General acid-base catalysis in the mechanism of a hepatitis delta virus ribozyme

Many protein enzymes use general acid-base catalysis as a way to increase r eaction rates. The amino acid histidine is optimized for this function beca use it has a pK(a) (where K-a is the acid dissociation constant) near physi ological pH. The RNA enzyme (ribozyme) from hepatitis delta virus catalyzes self-cleavage of a phosphodiester bond. Reactivity-pH profiles in monovale nt or divalent cations, as well as distance to the Leaving-group oxygen, im plicate cytosine 75 (C75) of the ribozyme as the general acid and ribozyme- bound hydrated metal hydroxide as the general base in the self-cleavage rea ction. Moreover, C75 has a pK(a) perturbed to neutrality, making it "histid ine-like." Anticooperative interaction is observed between protonated C75 a nd a metal ion, which serves to modulate the pK(a) of C75. General acid-bas e catalysis expands the catalytic repertoire of RNA and may provide improve d rate acceleration.