Fructose: what it is, where it is found, absorption, and metabolism

Fructose, also known as fruit sugar, is a six-carbon monosaccharide, so it is a hexose.
It was discovered by the French chemist Dubrunfaut A-P. in 1847, the same one who discovered, three years earlier, mutarotation, and later maltose. In 1857, the English chemist Miller W.A. named it fructose, from the Latin fructus, which means fruit, followed by the suffix –ose to designate it as a carbohydrate.
In solution, it occurs in both open-chain and cyclic form. Four stereoisomers are possible in the cyclic form.
It comes almost exclusively from the diet. It is present in fruit and vegetables, honey, sucrose, and industrial foods such as invert sugar and high fructose corn syrup. In animals, it can be synthesized from glucose or sorbitol through the polyol pathway.
An excessive intake of fructose may promote gout.
In humans, it is metabolized mainly in the liver by a pathway called fructolysis, with production of triose phosphates which can be used for both anabolic and catabolic purposes.
Two inborn errors of fructose metabolism are known: essential fructosuria and hereditary fructose intolerance.

CONTENTS

Chemical properties

Like the other hexoses, it has a molecular formula C6H12O6 and molecular weight 180.156 g/mol.
It can exist as two enantiomers, which, according to D-L system or Fischer-Rosanoff convention, are called D-fructose and L-fructose. In Nature, the D-enantiomer prevails, so the term fructose will be used to indicate D-fructose.
Like other monosaccharides, in solution it occurs in both open-chain and cyclic form. In the open-chain form, which may be represented by a Fischer projection, the carbonyl group at position 2 is part of a ketone group; hence, the monosaccharide is a ketohexose, unlike, for example, galactose, glucose, mannose and ribose which are aldohexoses, as the carbonyl group is part of an aldehyde group.
The carbonyl group makes fructose, like the other monosaccharides, and maltose and lactose among the disaccharides, a reducing sugar.
It is extremely soluble in water, about 3750 g/L at 20 °C, and among the monosaccharides, it is the most water-soluble. Its high solubility accounts for its hygroscopicity, that is, the tendency to absorb water from the surrounding atmosphere. This property has made it difficult to achieve the crystalline form, only recently been achieved with cheap and efficient methods. In the crystalline form it appears as white crystals.

Anomers

The open-chain form is thermodynamically unstable and is present only in trace amounts because of the cyclization due to the nucleophilic attack by the oxygen atom of one of the hydroxyl groups to the carbonyl carbon. This leads to the formation of a cyclic hemiketal, while the previous carbonyl carbon, bearing four different ligands, becomes an asymmetric center, i.e. a center of chirality, and is called hemiketal carbon.
The nucleophilic attack can occur from bottom site or topside of the sp2 plane of the carbonyl carbon, and, depending on the hydroxyl oxygen that performs the nucleophilic attack, four different configurations are possible, which differ in the configuration of the hemiketal carbon. This phenomenon is called mutarotation, and leads to the formation of two pairs of epimers:

  • two pyranose configurations, β-D-fructofuranose, α-D-fructofuranose, namely, six-member rings consisting of one oxygen atom and five carbon atoms;
  • two furanose configurations, β-D-fructopyranose and α-D-fructopyranose, namely, five-member rings consisting of one oxygen atom and four carbon atoms.
Fructose: from the open-chain form to the hemiketal cyclic forms
Cyclization of Fructose

Epimers differing only in the configuration of the hemiketal carbon are called alpha-anomer and beta-anomer, and the hemiketal carbon becomes the anomeric carbon or anomeric center.

Fructose sweetness

It is the sweetest of the naturally occurring sugars, and is exceeded only by some food additives used as sweeteners. However, its sweetness depends on its physical state, that is, whether it is in crystal form or dissolved in water and, in the latter case, on water temperature. These differences are due to the predominant cyclic structure.
In crystalline form, only β-D-fructopyranose is present. This is the anomer responsible for the sweetness of the monosaccharide, and is twice as sweet as sucrose, which is made up of α-D-glucose, in pyranose form, and β-D-fructose, in furanose form.
When it is dissolved in solution, the sweetness varies according to solution temperature. In fact, once dissolved, the four anomers are present, of which α-D-fructopyranose is present in trace amount.

