Gluconeogenesis inhibitor

Ohtsu Y, Sasamura H, Tsurumi Y, Yoshimura S, Takase S, Hashimoto M, Shibata T, Hino M, Fujii T (2003) The Novel Gluconeogenesis Inhibitors FR225659 and Related Compounds that Originate from Helicomyces sp. No. 19353 I. Taxonomy, Fermentation, Isolation and Physico-chemical Properties. J Antibiot 56 682... 

Insulin signaling stimulation PTEN, Glycogen regulation 4,GSK3, fGS Gluconeogenesis inhibitors, P-cell restoration... 

Gluconeogenesis inhibitors FR225659 and FR225656. Yoshimura and co-workers reported the elucidation of the structure of two new gluconeogenesis inhibitors from a Helicomyces sp. and used long-range data in the confirmation of the structure. 

A well-established inhibitor of gluconeogenesis is ethyl alcohol. This can cause problems in at least two situations. When alcoholic patients enter an alcoholic binge , they do not eat, so that liver glycogen is soon depleted. Since gluconeogenesis is inhibited, both hypoglycaemia and, as indicated below, lactic acidosis can develop. Indeed they may be the two most important factors that precipitate coma and collapse in the alcoholic patient. 

The above-mentioned procedure for the synthesis of C-fructosides has been used to synthesize the bisphosphono analog of / -D-fructose 2,6-bisphos-phate [ 16], which is, as reported in Sect. 2.3, an important activator of glycolysis and inhibitor of gluconeogenesis. To prepare the target molecule we first attempted the conversion of the firee hy iroxyl group of 21 into an iodide which in turn can be easily converted into a phosphonate. However, this conversion... 

When fructose 2,6-bisphosphate binds to its allosteric site on PFK-1, it increases that enzyme s affinity for its substrate, fructose 6-phosphate, and reduces its affinity for the allosteric inhibitors ATP and citrate. At the physiological concentrations of its substrates ATP and fructose 6-phosphate and of its other positive and negative effectors (ATP, AMP, citrate), PFK-1 is virtually inactive in the absence of fructose 2,6-bisphosphate. Fructose 2,6-bisphosphate activates PFK-1 and stimulates glycolysis in liver and, at the same time, inhibits FBPase-1, thereby slowing gluconeogenesis. 

Allosteric changes usually involve rate-determining reactions. For example, glycolysis in the liver is stimulated following a meal by an increase in fructose 2,6-bisphosphate, an allosteric activator of phosphofructokinase (see p. 98). Gluconeogenesis is inhibited by fructose 2,6-bisphosphate, an inhibitor of fructose 1,6-bisphos-phatase (see p. 118). 

In these examples, precursors of the enzyme-catalysed reaction act as feed-forward inhibitors (AMP for PFK and citrate for FBPase). The plenty signal F26BP (elevated as a result of the precursor elevated blood glucose conditions) also activates PFK. Conversely, down the track , end products act as feedback inhibitors (ATP and citrate for PFK and F26BP - that can be loosely seen as an end product of blood glucose elevation by gluconeogenesis - for FBPase). 

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