Fructolysis refers to the

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...

of fructose from

dietary In nutrition, diet is the sum of food consumed by a person or other organism. The word diet often implies the use of specific intake of nutrition for health or weight-management reasons (with the two often being related). Although humans are o ...

sources. Though the

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...

through glycolysis uses many of the same

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

s and intermediate structures as those in fructolysis, the two sugars have very different metabolic fates in human metabolism. Unlike glucose, which is directly metabolized widely in the body, fructose is almost entirely metabolized in the liver in humans, where it is directed toward replenishment of liver glycogen and

triglyceride A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''wikt:tri-#Prefix, tri-'' and ''glyceride''). Triglycerides are the main constituents of body fat in humans and other ...

synthesis. Under one percent of ingested fructose is directly converted to plasma triglyceride. 29% - 54% of fructose is converted in liver to glucose, and about a quarter of fructose is converted to lactate. 15% - 18% is converted to glycogen. Glucose and lactate are then used normally as energy to fuel cells all over the body. Fructose is a dietary monosaccharide present naturally in

fruit In botany, a fruit is the seed-bearing structure in flowering plants that is formed from the ovary after flowering. Fruits are the means by which flowering plants (also known as angiosperms) disseminate their seeds. Edible fruits in particu ...

s and

vegetable Vegetables are parts of plants that are consumed by humans or other animals as food. The original meaning is still commonly used and is applied to plants collectively to refer to all edible plant matter, including the flowers, fruits, stems, ...

s, either as free fructose or as part of the

disaccharide A disaccharide (also called a double sugar or ''biose'') is the sugar formed when two monosaccharides are joined by glycosidic linkage. Like monosaccharides, disaccharides are simple sugars soluble in water. Three common examples are sucrose, la ...

sucrose, and as its polymer

inulin Inulins are a group of naturally occurring polysaccharides produced by many types of plants, industrially most often extracted from chicory. The inulins belong to a class of dietary fibers known as fructans. Inulin is used by some plants as a m ...

. It is also present in the form of refined sugars including

granulated sugar White sugar, also called table sugar, granulated sugar, or regular sugar, is a commonly used type of sugar, made either of beet sugar or cane sugar, which has undergone a refining process. Description The refining process completely removes ...

s (white crystalline table sugar,

brown sugar Brown sugar is unrefined or partially refined soft sugar. Brown Sugar may also refer to: Arts, entertainment, and media Films * ''Brown Sugar'' (1922 film), a 1922 British silent film directed by Fred Paul * ''Brown Sugar'' (1931 film), a 1931 ...

, confectioner's sugar, and turbinado sugar), refined crystalline fructose , as

high fructose corn syrup High-fructose corn syrup (HFCS), also known as glucose–fructose, isoglucose and glucose–fructose syrup, is a sweetener made from corn starch. As in the production of conventional corn syrup, the starch is broken down into glucose by enzy ...

s as well as in honey. About 10% of the calories contained in the Western diet are supplied by fructose (approximately 55 g/day). Unlike glucose, fructose is not an insulin

secretagogue A secretagogue is a substance that causes another substance to be secreted. The word comes from Greek ''agōgos'', meaning "a leader" or "bringer"; thus "something that brings secretions". The same root is seen in completely unrelated words such as ...

, and can in fact lower circulating insulin. In addition to the liver, fructose is metabolized in the intestines, testis, kidney, skeletal muscle, fat tissue and brain, but it is not transported into cells via insulin-sensitive pathways (insulin regulated transporters

GLUT1 Glucose transporter 1 (or GLUT1), also known as solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), is a uniporter protein that in humans is encoded by the ''SLC2A1'' gene. GLUT1 facilitates the transport of glucose across ...

and

GLUT4 Glucose transporter type 4 (GLUT4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the ''SLC2A4'' gene. GLUT4 is the insulin-regulated glucose transporter found primarily in a ...

). Instead, fructose is taken in by GLUT5. Fructose in muscles and adipose tissue is phosphorylated by hexokinase.

Fructolysis and glycolysis are independent pathways

Although the metabolism of fructose and

share many of the same intermediate structures, they have very different metabolic fates in human metabolism. Fructose is metabolized almost completely in the liver in humans, and is directed toward replenishment of liver glycogen and

synthesis, while much of dietary glucose passes through the liver and goes to skeletal muscle, where it is metabolized to CO₂, H₂O and ATP, and to fat cells where it is metabolized primarily to glycerol phosphate for triglyceride synthesis as well as energy production. The products of fructose metabolism are liver glycogen and ''de novo'' lipogenesis of fatty acids and eventual synthesis of endogenous triglyceride. This synthesis can be divided into two main phases: The first phase is the synthesis of the trioses,

dihydroxyacetone Dihydroxyacetone (; DHA), also known as glycerone, is a simple saccharide (a triose) with formula . DHA is primarily used as an ingredient in sunless tanning products. It is often derived from plant sources such as sugar beets and sugar cane, an ...

