The metabolism paradigm

The sudden appearance on Earth of a system capable of both metabolism and replication is too unlikely to be taken seriously. All reasonable theories on the origin of life assume therefore that chemical evolution started from systems that could perform only one of those functions. Hence the great schism between metabolism-first theories (Oparin s paradigm) and replication-first scenarios 

In favour of the metabolism paradigm there are, first of all, the results of the simulation experiments, and in particular the fact that the abiotic production of amino acids is so much easier than that of nucleic acids. Chemistry tells us that the primitive Earth could indeed generate enormous amounts of organic molecules that were potentially capable of having some type of metabolism, and of producing structures as complex as Oparin s coacervates, Fox s microspheres, or Wachtershauser s vesicles. 

The problem, of course, is to evaluate the evolutionary potential of these structures. It is true that Fox s microspheres, for example, can grow and divide by budding or fission, but they lack any form of heredity, and the simulation experiments are too brief to inform us about their long-term potential. The only way of obtaining this kind of information is by using mathematical or chemical models, and such a solution, however imperfect, does have a certain degree of plausibility. 

The first model of a system that is capable of growing by metabolism and of dividing by fission was proposed - with the name of chemoton - by Ganti (1975). Such a system receives metabolites from the environment, expels waste products, and performs a metabolic cycle that begins with one molecule and ends by making two of them. The system is therefore autocatalytic, but it is not using enzymes, and this leaves us in the dark about its biological potential. 

In order to have a metabolic and enzymatic system, it would be necessary to have proteinaceous enzymes which can catalyse the synthesis of other enzymes, and for this they should be capable of making peptide bonds. Such systems have not been found in nature, so far, but according to Stuart Kauffman (1986) they could have existed in the past, and in primitive compartments could have produced autocatalytic networks which had the potential to jump from chaos to order. Even if we admit that those enzymes existed, however, we still have the problem of accounting for the origin of the complex autocatalytic networks that housed them. 

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We can say therefore that the metabolism-firsti ta. (the metabolism paradigm) goes back to Oparin, while the replication-first concept (the replication paradigm) goes back to Haldane. And since metabolism is based on proteins, and replication on nucleic acids, Oparin s paradigm is equivalent to saying that proteins (the hardware) came first, whereas Haldane s paradigm maintains that it was nucleic acids (the software) that had priority. 

The oxygen context for the acquired protomitochondria has remained the principal paradigm for understanding mitochondrial origins to the present day. In the metabolic complementary of symbiont and host, the symbiont was in charge of aerobic respiration and energy (ATP), while the host was... 

Somero, G.N., and J.J. Childress (1980). A violation of the metabolism-size scaling paradigm activities of glycolytic enzymes in muscle increase in larger size fishes. Physiol. Zool. 53 322-337. 

The fact that ribozymes came before protein enzymes does not mean that replication came before metabolism, but it is an historical fact that this is precisely the meaning that was given, almost universally, to the discovery of ribozymes. With very few exceptions, the RNA world has been interpreted with the logic of the replication paradigm if RNAs could behave as genes and as enzymes, then they did it immediately, at the very beginning, and became the first replicators in the history of life. 

We conclude that the replication paradigm has not been able, so far, to account for chemical evolution, but could be valid for postchemical evolution, and this, it will be remembered, is also Dyson s hypothesis (metabolism first, replication second). Let us examine therefore the evolutionary potential of primitive vesicles containing RNAs that could behave both as genes and enzymes. 

The paradigm for both modular PKSs and NRPSs is that each module incorporates one building block into the natural product (Figures 1 and 2). Within each module there are different domains and each domain catalyzes a specific reaction in the assembly of the metabolic product. Model examples of this colinearity between module and domain organization and metabolite structure for type I modular PKS and NRPS systems are respectively represented by erythromycin and tyrocidine biosyntheses. This colinearity is an important feature that underpins our ability to predict structural features of the metabolic products of novel modular PKS and NRPS systems discovered by genomics. 

The impact of novel medicines for unmet medical needs brought forward by the pharmaceutical industry in the last thirty years is tremendous drugs for metabolic diseases (cholesterol, hypertension, diabetes), HIV treatments, new antibiotics, treatments for rheumatoid arthritis, schizophrenia, etc. These medicines have profoundly transformed the treatment paradigm in their respective fields, with a major impact of extending and enhancing human life. 

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