Nucleoside Deaminases for Cytidine and Adenosine: Comparison with Deaminases Acting on RNA

Abstract

This chapter reviews the structure of Escherichia coli cytidine deaminase and implications for evolutionary relationships between members of the cytidine deaminase superfamily. It then summarizes details of the E. coli cytidine deaminase (ECCDA) reaction mechanism, with particular reference to the role of conserved residues and aspects of substrate specificity relating to the nucleoside modifying and editing enzymes. The chapter concludes with a discussion of models for RNA editing deaminases derived from sequence homologies and structural studies. APOBEC-1, the sole representative of what will likely be a family of editing cytidine deaminases acting on RNA substrates, shares this signature and, is outlined in detail, it likely has significant tertiary and quaternary homology to the E. coli cytidine deaminase, ECCDA. An attempt has been made to rationalize the naming of editing adenosine deaminases, calling them adenosine deaminases acting on RNA (ADARs). Conversion of cytidine to uridine involves two successive steps: hydration of the 3-4 double bond, and subsequent elimination of the leaving ammonia molecule with formation of the keto tautomer of the pyrimidine. A broad, representative sample of APOBEC-1 mutants was examined by biochemical assays for homodimerization, RNA binding, and RNA editing. The X-ray structure has been determined for murine adenosine deaminase, which catalyzes deamination of adenosine to inosine. The secondary and tertiary structure motifs of the two nucleoside deaminases are completely unrelated. The outlines described in the chapter of how C-to-U and A-to-I editing occurs provide coherent hypotheses based on known structures of related enzymes.