Fructose metabolism (Homo sapiens)

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3, 13-15, 22...1, 12, 16, 18, 21...5, 13, 28, 338, 11, 22, 27, 35...4, 9, 10, 15, 19...2, 7, 3017, 20, 22, 23, 25...38cytosolNADPHDHAPSORD tetramerFruD-sorbitolFru 1-PKHK dimerATPFruSORD NADHK+GLYCTKGlcALDH1A1 H+ALDOB ATPGANAD+ALDH1A1 tetramerH+AKR1B1ALDOB tetramerDGANADP+ADPDAK ADPADP3PDGANAD+Mg2+ H2OGA3PH+KHK H+Zn2+ ADPDAK dimerATPNADH2919332936356, 2832


Fructose is found in fruits, is one of the components of the disaccharide sucrose, and is a widely used sweetener in processed foods. Dietary fructose is catabolized in the liver via fructose 1-phosphate to yield dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, which then are converted to pyruvate via steps of canonical glycolysis (Hers & Kusaka 1953; Sillero et al. 1969). Excessive dietary intake of fructose and its metabolism have been associated with major disease risks in humans, although this issue remains controversial (Kolderup & Svihus 2015; DiNicolantonio et al. 2015; Bray 2013; Mayes 1993; Rippe & Angelopoulos 2013; van Buul et al. 2013). Fructose can also be synthesized from glucose via the polyol pathway (Hers 1960; Oates 2008). This synthetic process provides the fructose found in seminal fluid and, in other tissues, can contribute to pathologies of diabetes. View original pathway at:Reactome.


Pathway is converted from Reactome ID: 5652084
Reactome version: 66
Reactome Author 
Reactome Author: D'Eustachio, Peter

