How does the exchange of one oxygen atom with sulfur affect the catalytic cycle of carbonic anhydrase?

We have extended our investigations of the carbonic anhydrase (CA) cycle with the model system [(H3N)(3)ZnOH](+) and CO2 by studying further heterocumulenes and catalysts. We investigated the hydration of COS, an atmospheric trace gas. This reaction plays an important role in the global COS cycle since biological consumption, that is, uptake by higher plants, algae, lichens, and soil,, represents the dominant terrestrial sink for this gas. In this context, CA has been identified by a member of our group as the key enzyme for the consumption of COS by conversion into CO2 and H2S. We investigated the hydration mechanism of COS by using density functional theory to elucidate the details of the catalytic cycle. Calculations were first performed for the uncatalyzed gas phase reaction. The rate-determinig step for direct reaction of COS with H2O has an energy barrier of DeltaG = 53.2 kcal mol(-1). We then employed the CA model system [(H3N)(3)ZnOH](+) (1) and studied the effect on the catalytic hydration mechanism of replacing an oxygen atom with sulfur. When COS enters the carbonic anhydrase cycle, the sulfur atom is incorporated into the catalyst to yield [(H3N)(3)ZnSH](+) (27) and CO2. The activation energy of the nucleophilic attack on COS, which is the rate-determining step, is somewhat higher (20.1 kcal mol(-1) in the gas phase) than that previously reported for CO2. The sulfur-containing model 27 is also capable of catalyzing the reaction of CO2 to produce thiocarbonic acid. A larger barrier has to be overcome for the reaction of 27 with CO2 compared to that for the reaction of I with CO2. At a well-defined stage of this cycle, a different reaction path can emerge: a water molecule helps to regenerate the original catalyst 11 from 27, a process accompanied by the formation of thiocarbonic acid. We finally demonstrate that nature selected a surprisingly elegant and efficient group of reactants, the [L3ZnOH](+)/CO2/H2O system, that helps to overcome any deactivation of the ubiquitous enzyme CA in nature.