Structural formulas, drawn in Haworth projections, of fructose isomers
Fructose Isomers

If β-D-fructopyranose prevails at 25 °C, representing about 68% of the anomers, as the temperature increases its percentage decreases and at 80 °C it dropped to about 50%. Therefore, as furanose structures are void of sweet taste, as temperature increases its sweetening power decreases, and, for example, at 40 °C it has about the same sweetening power as sucrose, whereas at 60 °C it is about 20% less sweet.

Sources of fructose

It is a natural component of the human diet, being present in fruit, where it may make up to 5-8% of the weight, and in lesser amounts in vegetables, especially tuberous vegetables such as potatoes and onions.
Among the fruits, grapes, apples and pears contain good amounts, while the highest amount is found in dried figs, as a result of dehydration, and in apple and pear juices.
For thousands of years, before modernization and specialization in food processing and agricultural methods, humans had a fruit sugar intake estimated at 16-24 grams per day, mostly from fruit and honey.
Currently, however, its per capita intake is estimated to range from 8 to 100 grams, with an average of about 80 g in the USA. This increase is mainly derived from the consumption of the monosaccharide from food sources different from fruit and vegetable, such as:

  • honey, where it makes up to 40% of the weight of the product;
  • concentrated juices, for example, some homogenized fruits, where it makes over 60% of the weight of the product;
  • invert sugar, an equimolar mixture of fructose and glucose obtained from the hydrolysis of sucrose;
  • sucrose;
  • molasses, where it makes up to 10% of the weight of the product;
  • maple syrup, which contains about 63% by weight of sucrose;
  • high fructose corn syrup or HFCS, where it makes up to 90% of the weight of the product. HFCS is used by the food industry, for example to sweeten soft drinks.

Except for sucrose and sucrose-containing foods and beverages, in all other cases it is present in its free form. Obviously, the richest source is the pure crystalline form, often used as a sweetener.

Intestinal absorption

In mammals, carbohydrate digestion occurs by means of hydrolases, such as the disaccharidases located in the brush border of enterocytes and pancreatic alpha-amylase. These enzymes hydrolyze the glycosidic bonds of disaccharides, oligosaccharides and polysaccharides, releasing their constituent monosaccharides.
The free fructose in the small intestine can arise from the hydrolysis of sucrose or be ingested as such.
The absorption of the monosaccharides occurs in the small intestine, across the apical membrane of the enterocytes, and is mediated by specific transmembrane proteins that act as transporters. Fructose transporters belong to the glucose transporter family or GLUT family, proteins that mediate the facilitated diffusion of monosaccharides across the plasma membrane. In mammals, the GLUT family consists of 14 members, divided into three distinct classes, based on sequence homology and substrate selectivity. Seven GLUT transporters can transport fructose, and, in the intestine, the most important are GLUT2 and GLUT5. The other five transporters, namely, GLUT7, GLUT9a/b, GLUT8, GLUT11, and GLUT12, have different degrees of fructose selectivity.
Conversely, intestinal absorption of glucose and galactose is mainly mediated by the sodium-glucose linked transporter type I or SLGT1, a transmembrane protein belonging to the sodium-glucose cotransporter family. SGLT1 mediates an active transport of the two monosaccharides across the apical membrane, using as energy source the transmembrane electrochemical gradient of sodium ions.

GLUT5

Fructose absorption occurs in the distal part of the duodenum and in the jejunum, and is mainly mediated by GLUT5, an insulin-independent transporter.
Among the seven members of the GLUT family able to transport the monosaccharide, GLUT5 is the sole specific for it, for which it has a high affinity, with a Km of about 6 mM, whereas it is unable to transport glucose and galactose. It is mainly found in the small intestine, like GLUT2, but also in the kidney, adipose tissue, brain, sperm, and skeletal muscle.
In the prenatal phase, both mRNA levels of GLUT5 in enterocytes and the rate of fructose transport are very low, but they rapidly increase with weaning, regardless of diet. After weaning, mRNA levels of GLUT5 can be further induced by diets containing fructose. It seems that a diet rich in fruit sugar induces the intestinal synthesis of thioredoxin-interacting protein or TXNIP, a protein that binds and regulates GLUT5. It has also been shown that ChREBP, a transcription factor that responds to carbohydrate intake, and particularly glucose 6-phosphate levels, a key metabolite of glucose metabolism, can regulate TXNIP and intestinal GLUT5 expression, and is required for systemic tolerance to the monosaccharide.
In the intestine, fructose is absorbed at a slower rate than glucose. This could partly due to the low activity of GLUT5 and GLUT2 towards it and to the differences in the absorption process, as its absorption is carried out by passive transport.
Intestinal absorption rate of fructose increases in case of with its chronic intake, due to the rapid up-regulation of the gene coding for GLUT5.

