The Beginnings of Life on Earth
The Thioester World
It may well be, then, that clues to the nature of that early protometabolism exist within modern metabolism. Several proposals of this kind have been made. Mine centers around the bond between sulfur and a carbon-containing entity called an acyl group, which yields a compound called a thioester. I view the thioester bond as primeval in the development of life. Let me first briefly state my reasons.
A thioester forms when a thiol (whose general form is written as an organic group, R, bonded with sulfur and hydrogen, hence R-SH) joins with a carboxylic acid (R'-COOH). A molecule of water (H2O) is released in the process, and what remains is a thioester: R-S-CO-R'. The appeal in this bond is that, first, its ingredients are likely components of the prebiotic soup. Amino acids and other carboxylic acids are the most conspicuous substances found both in Miller's flasks and in meteorites. On the other hand, thiols may be expected to arise readily in the kind of volcanic setting, rich in hydrogen sulfide (H2S), likely to have been found on the prebiotic earth. Joining these constituents into thioesters would have required energy. There are several possible mechanisms for this, which I shall address later. For the time being, let us assume thioesters were present. What could they have done?
The thioester bond is what biochemists call a high-energy bond, equivalent to the phosphate bonds in adenosine triphosphate (ATP), which is the main supplier of energy in all living organisms. It consists of adenosine monophosphate (AMP)--actually one of the four nucleotides of which RNA is made--to which two phosphate groups are attached. Splitting either of these two phosphate bonds in ATP generates energy, which fuels the vast majority of biological energy-requiring phenomena. In turn, ATP must be regenerated for work to continue.
It is revealing that thioesters are obligatory intermediates in several key processes in which ATP is either used or regenerated. Thioesters are involved in the synthesis of all esters, including those found in complex lipids. They also participate in the synthesis of a number of other cellular components, including peptides, fatty acids, sterols, terpenes, porphyrins and others. In addition, thioesters are formed as key intermediates in several particularly ancient processes that result in the assembly of ATP. In both these instances, the thioester is closer than ATP to the process that uses or yields energy. In other words, thioesters could have actually played the role of ATP in a thioester world initially devoid of ATP. Eventually, their thioesters could have served to usher in ATP through its ability to support the formation of bonds between phosphate groups.
Among the substances that form from thioesters in present-day organisms are a number of bacterial peptides made of as many as 10 or more amino acids. This was discovered by the late German-American biochemist Fritz Lipmann, the "father of bioenergetics," toward the end of the 1960s. But even before that, Theodor Wieland of Germany had found in 1951 that peptides form spontaneously from the thioesters of amino acids in aqueous solution.
The same reaction could be expected to happen in a thioester world, where amino acids were present in the form of thioesters. Among the resulting peptides and analogous multi-unit macromolecules, which I like to call multimers to emphasize their chemical heterogeneity, a number of molecules could have been structurally and functionally similar to the small catalytic proteins that inaugurated metabolism. I therefore suggest that multimers derived from thioesters provided the first enzyme-like catalysts for protometabolism.
The thioester world thus represents a hypothetical early stage in the development of life that could have provided the energetic and catalytic framework of the protometabolic set of primitive chemical reactions that led from the first building blocks of life to the RNA world and subsequently sustained the RNA world until metabolism took over.
This hypothesis implies that thioesters could form spontaneously on the prebiotic earth. Assembly from thiols and acids could have occurred, although in very low yield, in a hot, acidic medium. They could also have formed in the absence of water, for example, in the atmosphere. Perhaps a more likely possibility is that thioesters formed, as they do in the present world, by reactions coupled to some energy-yielding process. The American chemist Arthur Weber, formerly of the Salk Institute, now at the NASA Ames Research Center in California, has described several simple mechanisms of this sort that could have operated under primitive-earth conditions.
So far, these ideas are highly speculative, being supported largely by the need for congruence between protometabolism and metabolism, by the key--and probably ancient--roles played by thioesters in present-day metabolism, and by the likely presence of thioesters on the prebiotic earth. But some experimental evidence has been obtained that supports the thioester-world model.
I have already mentioned the work of Wieland, Lipmann and Weber. Recently, highly suggestive evidence has come from the laboratory of Miller, where researchers have obtained under plausible prebiotic conditions the three molecules—cysteamine, b-alanine and pantoic acid—that make up a natural substance known as pantetheine. They have also observed the ready formation of this compound from its three building blocks under prebiotic conditions. It so happens that pantetheine is the most important biological thiol, a catalytic participant in a vast majority of the reactions involving thioester bonds.