The laboratory simulations of the early Earth are also important to understand the mechanisms by which biologically relevant molecules are made from the raw materials. These chemical pathways are generally referred to as prebiotic chemistry (Miller, Orgel, 1974; Raulin, 1990; Brack, 1998). Important in this regard are the roles of a limited number of key organic molecules such as nitriles (mainly HCN), and aldehydes (mainly formaldehyde). It is the chemical transformations of these compounds in aqueous solution that lead to the building blocks of life.
Today, the knowledge of the prebiotic synthesis of the main building blocks of life (the twenty amino acids of proteins and the five bases of the nucleic acids) is satisfactory. One can assemble prebiotically the amino acids into chains of polypeptides that make up proteins (see, for example, Brack, 1998; Zubay, 2000; and references therein). One can also obtain microstructures, with a membrane similar to those of living cells (see Chap. 1, Part II by Ourisson and Nakatami). On the other hand, neither the prebiotic synthesis of nucleosides (ribose and deoxyribose) nor that of nucleotides and polynucleotides have yet been conclusively demonstrated. The suggestion of a RNA world (see chapter by Maurel) implies that nucleic acids were the first living molecules on the planet; however, the extreme difficulty of their prebiotic synthesis seems to contradict this possibility. The prebiotic synthesis of proteins or at least of polypeptides is more or less much more accessible although there is still a lot of work to realize in this field where new pathways can be unraveled.
2.2.1 Prebiotic Chemistry of HCN:
Strecker Reaction or Oligomerization (see Box 2.1)
The main mechanism of formation of the amino acids in Miller's experiments is the reaction referred as "Strecker raction" (see Box 2.1, well known in organic chemistry for more than one century) (Miller, Orgel, 1974): reaction of HCN with ammonia and an aldehyde in aqueous medium leading to an aminonitrile (step 1), followed by hydrolysis of this aminonitrile into an amino-amide (step 2) and finally into the amino acid (step 3).
Indeed, in Miller's experiment, amino acids are not obtained directly, but are released from a precursor after hydrolysis. However, it has not yet been demonstrated in Miller-like simulation experiments that the precursors to the
Prebiotic chemistry is organic chemistry in aqueous solution, under plausible conditions for the primitive terrestrial environment, leading to compounds of biological interest. Elementary prebiotic chemistry uses simple and reactive organic compounds, such HCN, HCHO, HC3N or their oligomers.
Prebiotic synthesis of amino acids by Strecker reaction
Basic ingredients: aldehyde (RCHO), ammonia (NH3), hydrogen cyanide (HCN)
* Reaction of HCN with ammonia in aqueous medium leading to an aminonitrile:
* followed by the hydrolysis of this aminonitrile into an amino-amide then an amino acid:
R-CH(NH2) -CONH2 + H2O — R-CH(NH2) -COOH + NH3 (2.3) Case of the sulfurated amino acids: example of methionine (R = CH3-S-
* step (1) above uses a sulphurated aldehyde obtained prebiotically by reaction between methanethiol and acrolein:
Prebiotic chemistry of HCN
Trimer tetramer oligomers +—° amino acids purines and pyrimidines
Prebiotic chemistry of HC3N
HCC - CN + H2 O u—a OHC - CH2 - CN — cytosine + uracil
Box 2.1. Basic prebiotic chemistry (continued)
Prebiotic chemistry of HCHO
HCHO + HCHO HCH° CHO - CH2OH HCH° CHO - CHOH-CH2OH HCHH° C4 C4 + HCHO ^ C5 etc...
amino acids are the corresponding aminonitriles. Moreover, such a mechanism implies the (improbable) formation of a broad range of aldehydes required to yield the corresponding amino acids.
Another mechanism involves the polymerization of HCN. This idea was suggested by Matthews (see, for example, Matthews, Moser, 1967; Matthews, 1979; Refs. therein), which caused much controversy in all the conferences on the origin of life and prebiotic chemistry. The idea is tempting: it rests on the assumption that the polymerization of HCN leads to a polymer of well-defined structure, including a side-group imine. This group is suitable for forming, under conditions of soft hydrolysis, a peptide bond, leading thus directly to a polypeptide, without requiring the formation of amino acids. The latter can also be formed starting from polymers of HCN during more severe hydrolysis conditions. This mechanism has the enormous advantage of removing the difficult stage of condensation of the amino acids in the prebiotic synthesis of polypeptides. However, this assumption was constantly criticized and largely disputed, in particular by Ferris (see, for example, Ferris, 1979). This last author claimed that the proposed polymeric structure of HCN has not been supported by analytical means and, furthermore, that its formation depends on the prior formation of a hypothetical HCN dimer that has an improbable regular structure. Ferris, on the other hand, supports the role of the formation of HCN oligomers, with structures still poorly known but most probably much more irregular (Ferris, Hagan, 1984 and Refs. therein). The formation of these oligomers is dependent on the polymerization of the HCN tetramer, diaminomaleonitrile (DAMN, not to be confused with damned, although sometimes this type of compound makes one think of diabolical properties). In any case, without knowing their chemical structure, it is shown that hydrolysis of the HCN oligomers/polymers yields a large variety of amino acids (Ferris, Hagan, 1984 and Refs. therein).
