Science in Christian Perspective

The Physico-Chemical Synthesis
of ""Biological" Compounds *
RICHARD A. HENDRY, Ph.D.
Department of Chemistry, University of Illinois
Urbana, Illinois

From JASA 10 (March 1958): 2-5.

In any mechanistic hypothesis of the origin of life, one is faced with the problem of explaining the origin of the biochemical world. The problem of how inorganic matter was originally converted into organic matter, of a nature suitable for the ultimate formation of living systems, has been on men's minds for many years. As we view life processes today, we see that biochemical substances are formed and broken down (metabolized) by the action of biological catalysts which are, themselves, of a biochemical nature. The question of whether or not these biologically-active substances could have had a non-biological origin will be the subject of this paper.

An examination of living organisms, both plants and animals, reveals many differences in form and appearance; however, if we would examine the chemical makeup of living things, we would find that there are many striking similarities which transcend the boundaries of species, genus, and even kingdom. We find in plants and animals certain chemically similar substances which carry out the most basic processes of life. While there are a number of chemical substances found, more or less, universally in the world of living things, we will deal here only with three of the most important: enzymes, coenzymes, and nucleic acids.

The enzymes are proteins which possess the ability to speed up the multitude of chemical reactions taking place within an organism and without which life, as we know it today, would be impossible. Proteins are highmolecular weight polymers consisting of amino acids linked end to end in the form of long chains. The amino acids, or "building blocks" of proteins, are relatively small organic compounds possessing an amino and carboxylic acid group. There are about twenty different amino acids found to occur in proteins. The vast number of proteins vary only in the type, number, and arrangement of each of these amino acids. Some proteins do not contain all of the twenty varieties of amino acids; the protamines of certain fish sperm, for example, contain only about a third to a half of the known ones^l. For a given protein, of a given species, there is believed to be a rather definite sequence of amino acids.

*Paper presented at the Twelfth Annual Convention of the American Scientific Affiliation, Beverly Forms, Massachusetts, August, 1957.

The structures of some smaller proteins, such as insulin² and B-corticotropin³, have been recently worked out.

The nucleic acids are found within every living cell and usually associated with protein (nucleoprotein) ; they are, like proteins, high-molecular weight substances. They consist of units of purine and pyrimidine bases, a pentose sugar, and phosphoric acid linked together in a definite manner. The nucleic acids may be divided into two classes, ribonucleic (RNA) and deoxyribonucleic acids (DNA). These are distinguished from each other by the type of pentose sugar they contain; RNA contains ribose, whereas DNA contains the corresponding 2-deoxy derivative. Differences in RNA and DNA from different species lies in the relative amounts of each of the purine and pyrimidine bases and, therefore, also in the base sequence. Chromosomal matter of the nucleus contains essentially all of the cell DNA, whereas the RNA is more widely distributed throughout other sub-cellular particles, such as the microsomes and mitochondria. Some viruses, such as the tobacco mosaic virus, consist entirely of nucleic acid and protein. Viruses are known of both the DNA and RNA varieties. Recently, evidence has been obtained which indicates that nucleic acids are involved in protein synthesis4.

The coenzymes are relatively smaller molecular weight substances of a variety of structures, and which may be associated with one or more enzyme. They apparently take part in a reaction by forming a link between an enzyme and the substrate. Coenzymes vary considerably in their function, but playing a particularly important role in biological oxidation and reduction and also in phosphorylation reactions. It should be noted that not all reactions require the presence of a coenzyme. Some coenzymes are known which contain purines, pyrimidines, ribose and phosphoric acid, and others which contain amino acids in their structures, thereby showing similarities to the nucleic acids and enzymes. It is of interest to note that many of the known vitamins are coenzymes or part of coenzyme structures.

The three classes of compounds we have described consist of relatively few different "building blocks"; the number being something under fifty.

