The Implausibility of Metabolic Cycles on the Prebiotic Earth
Leslie E Orgel †
Published: January 22, 2008DOI: 10.1371/journal.pbio.0060018
Cycles occur widely in all branches of chemistry. The definition of a catalyst as an agent that facilitates the conversion of reactants to products without itself being changed almost guarantees that a catalyst can initiate successive “cycles” of the same reaction. Metabolic cycles are different. Strictly, they are by definition restricted to biochemistry. Like catalytic cycles, they too result in repeated conversions of substrates into products, but they involve much more complex sequences of chemical reactions. As far as I am aware, the formose reaction, which converts formaldehyde to a complicated mixture of products, including various sugars , is the only known nonenzymatic reaction sequence that is at all similar to a metabolic cycle, although the existence of one or two much simpler cycles has been established or made probable in the literature of prebiotic chemistry [2,3]. The possibility that reactions of hydrogen cyanide (HCN) might form the basis for a complex cyclic organization has been proposed , but there is as yet no experimental evidence to support this proposal.
If complex cycles analogous to metabolic cycles could have operated on the primitive Earth, before the appearance of enzymes or other informational polymers, many of the obstacles to the construction of a plausible scenario for the origin of life would disappear. If, for example, a complex system of nonenzymatic cycles could have made nucleotides available for RNA synthesis, many of the problems of prebiotic chemistry would become irrelevant. Perhaps a simpler polymer preceded RNA as the genetic material—for example, a polymer based on a glycerol-phosphate backbone  or a phosphoglyceric acid backbone. Could a nonenzymatic “metabolic cycle” have made such compounds available in sufficient purity to facilitate the appearance of a replicating informational polymer?
It must be recognized that assessment of the feasibility of any particular proposed prebiotic cycle must depend on arguments about chemical plausibility, rather than on a decision about logical possibility. Any reaction sequence that is allowed by thermodynamics could, in principle, be realized, given a sufficiently active and specific family of catalysts. Plants synthesize complex alkaloids, such as strychnine, from CO2, NH3, and reducing equivalents, so it must, in principle, be possible to achieve these syntheses starting from CO2, NH3, and H2, given a family of sufficiently active and specific prebiotic catalysts. However, few would believe that any assembly of minerals on the primitive Earth is likely to have promoted these syntheses in significant yield. Each proposed metabolic cycle, therefore, must be evaluated in terms of the efficiencies and specificities that would be required of its hypothetical catalysts in order for the cycle to persist. Then arguments based on experimental evidence or chemical plausibility can be used to assess the likelihood that a family of catalysts that is adequate for maintaining the cycle could have existed on the primitive Earth.
The metabolic cycles that have been identified by biochemists are of two kinds: simple cycles and autocatalytic cycles. The citric acid cycle, which brings about the oxidation of acetate to CO2 with the concomitant synthesis of ATP, and the urea cycle that results in the conversion of toxic NH3 to relatively harmless urea, are both examples of simple cycles. The initial step of the former cycle is the synthesis of citric acid from oxaloacetic acid and acetyl-CoA. After one turn of the cycle, acetate is completely “burned” to CO2 as one molecule of oxaloacetate is regenerated. The Calvin dark cycle and the reverse citric acid cycle, both of which result in the fixation of CO2 into important biochemical intermediates, are examples of autocatalytic cycles. The reverse (reductive) citric acid cycle (Figure 1) is initiated by the splitting of citric acid to give oxaloacetic acid and acetyl-CoA. After one turn of the cycle, two molecules of citric acid are formed, so long as no material is diverted from the cycle. That is why the cycle is described as autocatalytic—each molecule of citric acid introduced into the cycle results, after a turn of the cycle, in the generation of two molecules of citric acid. The proposal that the reverse citric acid cycle operated nonenzymatically on the primitive Earth has been a prominent feature of some scenarios for the origin of life [6–8].
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