A weak link in metabolism: the metabolic capacity for glycine biosynthesis does not satisfy the need for collagen synthesis.

In a previous paper, we pointed out that the capability to synthesize glycine from serine is constrained by the stoichiometry of the glycine hydroxymethyltransferase reaction, which limits the amount of glycine produced to be no more than equimolar with the amount of C 1 units produced. This constraint predicts a shortage of available glycine if there are no adequate compensating processes. Here, we test this prediction by comparing all reported fl uxes for the production and consumption of glycine in a human adult. Detailed assessment of all possible sources of glycine shows that synthesis from serine accounts for more than 85% of the total, and that the amount of glycine available from synthesis, about 3 g/day, together with that available from the diet, in the range 1.5–3.0 g/day, may fall signifi cantly short of the amount needed for all metabolic uses, including collagen synthesis by about 10 g per day for a 70 kg human. This result supports earlier suggestions in the literature that glycine is a semi-essential amino acid and that it should be taken as a nutritional supplement to guarantee a healthy metabolism.

From the RNA world to the DNA-protein world: clues to the origin and early evolution of life in the ribosome.

“What is life” is a more diffi cult question to answer than “What is a living being”. According to the classical defi nition, a living being is an entity capable of carrying out autosynthesis, autocatalysis and excitability. Autosynthesis means the capability of synthesising its own material from external materials, which involves nutrition, metabolism and growth; autocatalysis implies the capability of producing new beings (reproduction), and excitability is the capacity to respond to stimuli in such a way that the response is more than a passive refl ection of the stimulus. Although these three functions can be recognized in all living beings, the defi nition of life is a more diffi cult question, because some of these features – as well as others considered to be characteristic of life, such as self-organization – are also found in non-living materials like crystals and inert dissipative structures. In fact, what distinguishes life from inert material is its ability to evolve by natural selection. Therefore, a possible defi nition of life is that it is the totality of all the properties of a chemical transformation system that make it possible for the system to undergo Darwinian evolution by natural selection. (We say ‘chemical transformation system’ because the only forms of life known to us are based on chemistry. In principle, any transformation system would do so long as the above properties are satisfi ed.) Evolution by natural selection is, thus, the main and most characteristic feature of life. Therefore the conditions necessary for it are those essential for life. In order to evolve for by natural selection, an entity must possess three features: information, metabolism and a membrane. Metabolism is a facet of the chemical machinery of autosynthesis. It includes the capacity to produce all cellular structures and a source of storable energy (usually ATP) from external sources. Metabolism is determined by enzymes (catalytic molecules) whose main feature must be to catalyse reactions specifi cally – and also at a rate higher than the chemical background noise, so as to be able to favour specifi c chemical reactions. Information involves the capacity to safeguard the means through which the system can be perpetuated. Because this requires the ability to replicate, it is also the basis of autocatalysis and provides the necessary basis for cumulative evolution. Finally, natural selection demands that the system must become ‘selfi sh’, as it must safeguard its achieved improvements in the catalytic material, all the while being in competition with other similar entities that can take advantage of it in the sense of increasing their representation in the population relative to it. A selective membrane that determines its individuality is necessary in order to ensure that both metabolism and information can take place without compromising the integrity of the system (Meléndez-Hevia et al. 2008). The emergence of life was diffi cult, and it is obvious that life could not appear with the high complexity seen in present living beings – even the simplest ones that may imply around 2,000 different specifi c structural and catalytic molecules. Life had to start with the minimum possible necessary material, but enough to fulfi l the three basic requirements: information, metabolism and a membrane. If it were possible to demonstrate that a single entity could account for at least two of these three features, the a priori possibilities for life getting a start would improve and the problem of the origin of life would be simplifi ed. An interesting feature of life, which allows the reconstruction of its history, is that the materials used in any stage are generally preserved. That is, the emergence of new materials does not destroy the old ones; at least some of the earlier materials remain in the later structures. This feature is the logical consequence of life’s continuity. Otherwise, life would have had to start again many times. Therefore, it is expected that traces of many steps in the evolution of life remain at present as they were near the beginning, even if they are very ancient.

Branch-point stoichiometry can generate weak links in metabolism: the case of glycine biosynthesis.

Although the metabolic network permits conversion between almost any pair of metabolites,this versatility fails at certain sites because of chemical constraints (kinetic,thermodynamic and stoichiometric) that seriously restrict particular conversions. We call these sites weak links in metabolism,as they can interfere harmfully with management of matter and energy if the network as a whole does not include adequate safeguards. A critical weak link is created in glycine biosynthesis by the stoichiometry of the reaction catalyzed by glycine hydroxymethyltransferase (EC 2.1.2.1), which converts serine into glycine plus one C1 unit: this produces an absolute dependence of the glycine production flux on the utilization of C1 units for other metabolic pathways that do not work coordinately with glycine use. It may not be possible,therefore,to ensure that glycine is always synthesized in sufficient quantities to meet optimal metabolic requirements.