Many scientists, today, feel that life may have ori ginated from the inorganic world via these basic sub stances ( or part of them). What are the possibilities that this hypothesis may be true? Many investigators, not being satisfied with only a hypothesis, have looked into this problem, hoping to find at least a partial answer. If compounds such as proteins, nucleic acids, and coenzymes were formed via their sub-units during the prebiological period, tinder the conditions which existed on the earth's surface, these processes should be, in part, repeatable in the laboratory. If, as a result of experimentation, none of these substances could be pre pared under a variety of possible primitive earth conditions, we would have to regard this hypothesis as rather unlikely.

Physico-chemical methods which have been used or suggested for producing "biological" compounds may be outlined as follows:

Electrical discharges, high-energy radiation, and heat have been known for some time to be capable of break ing molecular linkages. Similar but naturally occurring energy sources, such as lightning, radioactivity, ultra violet and cosmic radiation, volcanic and also high pres sures could possibly have been the means of forming a number of organic chemical structures during the pre biological period.

In 1913, Loeb⁵ gave evidence for the formation of glycine after passing an electric discharge through a mixture of carbon monoxide, ammonia and water vapor. In recent years, electric discharge experiments have been carried out by Miller and others. MillerG,^7,8 passed an electric discharge through a mixture of methane, ammonia, water, and hydrogen. Within the apparatus was a refluxing aqueous phase which caused the gases to cir culate and acted as a solvent for water-soluble products.

After a week the aqueous solution was analyzed. The following biologically important compounds were iso lated and identified: glycine, alanine, sarcosine, B-alanine, aminobutyric acid, aspartic acid, glutamic acid, formic acid, acetic acid, propionic acid, glvcolic acid, lactic acid, succinic acid, and urea. Of particular interest is the fact that four of the amino acids common to proteins were produced. Abelson⁹ reported that vari ous mixtures of gases, including carbon dioxide-nitrogen-hydrogen-water, carbon n-ionoxide-nitrogen-hydrogen-water, and carbon dioxide-ammonia-hydrogen, when subjected to electric discharge, gave rise to amino acids such as alanine and glycine. The action of the electric discharge in each of these series of experiments was such to cause the formation of free radicals. The free radicals then recombined with each other produc ing a variety of reactive substances such as formaldehyde, acetaldehyde, and hydrogen cyanide. These latter three substances along with ammonia reacted in water to form amino acids. In conjunction with these experiments, Miller investigated the possibility that purine and pyrimidine bases were present in the re action products; however, using microtechniques, none could be detected.

We have mentioned that formaldehyde Is a starting material for the production of several compounds of biological importance. The reaction of formaldehyde with ammonia and hydrogen cyanide produces glycine, as was mentioned previously. Butlerow, in 1861¹⁴ found that formaldehyde condensed with itself, in the presence of alkali, producing a sugar-like substance. Fischer¹⁵, the great German organic chemist, reinvesti gated the substance, which was called formose, and was able to isolate a small amount of DL-glucose from what was apparently a mixture of different sugars. The variety of sugars present in formose is indeed great, as was shown recently by Marlani and Torraca^I6. Us ing the technique of paper chromatography, they were able to show that at least 24 different sugars were present. They were only able to identify eleven of these, glucose, fructose, galactose, mannose, sorbose, arabinose, xylose, lyxose, ribose, xylulose, and ribulose. The majority of these substances occur in nature as such or in the iorm of polymers. It is of interest that ribose, one of the components of RNA, is formed in this re action. Deoxyribose could, presumably, be formed by a similar reaction between formaldehyde and acetaldehyde.

Bahadur^l7,18 has given evidence for the form ation of a number of amino acids by the action of light on formaldehyde and potassium nitrate, in the pres ence of ferric chloride. Paper chromatography indi cated that glycine, serine, aspartic acid, asparagine, histidine, arginine, lysine, and proline were presen t. Of these only glycine, serine, aspartic acid and asparagine were positively identified. Oro¹⁹ has heated solutions of formaldehyde and either hydrazine or hydroxylaniine, two nitrogen-containing inorganic compounds, and ob tamed glycine, glycinamide, B-alanine, alanine, valine and lysine.

