Current Medicinal Chemistry - Volume 11, Issue 7, 2004

The Sir2 family of enzymes is a recently described class of NAD+-dependent protein deacetylases that use NAD+ as a reactant to deacetylate acetyllysine residues of protein substrates to form the aminolysine sidechain and a novel product 2’-O-acetyl-ADP-ribose. The founding member of the Sir2 proteins, the yeast Sir2p, has been identified as a key member of SIR complexes responsible for the long-term silencing of gene Read More

Cyclic ADP-ribose (cADPR), a general mediator involved in Ca2+ signaling, has the characteristic 18-membered ring consisting of an adenine, two riboses and a pyrophosphate, in which the two primary hydroxyl groups of the riboses are linked by a pyrophosphate unit. This review focuses on the chemical synthetic studies of cADPR analogs. These analogs have been used quite effectively in proving the mechanism of cADPR-m Read More

Cyclic adenosine diphosphoribose (cADPR) is an endogenous Ca2+ mobilizing nucleotide in many cell types and different species covering protozoa, plants and animals, including humans. cADPR is formed by ADP-ribosyl cyclases from nicotinamide adenine dinucleotide (NAD). Since at least some of the ADP-ribosyl cyclases are under the control of receptors for exogenous ligands, cADPR is regarded as a second messenger for Ca2 Read More

Mammalian ecto ADP-ribosyltransferases (ARTs) constitute a family of structurally related proteins expressed on the cell surface or secreted in the extracellular compartment. Using NAD+ as substrate, they transfer ADP-ribose groups onto target proteins. In contrast to intracellular poly(ADP-ribosyl)transferases (PARPs), these enzymes transfer a single ADPR and are thus mono-ARTs. Five paralogs (ART1-5) have been cloned b Read More

The enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT), a member of the nucleotidyltransferase α / β phosphodiesterase superfamily, catalyzes the reaction NMN + ATP = NAD + PPi, representing the final step in the biosynthesis of NAD, a molecule playing a fundamental role as a cofactor in cellular redox reactions. NAD also serves as the substrate for reactions involved in important regulator Read More

IMP dehydrogenase, the key enzyme in de novo synthesis of purine nucleotides, is an important therapeutic target. Three inhibitors of IMP dehydrogenase reached the market; ribavirin (Rebetol) a broadspectrum antiviral agent, which in combination with interferon-α is now used for treatment of hepatitis C virus infections, mizoribine (Bredinin) and mycophenolic mofetil (CellCept) have been introduced as immunosup Read More

Nutrient excess is associated with reduced insulin sensitivity (insulin resistance) and plays a central role in the pathogenesis of type 2 diabetes. Recently, free fatty acids as well as amino acids were shown to induce insulin resistance by decreasing glucose transport / phosphorylation with subsequent impairment of glycogen synthesis in human skeletal muscle. These results do not support the traditional concept of direct su Read More

It has been strongly suggested that androgens and the cognate receptor (AR) may play important roles in the development and progression of prostate cancer. The AR is a transcription factor consisting of three major domains, i.e., N-terminal transactivation, middle DNA binding, and C-terminal steroid binding domains. Molecular events of androgen induced activation of the AR include conformation change, phosphoryla Read More

Since the introduction of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) in mid-1950’s, treatment of depression has been dominated by monoamine hypotheses. The wellestablished clinical efficacy of TCAs and MAOIs is due, at least in part, to the enhancement of noradrenergic or serotonergic mechanisms, or to both. Unfortunately, their very broad mechanisms of action also include many unwant Read More