GLUT2

Fructose release from the enterocytes, which occurs across the basolateral membrane, is mediated by GLUT2, the second contributor to its intestinal transport, also responsible for the release of glucose and galactose.
It is a high capacity, low avidity transporter for glucose, fructose, and galactose, with Km of approximately 20 mM, 67 mM and 96 mM, respectively, and, like GLUT5, is an insulin-independent transporter.

Transporters

Approximate Km value (mM)
D-Glucose D-Galactose D-Fructose
SGLT1 0.5 1 No interaction
GLUT2 20 96 67
GLUT5 Not determined No interaction 6

In addition to the intestine, GLUT2 is also found in the epithelial cells of the kidney, in the hepatocytes, where GLUT5 is poorly expressed, and in the beta cells of the pancreas. As in hepatocytes and renal epithelial cells it mediate fructose uptake, it acts as a bidirectional facilitative transporter.
Moreover, in beta cells and hepatocytes, it also acts to sense blood glucose levels.
Note: GLUT8 may contribute to the hepatic uptake of fructose.

Glucose and intestinal absorption of fructose

The ability of the intestine to absorb fructose is saturable and ranges, in a healthy adult, from about 5 g to more than 50 g. Furthermore, it is influenced by the presence of glucose in the intestinal lumen.
When fruit sugar is ingested alone, it is not absorbed very efficiently and, under physiological conditions, the symptoms of its malabsorption occur in a dose-dependent manner, starting from about 12 g load. However, the intake of fructose alone is quite rare, as it is normally ingested, for example, with sucrose or, at meals, with starch, a polysaccharide made up by glucose units.
Experimentally, it has been observed that the coingestion of glucose with 50 g of fructose attenuates malabsorption symptoms in a dose-dependent manner, and, with equimolar mixtures of the two monosaccharides, no malabsorption have been observed up to 100 g of total sugars. Therefore, its absorption is maximal when it is present, in the lumen of small intestine, in equimolar ratio with glucose. Noteworthy, the biological mechanism underlying this phenomenon has not yet been clarified. These observations are very important, for example, in sports nutrition, as, during competition or training, athletes may require a high intake of carbohydrates the unit of time, which may be achieved by mixtures of maltodextrin, therefore glucose, and fructose.

Gastrointestinal side-effects of unabsorbed fructose

Unabsorbed fructose causes an increase in the intraluminal osmotic pressure in the distal part of the small intestine and in the colon, which draws fluid into the lumen.
Furthermore, like fibers, resistant starch and significant amounts of undigested or unabsorbed sugars, once in the colon, it can be fermented anaerobically by the bacteria of the gut microbiota, which is part of the larger human microbiota. All this leads to an excessive production of gas, such as methane, carbon dioxide and hydrogen, and short-chain fatty acids, namely, fatty acids whose carbon chain length is between two and six atoms, that is, acetic, propionic, butyric and caproic acids. In the intestine, the major short-chain fatty acids produced are acetic, propionic, butyric acids, in an approximate molar ratio of 60:20:20. Many of these bacterial metabolites can affect intestinal motility and cause various gastrointestinal symptoms, such as feelings of malaise, bloating, stomachache, and diarrhea, to which, of course, the net flow of water in the intestinal lumen, due to the presence of unabsorbed fructose, also concurs.

Blood fructose levels

Once absorbed, fruit sugar enters the portal circulation and is mainly transported to the liver. Its entrance into the circulation is slower than that of glucose, its levels are lower, but it persists longer in the bloodstream. In healthy adults, its serum concentration is about 0.008 mM, while its plasma concentration is about 0.03-0.04 mM. In healthy subjects who consume a high-fructose or sucrose diet:

  • in peripheral circulation, its plasma levels can acutely increase up to 10 folds, reaching values of 0.2-0.5 mM, therefore always in the micromolar range, and return to fasting levels within two hours;
  •  in portal circulation, its plasma concentration can reach the low millimolar range.

Therefore, there is a high concentration gradient of fructose between the blood reaching and leaving the liver, which means that the liver, and also the pancreas, is exposed to higher fructose concentrations than non-splanchnic organs, such as heart, skeletal muscle and brain.

