes the selective thiomethylation of an aspartic acid within protein S12, one of the components of the ribosome
Fichier image/jpeg, 96k
Titre Figure 9. The MiaE metalloprotein catalyses the selective oxidation of a nucleobase of a transfer RNA
Fichier image/jpeg, 120k
Titre Figure 10. Hydrogen combustion produces energy and water
Fichier image/png, 15k
Titre Figure 11. An example of “bio-inspired” chemistry
Légende The preparation of metallic complexes mimicking the active site, made of nickel and iron, hydrogenases and their coupling to nanostructure materials leads to original and cheap catalysts for the production of hydrogen.
Fichier image/png, 187k

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