Universality in intermediary metabolism

Abstract

We analyze the stoichiometry, energetics, and reaction concentration dependence of the reductive tricarboxylic acid (rTCA) cycle as a universal and possibly primordial metabolic core. The rTCA reaction sequence is a network-autocatalytic cycle along the relaxation pathway for redox couples in nonequilibrium reducing environments, which provides starting organic compounds for the synthesis of all major classes of biomolecules. The concentration dependence of its reactions suggests it as a precellular bulk process. We propose that rTCA is statistically favored among competing redox relaxation pathways under early-earth conditions and that this feature drove its emergence and also accounts for its evolutionary robustness and universality. The ability to enhance the rate of core reactions creates an energetic basis for selection of subsequent layers of biological complexity.

Fig. 1.

The reductive TCA cycle (boldface) as an engine of synthesis of the major classes of biomolecules (bold italic). Synthesis of categories usually begins with a specific molecule (lightface).

Fig. 2.

Δ_fG⁰ in kJ/mol per carbon atom of TCA cycle intermediates from CO₂(aq) and H₂(aq), together with reference molecules on the reduction pathway to CH₄(aq). For the reaction xCO₂ + yH₂ ⇋ X + zH₂O, reducing potential per carbon taken from the environment to form species X is plotted as y/x on the abscissa. Δ_fG⁰ values for cycle intermediates from ref. and for other organic compounds from ref. .

Fig. 3.

The rTCA cycle reactions. Synthesis from acetate → fumarate is repeated from succinate → cis-aconitate, with CH₂COOH replacing H as end group. Δ_rG⁰ values (kJ/mol, bold italic) are for reactions from CO₂(aq) and H₂(aq) in equilibrium with gases at 1atm partial pressure, and H₂O(l). Computed from Δ_fG⁰ values in ref. , using Δ_fG⁰ =–386 kJ/Mol for CO₂(aq), +17.7 kJ/Mol for H₂(aq), and –237.2 kJ/Mol for H₂O(l). Δ_rG⁰ =–34 kJ/Mol for ATP hydrolysis corresponds to a local stationary region ≈pH 6 and pMg 1.5 in ref. .