Differences in blood levels of fructose and glucose

In the portal circulation, fructose concentration is much lower than that of glucose, which is equal to about 5.5 mM. This arises from differences in the intestinal absorption rate and hepatic clearance of the two monosaccharides.
In the small intestine, fructose is absorbed at a slower rate than glucose. This may be due, as previously seen, to the low activity of GLUT5 and GLUT2 towards it, and to the fact that it is absorbed from the intestine into the plasma by passive transport systems.
Hepatic clearance of fructose is much more efficient than that of glucose. In fact, the liver, which is the main site for its metabolism, is able:

  • to extract about 50-70% of an oral fructose load from the portal blood, whereas it extracts only 15-30% of an oral glucose load;
  • to return its plasma concentration to fasting levels within two hours after an oral load.

The kidneys also contribute to the clearance of the monosaccharide, although to a lesser extent than the liver, with about 20%.

Hepatic fructolysis

The major sites for the metabolism of fructose, or fructolysis, are the liver, and, to a lesser extent, small intestine and kidneys. This is due to the presence in these sites of the enzymes necessary for the metabolism of the monosaccharide, namely, fructokinase (EC 2.7.1.4), fructose 1-phosphate aldolase or aldolase B (EC 4.1.2.13), and triose kinase or triokinase(EC 2.7.1.28). These enzymes catalyze its conversion into intermediates of glycolysis and gluconeogenesis, namely, glyceraldehyde 3-phosphate and dihydroxyacetone phosphate.
Once inside the hepatocyte, fructose is phosphorylated to fructose 1-phosphate, in a reaction catalyzed by fructokinase, at the expense of one ATP.

Fructose + ATP → Fructose 1-phosphate + ADP + H+

Fructokinase is characterized by a low Km for fructose, equal to about 0.5 mM, and can rapidly phosphorylate the monosaccharide. On the other hand, fruit sugar is a poor substrate for glucokinase (EC 2.7.1.2), for which the enzyme has an affinity about 20 times lower than that for glucose.
Unlike mammalian fructokinase, plant fructokinase phosphorylates fructose at the 6-position to form fructose 6-phosphate, similarly to the bacterial enzyme.
Phosphorylation traps the monosaccharide inside the cell, activates it for its further metabolism, and, keeping its cytosolic concentration low, favors its facilitated diffusion into the cell.
Fructose 1-phosphate is cleaved to dihydroxyacetone phosphate and glyceraldehyde, in a reaction catalyzed by fructose 1-phosphate aldolase.

Fructose 1-phosphate → Dihydroxyacetone phosphate + Glyceraldehyde

While dihydroxyacetone phosphate is an intermediate of glycolysis and gluconeogenesis, glyceraldehyde must be phosphorylated to glyceraldehyde 3-phosphate in order to enter the glycolytic or gluconeogenic pathway. The reaction is catalyzed by triose kinase, at the expense of one ATP.

Glyceraldehyde + ATP → Glyceraldehyde 3-phosphate + ADP + H+

The overall reaction is therefore:

Fructose + 2 ATP → 2 Glyceraldehyde 3-phosphate +2 ADP +2 H+

Regulation of hepatic fructolysis

Once triose phosphates are produced, glucose and fructose metabolic pathways converge. However, the steps leading to the conversion of fructose into two triose phosphate molecules require neither glucokinase nor phosphofructokinase-1. This means that those molecules enter the glycolytic pathway downstream of its key control points, and that, therefore, hepatic fructolysis is not regulated by the energy charge of the cell or hormones, such as insulin and glucagon.

Regulatory effects of fructose 1-phosphate

The increase in the intracellular concentration of fructose 1-phosphate influences hepatic glucose metabolism, as it modulate the activity of two glycolytic enzymes: glucokinase and pyruvate kinase (EC 2.7.1.40).
Fructose 1-phosphate enhances glucokinase activity by promoting its release from GRP, an inhibitory protein that sequesters the enzyme, in a inactive state, inside the nucleus. This promotes glucose phosphorylation and uptake, and glycogen synthesis.
Fructose 1-phosphate is an allosteric activator of pyruvate kinase, thus contributing to the increased circulating levels of lactate after fructose ingestion.
Furthermore, fructose 1-phosphate can:

  • increase glycogen synthesis by allosterically inhibiting glycogen phosphorylase (EC EC 2.4.1.1), an enzyme of glycogenolysis;
  • stimulate uric acid synthesis by allosterically activating AMP deaminase (EC 3.5.4.6).

