Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report here the cloning, expression, and characterization of human PDE11A1, a member of a distinct cyclic nucleotide phosphodiesterase (PDE) family. PDE11A exhibits </=50% amino acid identity with the catalytic domains of all other PDEs, being most similar to PDE5, and has distinct biochemical properties. The human PDE11A1 cDNA isolated contains a complete open reading frame encoding a 490-amino acid enzyme with a predicted molecular mass of 55,786 Da. At the N terminus PDE11A1 has a single GAF domain homologous to that found in other signaling molecules, including PDE2, PDE5, PDE6, and PDE10, which constitutes a potential allosteric binding site for cGMP or another small ligand. Tissue distribution studies indicate that PDE11A mRNA occurs at highest levels in skeletal muscle, prostate, kidney, liver, pituitary, and salivary glands and testis. PDE11A is expressed as at least three major transcripts of approximately 10.5, approximately 8.5, and approximately 6.0 kb, thus suggesting the existence of multiple subtypes. This possibility is further supported by the detection of three distinct proteins of approximately 78, approximately 65, and approximately 56 kDa by Western blotting of human tissues for PDE11A isoforms. Recombinant human PDE11A1 hydrolyzes both cGMP and cAMP with K(m) values of 0.52 microM and 1.04 microM, respectively, and similar V(max) values. Therefore, PDE11A represents a dual-substrate PDE that may regulate both cGMP and cAMP under physiological conditions. PDE11A is sensitive to the nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) as well as zaprinast and dipyridamole, inhibitors that are generally considered relatively specific for the cGMP-selective PDEs, with IC(50) values of 49.8 microM, 12.0 microM, and 0.37 microM, respectively.
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PMID:Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A. 1072 73

cDNAs encoding a novel phosphodiesterase, phosphodiesterase 11A (PDE11A), were isolated by a combination of reverse transcriptase-polymerase chain reaction using degenerate oligonucleotide primers and rapid amplification of cDNA ends. Their catalytic domain was identical to that of PDE11A1 (490 amino acids) reported during the course of this study. However, the cDNAs we isolated had N termini distinct from PDE11A1, indicating two novel N-terminal variants of PDE11A. PDE11A3 cDNA encoded a 684-amino acid protein including one complete and one incomplete GAF domain in the N-terminal region. PDE11A4 was composed of 934 amino acids including two complete GAF domains and shared 630 C-terminal amino acids with PDE11A3 but had a distinct N terminus containing the putative phosphorylation sites for cAMP- and cGMP-dependent protein kinases. PDE11A3 transcripts were specifically expressed in testis, whereas PDE11A4 transcripts were particularly abundant in prostate. Recombinant PDE11A4 expressed in COS-7 cells hydrolyzed cAMP and cGMP with K(m) values of 3.0 and 1.4 microm, respectively, and the V(max) value with cAMP was almost twice that with cGMP. Although PDE11A3 showed the same K(m) values as PDE11A4, the relative V(max) values of PDE11A3 were approximately one-sixth of those of PDE11A4. PDE11A4, but not PDE11A3, was phosphorylated by both cAMP- and cGMP-dependent protein kinases in vitro. Thus, the PDE11A gene undergoes tissue-specific alternative splicing that generates structurally and functionally distinct gene products.
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PMID:Isolation and characterization of two novel phosphodiesterase PDE11A variants showing unique structure and tissue-specific expression. 1090 26

PDE11A is a dual-substrate, cAMP and cGMP, cyclic nucleotide phosphodiesterase (PDE). Presently four unique variants carrying distinct GAF sequences in the N-terminal region have been identified. While human PDE11A3 and PDE11A4 are known to be specifically expressed in testis and prostate, respectively, PDE11A1 was mainly detected in skeletal muscle. The human PDE11A gene was investigated and revealed to span > 300 kb, contain 23 exons and be mapped on chromosome 2q31. The transcription start sites of PDE11A1, PDE11A3 and PDE11A4 were determined, and the promoter sequences were revealed. Although 5' flanking genomic regions of PDE11A1 and PDE11A3 had a consensus TATA motif, that of PDE11A4 was a TATA-less but contained CCAAT box and Sp1-binding sequence. Interestingly, we found that the exon 2 sequence for N-terminal region of PDE11A3 encoded an N-terminal sequence of the cytochrome c pseudogene in an alternate reading frame, and that C-terminal region of the cytochrome c pseudogene in intron 2 was disrupted by the insertion of Alu repetitive sequence. Furthermore, we examined the exon-intron organization of the PDE2A gene and compared the exon organization among GAF-PDE family. The exon organization of the PDE11A catalytic domain was very similar to those of PDE5A and PDE6B. However, other GAF-PDEs, PDE2A and PDE10A, displayed different exon organization from PDE11A although these three PDEs are similar in their amino-acid sequences to each other. The findings suggested that PDE11A has a common ancestral gene with PDE5A and PDE6s, whereas PDE2A and PDE10A are generated separately from these three GAF-PDEs.
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PMID:Genomic organization of the human phosphodiesterase PDE11A gene. Evolutionary relatedness with other PDEs containing GAF domains. 1112 Nov 18

The phosphodiesterase-11A (PDE11) family consists of four splice variants (PDE11A1-PDE11A4) that contain a conserved carboxyl-terminal (C-terminal) catalytic domain that hydrolyzes cAMP and cGMP; the amino-termini (N-termini) vary in length and amino acid sequence. PDE11A2, PDE11A3, and PDE11A4 contain one or more GAF (cGMP-binding phosphodiesterase, Anabaena adenylyl cyclase, and Escherichia coli FhlA) subdomains. In the present study, PDE11A1 and PDE11A2 demonstrated higher affinity for cAMP and cGMP when directly compared to that of the longest isoform, PDE11A4. Moreover, PDE11A3, PDE11A2, and PDE11A1, which contain progressively shorter N-termini, were more sensitive than PDE11A4 to inhibition by two structurally unrelated inhibitors, tadalafil (Cialis) and vardenafil (Levitra). The substrate and inhibitor affinity differences among the PDE11 isozymes could not be ascribed to differences in their quaternary structure since PDE11A4, PDE11A3, and PDE11A2 were determined to be dimers, and PDE11A1 was a tetramer. These data also demonstrate that PDE11 isozymes containing at least 123 C-terminal amino acids of the GAF-B domain are stable oligomers and that GAF-A is not required for oligomerization. The isolated PDE11 catalytic domain (Met-563-Asn-934) displayed both monomeric and dimeric forms, and upon dilution, this domain was primarily monomeric, indicating that the main oligomerization contacts are within the N-termini of PDE isozymes. This report is the first to describe an inhibitory effect of the N-terminal region of PDE11A4 on the affinity of the catalytic domain for both substrates and inhibitors and the first to define the quaternary structure and the regions that contribute to this structure within the human PDE11A family.
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PMID:N-Terminal domain of phosphodiesterase-11A4 (PDE11A4) decreases affinity of the catalytic site for substrates and tadalafil, and is involved in oligomerization. 1769 99