Cyanogen, a gas produced by the action of heat or an electric discharge on a mixture of acetylene and nitrogen, has been suggested as a precursor to bio chemical compounds. The gas, by the action of water, slowly decomposes to form such substances as formic and oxalic acids, amnionia, hydrogen cyanide, and urea²⁰. Many of these could, through further reactions, give amino acids, etc.

Thermal reactions, which restilt in the formation of biologically important compounds, have been in vestigated by Fox and his co-workers ^21,22,23. Heating the ammonium salt of malic acid or a mixture of the acid and urea, they obtained aspartic acid. The yield of amino acid increased when the product was hydro lyzed by acid, indicating that the aspartic acid formed existed as some type of polymer^2l,22. Further experi ments with aspartic acid showed that a protein-like substance is formed, among other products, by heating the amino acid at 200' C. for 0.3 to 3 hours²³. Under similar conditions to these, Meggy24 was able to poly merize glycine. Other experiments by Fox and his group have shown that alanine and the isomeric B- alanine are also formed on heating aspartic acid^2l.22. B-alanine is of interest in that it is a constituent of Coenzyme A.

Lippich25, in 1908, showed that an aqueous solu tion of aspartic acid and urea, in the presence of barium hydroxide, yielded ureidosuccinic acid. Fox reinvesti gated this reaction and found that various alkaline substances catalyzed the reaction, giving a good yield of the product²². Ureidosuccinic acid is of particular interest since it is a known precursor of pyrimidines²⁶ and, therefore, also of nucleic acid.

As yet, there has been no production of the known purine and pyrimidine bases by the rather simple physico-chemical means previously described. Uricacid, an end-product of purine metabolism in some animals, possesses the purine ring system. This de rivative was first synthesized, in 1882, by the rather simple method of heating a mixture of urea and glycine²⁷, substances we have shown previously to be formed by other physico-chemical means. Davidson and Baudisch²⁸ found that urea and malic acid, when treated with fuming, sulfuric acid, which acted as a dehydrating agent, yielded uracil, a pyrimidine found in RNA and certain coenzymes.

We have, to this time, discussed, primarily, the formation of the basic "building blocks" of proteins, nucleic acids and coenzymes. Further comment should be made about procedures for forming the more com plex substances. The fon-nation of polymers of aminoacids, for example, requires considerable free energy. This means that within an aqueous solution of a given amino acid, relatively very few of the molecules will react with each other to form dipeptides and still fewer to form high polymers. In experiments which involve the heating of amino acids such as were men tioned for aspartic acid and glycine, water, a product of the reaction, is removed under conditions of a high temperature. Such a reaction, as we pointed out, gives other undesired by-products. Curtis²⁹ and later, Frankel and Katchalski³⁰ showed that glycine ethyl ester condensed to form polymers, possessing many of the chemical properties of proteins. It is rather un likely that such amino acid ester derivatives were formed during prebiological times; however, there is the possibility that "activated" amino acid derivatives could be formed in other ways. Certain inorganic phosphoric acid derivatives, the pyro,phosphates, have been suggested by a number of writers^11,31 as being possible condensing agents. Recent evidence³² indi cated that amino acids, most likely, condense in vivo through phosphoric anhydride intermediates ' adenos ine triphosphate (ATP) being the phosphorylating agent.

Bernal³³ has suggested that as amino acids were formed, they were absorbed and then condensed on clay particles. This idea helps overcome some of the claims that the concentrations of amino acids and other "building blocks" were too dilute for condensation to take place.

In summary, we have presented evidence that a number of biologically-important compounds, such as amino acids, can be formed by rather simple means. The problem of how these sub-units condensed to form more complex biologically-active compounds has also been considered. There is need for additional research to be carried out in this field, since a hypothesis be comes more satisfactory only as it is supported by more and more experimental data.

References