Fate of triose phosphates

Triose phosphates derived from fructolysis can enter gluconeogenesis, lipogenesis or oxidative pathways.
In the liver, the main metabolic fate of fructose is to be converted into glucose via gluconeogenesis, to be released into the circulation or stored as glycogen, based on blood glucose levels. For example, in a fasting subject, the low levels of fructose-2,6-bisphosphate inhibit phosphofructokinase-1 (EC 2.7.1.11), and therefore glycolysis, while allow the activation of fructose 1,6-bisphosphatase, and therefore of gluconeogenesis. Under these conditions, triose phosphates deriving from fructose are mainly used as a substrate for gluconeogenesis, and the glucose produced is released into the bloodstream to maintain normal blood glucose levels. A similar argument applies to physical exercise. Conversely, in the fed state, triose phosphates deriving from fructolysis are mainly used as a substrate for glycogen synthesis.
Part of the fructose can also be oxidized to carbon dioxide and water for the production of ATP through the Krebs cycle, or to lactate, which is then released into the circulation, in a sort of reverse Cori cycle, that may be advantageous to the working muscle cell as it provides an additional energy substrate.
A small amount of the triose phosphates may be used as a substrate for fatty acid synthesis, and therefore for the synthesis of triglycerides.
Finally, it was observed that, in healthy subjects, an acute fructose ingestion is associated with a reduction in circulating free fatty acid levels. This may be due either to an increased fatty acid clearance or to an inhibition of adipose tissue lipolysis; however, the mechanism behind this effect has not yet been elucidated.

Fructose and gout

Gout is an inflammatory condition of the joints caused by the deposition of uric acid crystals, deposition which is consequent to the high circulating levels of uric acid.
Gout has also been associated with high intakes of fructose. Why?
In the liver, the rapid phosphorylation of fructose may reduce the intracellular free phosphate, which, in turn, may increase uric acid production through the activation of AMP deaminase, which is also activated by fructose 1-phosphate. The rapid phosphorylation of fructose reduces ATP levels while increases AMP levels. AMP deaminase, by converting AMP to IMP, directs the nucleotide towards the conversion into uric acid.
Finally, fructose can contribute to uric acid production also through stimulating purine synthesis.

Endogenous synthesis

Although fructose is mainly derives from diet, animals are able to produce it through the polyol pathway. This pathway, which is present in numerous tissues and organs, converts glucose into fructose via sorbitol.
In the first step, glucose is reduced to sorbitol, in a reaction catalyzed by aldose reductase (EC 1.1.1.21), a NADPH-dependent reductase, which has a broad specificity for monosaccharides, being able to reduce galactose to galactitol, too.
In the second step, sorbitol is oxidized to fructose, in a reaction catalyzed by sorbitol dehydrogenase (EC 1.1.1.14), a NADH-dependent reductase. Of course, it is also possible to synthesize the monosaccharide directly from sorbitol, which is widely distributed in fruits and vegetables.
Endogenously synthesized fructose is the primary source of energy for sperm and may be important for fertility.

Inborn errors of fructose metabolism

Two inborn errors affect fructose metabolism: essential or benign fructosuria and hereditary fructose intolerance, both autosomal recessive diseases.

  • Essential or benign fructosuria is due to hepatic fructokinase deficiency. First described in 1876, it is an asymptomatic and benign condition, and in many cases it is not even detected. Following fructose, sucrose or sorbitol ingestion, high blood fructose levels are detected, the monosaccharide is partially excreted in the urine and the rest can be phosphorylated by hexokinase in muscle and adipose tissue to form fructose 6-phosphate.
    Due to its benign nature, no dietary restrictions are recommended.
  • Hereditary fructose intolerance usually occurs at the time of weaning, when foods containing the monosaccharide are introduced into the diet.

It is caused by the deficiency of fructose 1-phosphate aldolase. Due to the high fructokinase activity, a cytosolic accumulation of fructose 1-phosphate and a trapping of phosphate occur. This leads to a drop in postprandial blood glucose levels caused by the inhibition of glycogenolysis and gluconeogenesis.
Furthermore, the high utilization of ATP, which is the phosphate donor in the reaction catalyzed by fructokinase, and its diminished regeneration lead to its depletion, which results in an increased release of magnesium ions and production of uric acid.
This inborn error causes renal and liver dysfunctions and can be fatal. However, affected subjects develop symptoms only when they are exposed to monosaccharide, so the therapy is a fructose-free diet.

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Biochemistry, metabolism and nutrition