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  1. Funari VA, Herrera VL, Freeman D, Tolan DR.; ''Genes required for fructose metabolism are expressed in Purkinje cells in the cerebellum.''; PubMed Europe PMC
  2. Sass JO, Fischer K, Wang R, Christensen E, Scholl-Bürgi S, Chang R, Kapelari K, Walter M.; ''D-glyceric aciduria is caused by genetic deficiency of D-glycerate kinase (GLYCTK).''; PubMed Europe PMC
  3. Sillero MA, Sillero A, Sols A.; ''Enzymes involved in fructose metabolism in lir and the glyceraldehyde metabolic crossroads.''; PubMed Europe PMC
  4. Ruiz F, Hazemann I, Mitschler A, Joachimiak A, Schneider T, Karplus M, Podjarny A.; ''The crystallographic structure of the aldose reductase-IDD552 complex shows direct proton donation from tyrosine 48.''; PubMed Europe PMC
  5. O'Brien MM, Schofield PJ, Edwards MR.; ''Polyol-pathway enzymes of human brain. Partial purification and properties of sorbitol dehydrogenase.''; PubMed Europe PMC
  6. Maret W, Auld DS.; ''Purification and characterization of human liver sorbitol dehydrogenase.''; PubMed Europe PMC
  7. Van Schaftingen E.; ''D-glycerate kinase deficiency as a cause of D-glyceric aciduria.''; PubMed Europe PMC
  8. Tolan DR.; ''Molecular basis of hereditary fructose intolerance: mutations and polymorphisms in the human aldolase B gene.''; PubMed Europe PMC
  9. Grimshaw CE.; ''Aldose reductase: model for a new paradigm of enzymic perfection in detoxification catalysts.''; PubMed Europe PMC
  10. Nishimura C, Matsuura Y, Kokai Y, Akera T, Carper D, Morjana N, Lyons C, Flynn TG.; ''Cloning and expression of human aldose reductase.''; PubMed Europe PMC
  11. Penhoet EE, Kochman M, Rutter WJ.; ''Ioslation of fructose diphosphate aldolases A, B, and C.''; PubMed Europe PMC
  12. Ishimoto T, Lanaspa MA, Le MT, Garcia GE, Diggle CP, Maclean PS, Jackman MR, Asipu A, Roncal-Jimenez CA, Kosugi T, Rivard CJ, Maruyama S, Rodriguez-Iturbe B, Sánchez-Lozada LG, Bonthron DT, Sautin YY, Johnson RJ.; ''Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice.''; PubMed Europe PMC
  13. HERS HG.; ''[The mechanism of the formation of seminal fructose and fetal fructose].''; PubMed Europe PMC
  14. Kolderup A, Svihus B.; ''Fructose Metabolism and Relation to Atherosclerosis, Type 2 Diabetes, and Obesity.''; PubMed Europe PMC
  15. Oates PJ.; ''Aldose reductase, still a compelling target for diabetic neuropathy.''; PubMed Europe PMC
  16. Diggle CP, Shires M, McRae C, Crellin D, Fisher J, Carr IM, Markham AF, Hayward BE, Asipu A, Bonthron DT.; ''Both isoforms of ketohexokinase are dispensable for normal growth and development.''; PubMed Europe PMC
  17. Perdomo AB, Ciccosanti F, Iacono OL, Angeletti C, Corazzari M, Daniele N, Testa A, Pisa R, Ippolito G, Antonucci G, Fimia GM, Piacentini M.; ''Liver protein profiling in chronic hepatitis C: identification of potential predictive markers for interferon therapy outcome.''; PubMed Europe PMC
  18. Bonthron DT, Brady N, Donaldson IA, Steinmann B.; ''Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase).''; PubMed Europe PMC
  19. Jaquinod M, Potier N, Klarskov K, Reymann JM, Sorokine O, Kieffer S, Barth P, Andriantomanga V, Biellmann JF, Van Dorsselaer A.; ''Sequence of pig lens aldose reductase and electrospray mass spectrometry of non-covalent and covalent complexes.''; PubMed Europe PMC
  20. Xu MY, Jia XF, Qu Y, Zheng RD, Yuan ZH, Weng HL, Dooley S, Wang XP, Zhang LJ, Lu LG.; ''Serum dihydroxyacetone kinase peptide m/z 520.3 as predictor of disease severity in patients with compensated chronic hepatitis B.''; PubMed Europe PMC
  21. Asipu A, Hayward BE, O'Reilly J, Bonthron DT.; ''Properties of normal and mutant recombinant human ketohexokinases and implications for the pathogenesis of essential fructosuria.''; PubMed Europe PMC
  22. HERS HG, KUSAKA T.; ''[The metabolism of fructose-1-phosphate in the liver].''; PubMed Europe PMC
  23. Cabezas A, Costas MJ, Pinto RM, Couto A, Cameselle JC.; ''Identification of human and rat FAD-AMP lyase (cyclic FMN forming) as ATP-dependent dihydroxyacetone kinases.''; PubMed Europe PMC
  24. Mayes PA.; ''Intermediary metabolism of fructose.''; PubMed Europe PMC
  25. Beutler E, Guinto E.; ''Dihydroxyacetone metabolism by human erythrocytes: demonstration of triokinase activity and its characterization.''; PubMed Europe PMC
  26. DiNicolantonio JJ, O'Keefe JH, Lucan SC.; ''Added fructose: a principal driver of type 2 diabetes mellitus and its consequences.''; PubMed Europe PMC
  27. Lebherz HG, Rutter WJ.; ''Distribution of fructose diphosphate aldolase variants in biological systems.''; PubMed Europe PMC
  28. Pauly TA, Ekstrom JL, Beebe DA, Chrunyk B, Cunningham D, Griffor M, Kamath A, Lee SE, Madura R, Mcguire D, Subashi T, Wasilko D, Watts P, Mylari BL, Oates PJ, Adams PD, Rath VL.; ''X-ray crystallographic and kinetic studies of human sorbitol dehydrogenase.''; PubMed Europe PMC
  29. Inoue K, Nishimukai H, Yamasawa K.; ''Purification and partial characterization of aldehyde dehydrogenase from human erythrocytes.''; PubMed Europe PMC
  30. Guo JH, Hexige S, Chen L, Zhou GJ, Wang X, Jiang JM, Kong YH, Ji GQ, Wu CQ, Zhao SY, Yu L.; ''Isolation and characterization of the human D-glyceric acidemia related glycerate kinase gene GLYCTK1 and its alternatively splicing variant GLYCTK2.''; PubMed Europe PMC
  31. Bray GA.; ''Energy and fructose from beverages sweetened with sugar or high-fructose corn syrup pose a health risk for some people.''; PubMed Europe PMC
  32. Rodrigues JR, Couto A, Cabezas A, Pinto RM, Ribeiro JM, Canales J, Costas MJ, Cameselle JC.; ''Bifunctional homodimeric triokinase/FMN cyclase: contribution of protein domains to the activities of the human enzyme and molecular dynamics simulation of domain movements.''; PubMed Europe PMC
  33. Karlsson C, Maret W, Auld DS, Höög JO, Jörnvall H.; ''Variability within mammalian sorbitol dehydrogenases. The primary structure of the human liver enzyme.''; PubMed Europe PMC
  34. Rippe JM, Angelopoulos TJ.; ''Sucrose, high-fructose corn syrup, and fructose, their metabolism and potential health effects: what do we really know?''; PubMed Europe PMC
  35. Dalby AR, Tolan DR, Littlechild JA.; ''The structure of human liver fructose-1,6-bisphosphate aldolase.''; PubMed Europe PMC
  36. Trinh CH, Asipu A, Bonthron DT, Phillips SE.; ''Structures of alternatively spliced isoforms of human ketohexokinase.''; PubMed Europe PMC
  37. Ali M, Rellos P, Cox TM.; ''Hereditary fructose intolerance.''; PubMed Europe PMC
  38. Yoval-Sánchez B, Pardo JP, Rodríguez-Zavala JS.; ''New insights into the half-of-the-sites reactivity of human aldehyde dehydrogenase 1A1.''; PubMed Europe PMC
  39. van Buul VJ, Tappy L, Brouns FJ.; ''Misconceptions about fructose-containing sugars and their role in the obesity epidemic.''; PubMed Europe PMC
  40. HERS HG.; ''[Aldose reductase].''; PubMed Europe PMC
  41. Schapira F.; ''Kinetic and immunological abnormalities of aldolase B in herediatry fructose intolerance.''; PubMed Europe PMC


