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Activation reactions involve modification of recalcitrant substrates to forms that are more readily degradable. These reactions require specialized enzymes and cosubstrates, including molecular oxygen and reduced electron carriers. In these reactions, microorganisms invest electrons and cannot capture energy or carbon for synthesis. The subsequent degradation of the intermediates formed in activation reactions releases electrons, energy, and carbon that the organisms use for growth. The overall yield is reduced due to the required activation investments. A mathematical method to predict cell yields of oxygenase activation reactions is developed using electron and energy balances. Predicted yields are compared with experimental yields for methane, organic chelating agents, and aromatic hydrocarbons.