Fructose, IMP, and Aldolase B

This article has an interesting discussion of some mechanisms by which fructose can lead to the sequestration of inorganic phosphate (Pi, or just phosphate), as fructose-1-phosphate, and thereby produce ATP depletion in the liver (or kidneys, but the kidneys don't usually get the brunt of "fructose loads"). Given that the activity of adenosine monophosphate deaminase (AMP deaminase), an enzyme that converts AMP into inosine monophosphate, is normally inhibited by Pi, the phosphate sequestration by fructose-1-phosphate is thought to disinhibit AMP deaminase and lead to IMP accumulation (and, subsequently, uric acid). This article talks about the effect that IMP may have of inhibiting aldolase B and thereby further exacerbating the accumulation of fructose-1-phosphate:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abstract&artid=301436 (Greene et al., 1974)

The authors of this article below discuss the way the steady-state concentration of Pi, in the absence of something producing phosphate sequestration, reduces the stimulation of AMP deaminase by ATP and increases the binding affinity of another major inhibtor, GTP. These authors also found evidence that the fructose-induced GTP depletion may be a more important factor in the activation of AMP deaminase than the sequestration of Pi by fructose-1-phosphate. The authors state that both factors work together, however. It's also interesting that they think the fructose-induced ATP depletion is self-limiting (after 2/3rds of the ATP is gone from the liver), given that ATP depletion, past a certain point, produces inhibition of AMP deaminase (given that ATP strongly activates AMP deaminase in the absence of the inhibitory effects of GTP and Pi).

The authors also make a convincing argument against the role of IMP-induced aldolase inhibition as a mechanism explaining the accumulation of fructose-1-phosphate. Their argument is that fructokinase has a very high reaction rate and that the combined reaction rates of fructose-1-aldolase activity [they're referring to aldolase B, an isoform of fructose-1,6-bisphosphatase that converts, reversibly, fructose-1-phosphate into dihydroxyacetone phosphate (DHAP) and glyceraldehyde (GA)] and the enzymes that metabolize its products are not high enough to prevent fructose-1-phosphate from accumulating.

I wonder if the accumulation of dihydroxyacetone phosphate, to the extent that it might accumulate as a result of the metabolism of fructose-1-phosphate by aldolase B, would influence the G3P/DHAP ratio and contribute to lipogenesis and hypertriglyceridemia by that mechanism. This is a great article:

(http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1164643 (van den Berghe et al., 1977)

This article discusses the influence of the pH in various parts of the liver on the site-specific accumulation of fructose-1-phosphate (and the inhibition of an increase in glycolysis by the low pH, evidently):

http://www.biochemj.org/bj/349/0539/bj3490539.htm