Nutrition Guide

As of late 2007, only one structure has been solved for this class of enzymes, with the PDB accession code 1VJ7.

In enzymology, a guanosine-3′,5′-bis(diphosphate) 3′-diphosphatase (EC 3.1.7.2) is an enzyme that catalyzes the chemical reaction
guanosine 3′,5′-bis(diphosphate) + H2O guanosine 5′-diphosphate + diphosphate

Thus, the two substrates of this enzyme are guanosine 3′,5′-bis(diphosphate) and H2O, whereas its two products are guanosine 5′-diphosphate and diphosphate.

This enzyme belongs to the family of hydrolases, specifically those acting on diphosphoric monoester bonds. The systematic name of this enzyme class is guanosine-3′,5′-bis(diphosphate) 3′-diphosphohydrolase. Other names in common use include guanosine-3′,5′-bis(diphosphate) 3′-pyrophosphatase, PpGpp-3′-pyrophosphohydrolase, and PpGpp phosphohydrolase. This enzyme participates in purine metabolism.

Iduronate-2-sulfatase is a sulfatase enzyme associated with Hunter syndrome.

Iduronate-2-sulfatase is required for the lysosomal degradation of heparan sulfate and dermatan sulfate. Mutations in this X-chromosome gene that result in enzymatic deficiency lead to the sex-linked Mucopolysaccharidosis Type II, also known as Hunter Syndrome. Iduronate-2-sulfatase has a strong sequence homology with human arylsulfatases A, B, and C, and human glucosamine-6-sulfatase. A splice variant of this gene has been described.[1]

Zinc dependent prokaryotic phospholipases C is a family of bacterial phospholipases C, some of which are also known as alpha toxins.

Bacillus cereus contains a monomeric phospholipase C EC 3.1.4.3 (PLC) of 245 amino-acid residues. Although PLC prefers to acton phosphatidylcholine, it also shows weak catalytic activity with sphingomyelin and phosphatidylinositol[1]. Sequence studies have shown the protein to be similar both to alpha toxin fromClostridium perfringens and Clostridium bifermentans, a phospholipase C involved in haemolysis and cell rupture[2], and to lecithinase from Listeria monocytogenes, which aids cell-to-cell spread by breaking down the 2-membrane vacuoles that surround the bacterium during transfer[3].

Each of these proteins is a zinc-dependent enzyme, binding 3 zinc ions per molecule[4]. The enzymes catalyse the conversion of phosphatidylcholine and water to 1,2-diacylglycerol and choline phosphate[1][2][4].

In Bacillus cereus, there are nine residues known to be involved in binding the zinc ions: 5 His, 2 Asp, 1 Glu and 1 Trp. These residues are all conserved in the Clostridium alpha-toxin.

PDE enzymes are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties. [8]

Inhibitors of PDE can prolong or enhance the effects of physiological processes mediated by cAMP or cGMP by inhibition of their degradation by PDE.

Sildenafil (Viagra) is an inhibitor of cGMP-specific phosphodiesterase type 5, which enhances the vasodilatory effects of cGMP in the corpus cavernosum and is used to treat erectile dysfunction.

PDE inhibitors have been identified as new potential therapeutics in areas such as pulmonary arterial hypertension, coronary heart disease, dementia, depression, and schizophrenia.

Cilostazol (Pletal) inhibits PDE3. This inhibition allows Red Blood Cells to be more able to bend. This is useful in conditions such as intermittent claudication, as the cells can maneuver through constricted veins and arteries more easily.

The PDE superfamily of enzymes is classified into 11 families, namely PDE1-PDE11, in mammals. The classification is based on:
amino acid sequences
substrate specificities
regulatory properties
pharmacological properties
tissue distribution.

Different PDEs of the same family are functionally related despite the fact that their amino acid sequences can show considerable divergence [6]. PDEs have different substrate specificities. Some are cAMP selective hydrolases (PDE4, 7 and 8), others are cGMP selective(PDE5, 6 and 9). Others can hydrolyse both cAMP and cGMP (PDE1, 2, 3, 10 and 11). PDE3 is sometimes referred to as cGMP-inhibited phosphodiesterase. Although PDE2 can hydrolyze both cyclic nucleotides, binding of cGMP to the regulatory GAF-B domain will increase cAMP affinity and hydrolysis to the detriment of cGMP. This mechanism, as well as other, allows for cross-regulation of the cAMP and cGMP pathways.

The nomenclature for PDE indicates PDE family by an Arabic numeral that is followed by a capital letter to denote the gene within a family. A second Arabic numeral indicates the splice variant derived from a single gene (e.g., PDE1C3: family 1, gene C, splicing variant 3)[7]

These multiple forms (isoforms or subtypes) of phosphodiesterase were isolated from rat brain using polyacrylamide gel electrophoresis in the early 1970s[1][2] and were soon afterward shown to be selectively inhibited by a variety of drugs in brain and other tissues.[3][4]

The potential for selective phosphodiesterase inhibitors to be used as therapeutic agents was predicted as early as 1977 by Weiss and Hait.[5] This prediction has now come to pass in a variety of fields.

A phosphodiesterase is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, many other enzyme families are, in the technical sense, phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNAses, RNAses, and restriction endonucleases (which all break the phosphodiester backbone of DNA or RNA), as well as numerous less-well-characterized small-molecule phosphodiesterases.

The remainder of this article discusses the cyclic nucleotide phosphodiesterases:

The cyclic nucleotide phosphodiesterases (PDE) comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They regulate the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains. PDEs are therefore important regulators of signal transduction mediated by these second messenger molecules

Sildenafil has been shown to significantly improve neurovascular coupling without affecting overall cerebral blood flow by increasing brain levels of cGMP, evoking neurogenesis and reducing neurological deficits in rats 2 or 24 hours after stroke. This data suggest that PDE5 inhibitors may have a role in promoting recovery from stroke.[4],[8],[6

Sildenafil has been shown to improve endothelial function in diabetes and congestive heart failure.[16],[4] It has also been shown to reduce aortic pressure through vasodilation, reduced arterial stiffness and wave reflection and could be used in the management of systemic hypertension.[4]