Molecular cloning and ch human phosphodiesteras

PDE11A1 cDNA isolated contains a complete open reading fr4 encoding a 490-amino acid enzyme with a predicted molec mass of 55,786 Da. At the N terminus PDE11A1 has a single domain homologous to that found in other signaling molecL including PDE2, PDE5, PDE6, and PDE10, which constitutes a tential allosteric binding site for cGMP or another small lig. Tissue distribution studies indicate that PDE11A mRNA occur highest levels in skeletal muscle, prostate, kidney, liver, pituit and salivary glands and testis. PDE1 1A is expressed as at least tt major transcripts of =10.5, =8.5, and =6.0 kb, thus suggesting existence of multiple subtypes. This possibility is further suppo by the detection of three distinct proteins of -78, -65, and kDa by Western blotting of human tissues for PDE11A isofo Recombinant human PDE11A1 hydrolyzes both cGMP and c with Km values of 0.52 ILM and 1.04 MzM, respectively, and sin Vmax values. Therefore, PDE11A represents a dual-substrate that may regulate both cGMP and cAMP under physioloc conditions. PDE11A is sensitive to the nonselective PDE inhib 3-isobutyl-l-methylxanthine (IBMX) as well as zaprinast and d ridamole, inhibitors that are generally considered relatively cific for the cGMP-selective PDEs, with IC5s values of 49.8 uIM, piM, and 0.37 ArM, respectively.