Question

Background

Numerous studies have shown that the intracellular redox potential of the cell is important to cell growth. Cellular redox potential can be determined by the amounts of the reduced coenzyme NADPH, a principal product of the oxidative branch of the pentose phosphate pathway (PPP). The investigators in the study presented here sought to demonstrate links between the activity of the enzyme glucose-6-phosphate dehydrogenase (G6PD) activity, cellular NADPH concentrations, and rates of cell growth. Previous studies have shown that the glucose-6- phosphate dehydrogenase enzyme can be activated on the order of minutes or even seconds, possibly through the action of growth factors that release a bound, inactive G6PD to the cytosol, where, via a mechanism that might involve tyrosine phosphorylation of a membrane-bound receptor, the unbound G6PD translocates to the cytosol and becomes active.

NADPH is important to the cell in a variety of ways. The reduced coenzyme can react with potential damaging oxidizing agents, ridding the cell of these agents before they can damage important cellular components.

Question

List general cellular mechanisms that would affect the activity of G6PD. Which of these mechanisms would result in long-term (on the order of minutes to hours) vs. short-term (minutes to seconds) regulation of the enzyme's activity?

Answer 1

As explained above G6PD(glucose 6 phosphate dehydrogenease) is a rate limiting enzyme involved in PPP (pentose phosphate pathyway) which produces more co-enzyme NADPH responsible for maintainance of cellular redoxpotential.

There are list of regulators which affects on the increase or decrease in the activity of G6PD.

Main function: increase in the concentration of NADP+ increases the activity of G6PD enzyme which converts NADP+ into NADPH.

Regulators: There are list of regulators which affects the activity of G6PD enzyme such as cAMP, aldosterone, cAMP dependent PKA, CREM, Arachidonic acid p38 MAP kinase, P53, TNF-alpha, AMP kinase etc.

G2PH is majorly inhibited at the level of trancription, translation & post-translational modifications.

cAMP & cAMP dependent protein kinase A(PKA): high glucose level increase in the level of cAMP which increases the activity of protein kinase A which does serine/threonine phosphorylation on G6PD domain thus decreases the activity of G6PD enzyme results in high glucose induced cellular damage.

p53: P53 is a tumour suppressor protein which binds to G6PD and prevents formation of dimerization of G6PH enzyme (active structure responsible glucose consumption if PPP pathway).

Aldosterone effect of vascularization: Aldosterone is steroide hormone produced in the adrenal gland which controls blood pressure by maintaining sodium & potassium levels in many tissues.

Aldosterone decreases the activity of G6PD by increasing the expression of CREM (cAMP response element modulator) which inhibits CREB (cAMP response element binding protein) mediated transcription of G6PD enzyme. Decrease in the level of G6PD enzyme effects on the dimirization of nitric oxide synthase which reduces the nitric oxide production and increase in the level of reactive oxygen species.

Arachidonic acid: is a polyunsaturated fatty acid which inhibits insulin mediated increase in tranctiption of G6PD by stimulating p38 MAP kinase pathway.