Finally, the last mechanism that should be mentioned calls upon even more complex compounds generically referred to as "tholins" (see below) for the formation of amino acids, but this assumption is not in contradiction with that of Ferris: HCN oligomers can also be regarded as made of tholins.
In any case, it is clearly established that HCN in aqueous solution is easily polymerized into oligomers or "polymers" (actually macromolecules built with nonrepetitive structures) that release a complex suite of organic compounds, in cluding biological amino acids, purines (such as adenine) and pyrimidines upon hydrolysis. The mechanism of HCN polymerization in aqueous solution was studied thoroughly in the 1960s, within the framework of prebiotic chemistry and is now well established (Toupance et al., 1970; Ferris, Hagan, 1984). The first stage is the nucleophilic attack of cyanide (CN-) into hydrogen cyanide (HCN). This nucleophilic attack can only occur under a narrow range of pH for the reaction to proceed rapidly. Indeed, it was shown (Toupance et al., 1970) that the rate limiting step is precisely the dimerisation occurring at a pH close to the pKa of the acid/base couple: HCN/CN- that is to say, pH 8 to 9, and at temperatures ranging between 0 and 60°C.
The chemistry of cyanoacetylene, HC3N, can lead in aqueous solution to the prebiotic synthesis of pyrimidines. However, the direct involvement of this compound does not seem very probable, taking into account its strong reactivity, in particular with ammonia and water. Indeed, this compound is hydrolyzed very easily into cyanoacetaldehyde (Ferris et al., 1968). In fact, it is cyanoacetalde-hyde that has an important role in prebiotic chemistry, in spite of pH constraints, taking into account its easy dimerization (Raulin, Toupance, 1975). In particular, the reaction between cyanoacetaldehyde and guanidine provides a relatively simple and efficient pathway for the prebiotic synthesis of cytosine and uracil (Ferris et al., 1974).
2.2.2 Prebiotic Chemistry of HCHO, Formose Reaction
Methanal (commonly called formaldehyde or formol) also undergoes a polymerization reaction in aqueous solution - a reaction known as formose reaction, which is quite relevant in prebiotic chemistry since it leads to the formation of sugars, and among them ribose. This process of polymerization is to some extent similar to the HCN polymerization. It starts by the attack of a monomer molecule, playing the role of nucleophilic reagent, on the carbon of a second monomer molecule, leading, by nucleophilic addition, to a dimer. This dimer can itself undergo the attack of the monomer to give a trimer, etc. One can thus obtain in aqueous solution sugars with 2, 3,...,n carbon atoms (C2, C3j ..., C„), including pentoses (C5 such as ribose) and hexoses (C6 such as glucose).
However, for this reaction to proceed it is required to have high concentrations of formaldehyde and very alkaline solutions. These are unlikely conditions for the terrestrial primitive environment. Moreover, this reaction leads to an extremely complex mixture of sugars. Living systems only use one of these sugars in their genetic material: ribose (in the case of RNA). Therefore one of the biggest puzzles in the field of prebiotic chemistry is the problem of selection. In the absence of living systems, what was the natural process that led 1) to the selection of ribose among hundreds of sugars potentially available in the environment of the primitive Earth and 2) to its specific incorporation in polynucleotides? If the prebiotic synthesis of the amino acids, the building blocks of proteins, and polypeptides is well established, this is not the case for nucleotides, the building blocks of nucleic acids and polynucleotides (Shapiro, 1988).
In all the experiments simulating the evolution of a gas mixture under an energy-source effect there is always the formation of complex organic material of two types. The first type corresponds to simple volatile organic compounds able to participate in prebiotic reactions, such as HCN, HCHO, HC3N, etc. (see Box 2.1). The second type of products is much less well defined; they are macromolecular products with a bidimensional structure (mainly made of polyaromatic groups) or tridimensional structures, branched or not but still very poorly characterized.
In order to refer generically to this type of material, Sagan and Khare (1979) proposed the word "tholins", derived from the Greek word "tholos", which means muddy. The name "tholins" is assigned to refractory macromolecular organic materials, often obtained in a viscous form, which are systematically formed in simulation experiments. Their composition and chemical structure (which is still very poorly known) depends on parameters such as initial gas composition, energy source, temperature and pressure, etc., among others. However, regardless of their mode of formation, they release biological amino acids upon acid hydrolysis (Khare et al., 1986). Therefore they could be the precursors of these biological compounds in aqueous solution. Many studies were developed during recent years on the chemical and physical properties of "tholins", mainly in the case of Titan, but this topic will be discussed in a next section.
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