(DHAP) and

glyceraldehyde Glyceraldehyde (glyceral) is a triose monosaccharide with chemical formula C3 H6 O3. It is the simplest of all common aldoses. It is a sweet, colorless, crystalline solid that is an intermediate compound in carbohydrate metabolism. The word comes ...

; the second phase is the subsequent metabolism of these trioses either in the gluconeogenic pathway for glycogen replenishment and/or the complete metabolism in the fructolytic pathway to pyruvate, which enters the

Krebs cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...

, is converted to

citrate Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, which occurs in the ...

and subsequently directed toward ''de novo'' synthesis of the free fatty acid

palmitate Palmitic acid (hexadecanoic acid in IUPAC nomenclature) is a fatty acid with a 16-carbon chain. It is the most common saturated fatty acid found in animals, plants and microorganisms.Gunstone, F. D., John L. Harwood, and Albert J. Dijkstra. The L ...

The metabolism of fructose to DHAP and glyceraldehyde

The first step in the metabolism of fructose is the phosphorylation of fructose to

fructose 1-phosphate Fructose-1-phosphate is a derivative of fructose. It is generated mainly by hepatic fructokinase but is also generated in smaller amounts in the small intestinal mucosa and proximal epithelium of the renal tubule. It is an important intermediate o ...

fructokinase Fructokinase (/fruc•to•ki•nase/ ki´nas, also known as D-fructokinase or D-fructose (D-mannose) kinase,Km = 0.5 mM, ≈ 9 mg/100 ml), thus trapping fructose for metabolism in the liver. Hexokinase IV (

Glucokinase Glucokinase () is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role i ...

), also occurs in the liver and would be capable of phosphorylating fructose to

fructose 6-phosphate Fructose 6-phosphate (sometimes called the Neuberg ester) is a derivative of fructose, which has been phosphorylated at the 6-hydroxy group. It is one of several possible fructosephosphates. The β-D-form of this compound is very common in cells. ...

(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. Much of the glucose, on the other hand, is not phosphorylated (Km of hepatic glucokinase (hexokinase IV) = 10 mM), passes through the liver directed toward peripheral tissues, and is taken up by the insulin-dependent glucose transporter, GLUT 4, present on

adipose tissue Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular ...

and skeletal muscle. Fructose-1-phosphate then undergoes hydrolysis by fructose-1-phosphate aldolase (aldolase B) to form

dihydroxyacetone phosphate Dihydroxyacetone phosphate (DHAP, also glycerone phosphate in older texts) is the anion with the formula HOCH2C(O)CH2OPO32-. This anion is involved in many metabolic pathways, including the Calvin cycle in plants and glycolysis.Nelson, D. L.; Co ...

(DHAP) and glyceraldehyde; DHAP can either be

isomerized In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers. Is ...

to glyceraldehyde 3-phosphate by triosephosphate isomerase or undergo reduction to glycerol 3-phosphate by glycerol 3-phosphate dehydrogenase. The glyceraldehyde produced may also be converted to glyceraldehyde 3-phosphate by glyceraldehyde kinase or converted to glycerol 3-phosphate by glyceraldehyde 3-phosphate dehydrogenase. The metabolism of fructose at this point yields intermediates in gluconeogenic pathway leading to glycogen synthesis, or can be oxidized to pyruvate and reduced to lactate, or be decarboxylated to acetyl CoA in the mitochondria and directed toward the synthesis of free fatty acid, resulting finally in triglyceride synthesis. Fructose to trioses

Synthesis of glycogen from DHAP and glyceraldehyde-3-phosphate

The synthesis of glycogen in the liver following a fructose-containing meal proceeds from gluconeogenic precursors. Fructose is initially converted to DHAP and glyceraldehyde by fructokinase and aldolase B. The resultant glyceraldehyde then undergoes phosphorylation to glyceraldehyde-3-phosphate. Increased concentrations of DHAP and glyceraldehyde-3-phosphate in the liver drive the gluconeogenic pathway toward glucose-6-phosphate, glucose-1-phosphate and glycogen formation. It appears that fructose is a better substrate for glycogen synthesis than glucose and that glycogen replenishment takes precedence over triglyceride formation. Once liver glycogen is replenished, the intermediates of fructose metabolism are primarily directed toward triglyceride synthesis. Fructose-glycogen

Synthesis of triglyceride from DHAP and glyceraldehyde-3-phosphate

Carbons from dietary fructose are found in both the FFA and glycerol moieties of plasma

s (TG). Excess dietary fructose can be converted to pyruvate, enter the

and emerges as

directed toward

free fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...

synthesis in the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

hepatocytes A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, ...

. The DHAP formed during fructolysis can also be converted to glycerol and then glycerol 3-phosphate for TG synthesis. Thus, fructose can provide trioses for both the glycerol 3-phosphate backbone, as well as the free fatty acids in TG synthesis. Indeed, fructose may provide the bulk of the carbohydrate directed toward ''de novo'' TG synthesis in humans. Fructose-triglyceride

Fructose induces hepatic lipogenic enzymes

Fructose consumption results in the insulin-independent induction of several important hepatic lipogenic enzymes including

pyruvate kinase Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. P ...

