Excess fruit juice (also rich in fructose) is associated with the development of obesity in children. One distinction between fructose and glucose metabolism is that the metabolism of fructose results in increases in serum uric acid concentration. The increased production of uric acid as a result of fructose metabolism is related to the activity of KHK. The activity of KHK is different from the other hexokinases by virtue of the fact that it induces transient ATP depletion in the cell. The mechanism is due to the fact that KHK rapidly phosphorylates fructose to fructose-1-phosphate.
The first step in the metabolism of fructose is the phosphorylation of fructose to fructose 1-phosphate by fructokinase, thus trapping fructose for metabolism in the liver. Fructose 1-phosphate then undergoes hydrolysis by aldolase B to form DHAP and glyceraldehydes; DHAP can either be isomerized to glyceraldehyde 3-phosphate by triosephosphate isomerase or undergo reduction to glycerol 3-phosphate by glycerol 3-phosphate dehydrogenase.
Whether dietary fructose (as sucrose or high fructose corn syrup) has unique effects separate from its role as carbohydrate, or, in fact, whether it can be considered inherently harmful, even a toxin, has assumed prominence in nutrition. Much of the popular and scientific media have already decided against fructose and calls for regulation and taxation come from many quarters. There are conflicting data, however. Outcomes attributed to fructose — obesity, high triglycerides and other features of metabolic syndrome — are not found in every experimental test and may be more reliably caused by increased total carbohydrate. In this review, we try to put fructose in perspective by looking at the basic metabolic reactions. We conclude that fructose is best understood as part of carbohydrate metabolism. The pathways of fructose and glucose metabolism converge at the level of the triose-phosphates and, therefore, any downstream effects also occur with glucose. In addition, a substantial part of ingested fructose is turned to glucose. Regulation of fructose metabolism per se, is at the level of substrate control — the lower Km of fructokinase compared to glucokinase will affect the population of triose-phosphates. Generally deleterious effects of administering fructose alone suggest that fructose metabolism is normally controlled in part by glucose. Because the mechanisms of fructose effects are largely those of a carbohydrate, one has to ask what the proper control should be for experiments that compare fructose to glucose. In fact, there is a large literature showing benefits in replacing total carbohydrate with other nutrients, usually fat, and such experiments sensibly constitute the proper control for comparisons of the two sugars. In terms of public health, a rush to judgement analogous to the fat-cholesterol-heart story, is likely to have unpredictable outcome and unintended consequences. Popular opinion cannot be ignored in this problem and comparing fructose to ethanol, for example, is without biochemical correlates. Also, nothing in the biochemistry suggests that sugar is a toxin. Dietary carbohydrate restriction remains the best strategy for obesity, diabetes and metabolic syndrome. The specific contribution of the removal of fructose or sucrose to this effect remains unknown.
The first step in the metabolism of fructose is the phosphorylation of fructose to fructose 1-phosphate by fructokinase (Km = 0. 5 mM, ˜ 9 mg/100 ml), thus trapping fructose for metabolism in the liver. Hexokinase IV (Glucokinase), also occurs in the liver and would be capable of phosphorylating fructose to fructose 6-phosphate (an intermediate in the gluconeogenic pathway); however, it has a relatively high Km (12 mM) for fructose and, therefore, essentially all of the fructose is converted to fructose-1-phosphate in the human liver.