Among the human diseases that result from
chromosomal aberrations, a de novo deletion in chromosome 11p13 is clinically associated with a syndrome characterized by
Wilms' tumor,
aniridia, genitourinary anomalies, and
mental retardation (WAGR). Not all genes in the deleted region have been characterized biochemically or functionally. We have recently identified the first Class III
cyclic nucleotide phosphodiesterase, Rv0805, from Mycobacterium tuberculosis, which biochemically and structurally belongs to the superfamily of metallophosphoesterases. We performed a large scale bioinformatic analysis to identify orthologs of the Rv0805
protein and identified many eukaryotic genes that included the human 239FB gene present in the region deleted in the
WAGR syndrome. We report here the first detailed biochemical characterization of the rat 239FB
protein and show that it possesses metallophosphodiesterase activity. Extensive mutational analysis identified residues that are involved in
metal interaction at the binuclear
metal center. Generation of a rat 239FB
protein with a mutation corresponding to a single nucleotide polymorphism seen in human 239FB led to complete inactivation of the
protein. A close ortholog of 239FB is found in adult tissues, and biochemical characterization of the 239AB
protein demonstrated significant hydrolytic activity against 2',3'-cAMP, thus representing the first evidence for a Class III
cyclic nucleotide phosphodiesterase in mammals. Highly conserved orthologs of the 239FB
protein are found in Caenorhabditis elegans and Drosophila and, coupled with available evidence suggesting that 239FB is a
tumor suppressor, indicate the important role this
protein must play in diverse cellular events.