Analysis of the energy diagram for the uncatalyzed rTCA cycle demonstrates that while the pathway satisfies the thermodynamic requirements for carbon fixation, it fails to meet the necessary kinetic criteria for spontaneity (Fig. ). The overall cycle shows clear thermodynamic favorability with a net free energy change of -12.1 kcal⸱mol -1 for converting two CO2 and four H2 molecules to acetate and water. However, examination of the complete energy landscape reveals systematic kinetic barriers that prevent this thermodynamically favorable conversion. Five main cycle reactions exhibit at least one side reaction that is kinetically favored despite being more endothermic than the main cycle reaction. Two representative cases are highlighted in Figs. with their transition states and competing reactions. The carboxylation of succinate to 2oxoglutarate competes with a kinetically favorable CO2 addition that is geometrically favored (the TS is a direct adduct to the carboxylic acid) but forms a relatively unstable four-membered ring (Fig. ). Similarly, the cleavage of citrate to acetate and oxaloacetate competes with an intramolecular isomerization that is kinetically favored by 18.2 kcal⸱mol -1 (Fig. ). These offtarget fluxes are expected to be irreversible to the extent that these species undergo additional kinetically favored reactions besides the reverse reaction. The energy diagram also reveals that the main cycle intermediate, 2-oxoglutarate (S7), is a local thermodynamic sink in the cycle that resides ~6 kcal/mol lower in energy than the globally favored production of acetic acid (Fig. , green). In kinetic terms, this means that the second CO2 addition and other steps downstream of 2-oxoglutarate must compete with their reverse reactions, which locally favor 2-oxoglutarate accumulation. This may be within the error of the DFT level of theory and PCA model used here, nevertheless it is indicative of the finely balanced energetics of the rTCA cycle and shows how the thermodynamics of intermediates can also modulate the overall cycle kinetics.