AbstractIn this manuscript we provide computational support to the catalytic role of water in all kinds of pseudopericyclic reactions operating in the reductive acid cycle, as well as in other metabolic processes. Water catalysis is not limited to those reactions where simple translocation of hydrogen atoms occurs, such as those represented by NuH+E→Nu‐EH general equation. Indeed, water catalysis is more general and extremely important in tautomerization reactions of the type HX−Y=Z→X=Y−ZH, which operate in the reductive citric acid cycle and metabolic processes. Moreover, the comprehensive theoretical study reported herein illustrates that these reactions appear to behave as authentic enzyme‐catalyzed reactions showing Michaelis‐Menten behavior, however with the abnormal singularity that the concentration of the catalytic “water clusters” of different length and nature must be taken as a huge number. Overall, the results presented are suggestive of the workability of the so‐called “metabolism first” proposal in a hot water world, as water catalysis eliminates the dilution problem frequently associated to this proposal.