Phosphodiesterases enzyme structure

Phosphodiesterase enzymes show a distinctive molecular structure 373... 

There are a variety of structural classes of compounds that are active against each phosphodiesterase, and evidence suggests that selective inhibitors of PDEs can be identified. The structural diversity of PDE inhibitors provides a multitude of opportunities for development of compounds with drug-like properties. Furthermore, phosphodiesterase inhibition, which avoids direct interaction of a compound with a cell surface or nuclear receptor, may circumvent some of the target selectivity issues that can complicate receptor-based therapeutic approaches. As noted above, the specific subcellular distribution of phosphodiesterase enzymes is a key feature of their ability to modulate intracellular signaling pathways. This localization of the enzyme may minimize non-specific target... 

Polynucleoside Monophosphates. - The isodideoxyadenosine containing dinucleotide (53) has been prepared by phosphoramidite chemistry as a potential HIV inhibitor which mimics the DNA terminus obtained by the incorporation of isoddATP by the enzyme. The physical properties of the dinucleotide have been investigated and indicate that it has a similar structure to that of ApA but is much more stable to the action of various phosphodiesterase enzymes. 

C. Degradation Stimulation and inhibition of cyclic nucleotide degradation (Sites 5 and 6) are very important mechanisms for controlling their intracellular levels, and to date represent the most fertile sources of prototype drugs. The variety of structures that can influence the activity of the phosphodiesterase enzymes (PDE s) and the importance of these enzymes in drug development have been recently reviewed . Since PDE s are influenced by a number of hormones, e.g., insulin and cholecysto-kinin, it is at least theoretically possible that some drugs could block the action of these hormones on PDE s (Site 7). However, no such drug has yet been found. 

M. M. Benning, J. M. Kuo, F. M. Raushel, H. M. Holden, Three-Dimensional Structure of Phosphodiesterase An Enzyme Capable of Detoxifying Organophosphate Nerve Agents , Biochemistry 1994, 33, 15001-15007. 

An entire new field of therapeutics arose with the serendipitous discovery of the effect on erectile function of sildefanil (see Chapter 15), far better known as Viagra . The enormous and still rising market opened by that drug has predictably led to the search for other inhibitors of phosphodiesterase 5, the enzyme responsible for this activity. The stmctures of many follow-on agents have hewed fairly close to the original PDE 5 inhibitor. Others, such as avanafil (58-9), differ markedly from sildefanil in structure. The synthesis of this agent in effect consists of a series of displacement reactions. Thus, reaction of the benzylamine (58-1) with chloropyrimidine... 

Apart from important similarities in the endo- and exonucleolytic properties of staphylococcal nuclease and other well-studied phosphodiesterases (67), those from snake venom and spleen, the basic structural substrate elements for these enzymes appear to be quite different... 

Fig. 2. Proposed structural requirements for substrates of phosphodiesterases that hydrolyze DNA and RNA, those from (a) snake venom, (b) spleen, and (c) staphylococcus (R = thymine and R — p-nitrophenyl). The studies indicated for the venom and spleen enzymes are those suggested by Khorana (67) [data from Cuatrecasas el al. (61)).

This enzyme is categorized as a phosphodiesterase, but it also has trans-phosphatidylation (transfer) activity as well. As a phosphodiesterase it can be a useful reagent for use in structure proof studies on diacylphosphatidylcho-... 

Some other hydrolytic enzymes, in addition to proteases, that are important drug targets include protein phophatases, phosphodiesterases, nucleoside hydrolases, acetylhydolases, glycosylases, and phospholipases. Structure-based inhibitor design is currently being applied to a number of these enzymes. The last three mentioned have been successfully tar-... 

The tyrosyl-DNA phosphodiesterase is also composed of two similar domains related by a 2-fold axis of symmetry [15]. Conserved His, Lys and Asn residues are contributed by each domain to form the active site. Thus the structure and catalytic mechanism of this enzyme are very similar to those of other PLD superfamily members. A derived structure for the catalytic core of mammalian PLDl is shown... 

Phospholipases are very versatile enzymes which allow the transformation of inexpensive natural products into highly valuable compounds like specific structurally defined phospholipids, organic monophosphates or diphosphates and DAG with the natural absolute configuration. Of particular synthetic utility is PLD from bacterial sources which is able to effect the phosphoryl transfer in a water-containing biphasic system. PLD shows a wide substrate specificity for both the polar head and the alcohol acceptors as well as for the lipophilic part of the molecule. The enzyme behaves like a generic phosphodiesterase with broad substrate specificity and high transphosphatidylation ability. The molecular basis of this behavior should become clear by inspection of the three-dimensional structure and comparison with other phosphoric acid ester hydrolytic enzymes. The crystal structure of this enzyme has not been elucidated. The potential of the many different PLD from plants which show peculiar substrate specificity should allow one to expand the synthetic utility to the hydrolysis-synthesis of natural and unnatural phosphatidylinositols. 

Four examples of structurally characterised, vanadate-inhibited phosphorylation enzymes working on the hydrolysis of phospho-ester bonds in nucleotides I, the vanadate-uridine complex of bovine pancreatic ribonuclease-A II, the vanadate complex of ribonuclease-Tj from the fungus Aspergillus oryzae-. III, the vanadate-uridine complex of cyclic nucleotide phosphodiesterase from the cruciferous plant Arabidopsis thaliana-, IV, human tyrosyl-DNA phosphodiesterase (Ur = uridine). 

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