, NADP⁺-dependent malate dehydrogenase, citrate lyase,

acetyl CoA carboxylase Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme () that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is ...

fatty acid synthase Fatty acid synthase (FAS) is an enzyme that in humans is encoded by the ''FASN'' gene. Fatty acid synthase is a multi-enzyme protein that catalyzes fatty acid synthesis. It is not a single enzyme but a whole enzymatic system composed of two iden ...

, as well as

pyruvate dehydrogenase Pyruvate dehydrogenase is an enzyme that catalyzes the reaction of pyruvate and a lipoamide to give the acetylated dihydrolipoamide and carbon dioxide. The conversion requires the coenzyme thiamine pyrophosphate. Pyruvate dehydrogenase is u ...

. Although not a consistent finding among metabolic feeding studies, diets high in refined fructose have been shown to lead to

hypertriglyceridemia Hypertriglyceridemia is the presence of high amounts of triglycerides in the blood. Triglycerides are the most abundant fatty molecule in most organisms. Hypertriglyceridemia occurs in various physiologic conditions and in various diseases, and ...

in a wide range of populations including individuals with normal glucose metabolism as well as individuals with impaired glucose tolerance, diabetes, hypertriglyceridemia, and hypertension. The hypertriglyceridemic effects observed are a hallmark of increased dietary carbohydrate, and fructose appears to be dependent on a number of factors including the amount of dietary fructose consumed and degree of insulin resistance. ‡ = Mean ± SEM activity in nmol/min per mg protein § = 12 rats/group * = Significantly different from control at p < 0.05

Abnormalities in fructose metabolism

The lack of two important enzymes in fructose metabolism results in the development of two inborn errors in carbohydrate metabolism – essential fructosuria and hereditary fructose intolerance. In addition, reduced phosphorylation potential within hepatocytes can occur with intravenous infusion of fructose.

Inborn errors in fructose metabolism

Essential fructosuria

The absence of fructokinase results in the inability to phosphorylate fructose to fructose-1-phosphate within the cell. As a result, fructose is neither trapped within the cell nor directed toward its metabolism. Free fructose concentrations in the liver increase and fructose is free to leave the cell and enter plasma. This results in an increase in plasma concentration of fructose, eventually exceeding the kidneys' threshold for fructose reabsorption resulting in the appearance of fructose in the urine. Essential fructosuria is a benign asymptomatic condition.

Hereditary fructose intolerance

The absence of fructose-1-phosphate aldolase (aldolase B) results in the accumulation of fructose 1 phosphate in hepatocytes, kidney and small intestines. An accumulation of fructose-1-phosphate following fructose ingestion inhibits glycogenolysis (breakdown of glycogen) and gluconeogenesis, resulting in severe hypoglycemia. It is symptomatic resulting in severe hypoglycemia, abdominal pain, vomiting, hemorrhage, jaundice, hepatomegaly, and hyperuricemia eventually leading to liver and/or

kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

and death. The incidence varies throughout the world, but it is estimated at 1:55,000 (range 1:10,000 to 1:100,000) live births.

Reduced phosphorylation potential

Intravenous (i.v.) infusion of fructose has been shown to lower phosphorylation potential in liver cells by trapping inorganic phosphate (Pi) as fructose 1-phosphate. The fructokinase reaction occurs quite rapidly in hepatocytes trapping fructose in cells by phosphorylation. On the other hand, the splitting of fructose 1 phosphate to DHAP and glyceraldehyde by Aldolase B is relatively slow. Therefore, fructose-1-phosphate accumulates with the corresponding reduction of intracellular Pi available for phosphorylation reactions in the cell. This is why fructose is contraindicated for

total parenteral nutrition Parenteral nutrition (PN) is the feeding of nutritional products to a person intravenously, bypassing the usual process of eating and digestion. The products are made by pharmaceutical compounding companies. The person receives a nutritional mix ...

(TPN) solutions and is never given intravenously as a source of carbohydrate. It has been suggested that excessive dietary intake of fructose may also result in reduced phosphorylation potential. However, this is still a contentious issue. Dietary fructose is not well absorbed and increased dietary intake often results in malabsorption. Whether or not sufficient amounts of dietary fructose could be absorbed to cause a significant reduction in phosphorylating potential in liver cells remains questionable and there are no clear examples of this in the literature.

References

External links

The Entry of Fructose and Galactose into Glycolysis
Chapter 16.1.11. ''Biochemistry'', 5th edition, Jeremy M Berg, John L Tymoczko, and Lubert Stryer, New York: W H Freeman; 2002. * {{Fructose and galactose metabolism enzymes Biochemistry Carbohydrates Cellular respiration Metabolic pathways