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101629view11:49, 1 November 2018ReactomeTeamreactome version 66
101165view21:35, 31 October 2018ReactomeTeamreactome version 65
100691view20:08, 31 October 2018ReactomeTeamreactome version 64
100241view16:54, 31 October 2018ReactomeTeamreactome version 63
99793view15:19, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99344view12:48, 31 October 2018ReactomeTeamreactome version 62
93270view11:18, 9 August 2017ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
3PDGAMetaboliteCHEBI:17794 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
AKR1B1ProteinP15121 (Uniprot-TrEMBL)
ALDH1A1 ProteinP00352 (Uniprot-TrEMBL)
ALDH1A1 tetramerComplexR-HSA-71689 (Reactome)
ALDOB ProteinP05062 (Uniprot-TrEMBL)
ALDOB tetramerComplexR-HSA-70340 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
D-sorbitolMetaboliteCHEBI:17924 (ChEBI)
DAK ProteinQ3LXA3 (Uniprot-TrEMBL)
DAK dimerComplexR-HSA-5652070 (Reactome)
DGAMetaboliteCHEBI:32398 (ChEBI)
DHAPMetaboliteCHEBI:16108 (ChEBI)
Fru 1-PMetaboliteCHEBI:18105 (ChEBI)
FruMetaboliteCHEBI:15824 (ChEBI)
GA3PMetaboliteCHEBI:29052 (ChEBI)
GAMetaboliteCHEBI:17378 (ChEBI)
GLYCTKProteinQ8IVS8 (Uniprot-TrEMBL)
GlcMetaboliteCHEBI:17925 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
K+MetaboliteCHEBI:29103 (ChEBI)
KHK ProteinP50053 (Uniprot-TrEMBL)
KHK dimerComplexR-HSA-3006523 (Reactome)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NADHMetaboliteCHEBI:16908 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
SORD ProteinQ00796 (Uniprot-TrEMBL)
SORD tetramerComplexR-HSA-5652211 (Reactome)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
3PDGAArrowR-HSA-6799495 (Reactome)
ADPArrowR-HSA-6799495 (Reactome)
ADPArrowR-HSA-70333 (Reactome)
ADPArrowR-HSA-70349 (Reactome)
ADPTBarR-HSA-70333 (Reactome)
AKR1B1mim-catalysisR-HSA-5652172 (Reactome)
ALDH1A1 tetramermim-catalysisR-HSA-6813749 (Reactome)
ALDOB tetramermim-catalysisR-HSA-70342 (Reactome)
ATPR-HSA-6799495 (Reactome)
ATPR-HSA-70333 (Reactome)
ATPR-HSA-70349 (Reactome)
D-sorbitolArrowR-HSA-5652172 (Reactome)
D-sorbitolR-HSA-5652195 (Reactome)
DAK dimermim-catalysisR-HSA-70349 (Reactome)
DGAArrowR-HSA-6813749 (Reactome)
DGAR-HSA-6799495 (Reactome)
DHAPArrowR-HSA-70342 (Reactome)
Fru 1-PArrowR-HSA-70333 (Reactome)
Fru 1-PR-HSA-70342 (Reactome)
FruArrowR-HSA-5652195 (Reactome)
FruR-HSA-70333 (Reactome)
GA3PArrowR-HSA-70349 (Reactome)
GAArrowR-HSA-70342 (Reactome)
GAR-HSA-6813749 (Reactome)
GAR-HSA-70349 (Reactome)
GLYCTKmim-catalysisR-HSA-6799495 (Reactome)
GlcR-HSA-5652172 (Reactome)
H+ArrowR-HSA-5652195 (Reactome)
H+ArrowR-HSA-6799495 (Reactome)
H+ArrowR-HSA-6813749 (Reactome)
H+R-HSA-5652172 (Reactome)
H2OR-HSA-6813749 (Reactome)
K+ArrowR-HSA-70333 (Reactome)
KHK dimermim-catalysisR-HSA-70333 (Reactome)
NAD+R-HSA-5652195 (Reactome)
NAD+R-HSA-6813749 (Reactome)
NADHArrowR-HSA-5652195 (Reactome)
NADHArrowR-HSA-6813749 (Reactome)
NADP+ArrowR-HSA-5652172 (Reactome)
NADPHR-HSA-5652172 (Reactome)
R-HSA-5652172 (Reactome) Cytosolic AKR1B1 (aldose reductase) catalyzes the reaction of glucose (Glc) and NADPH + H+ to form D-sorbitol and NADP+. This reaction was first described by Hers (1960) in sheep seminal vesicles; the human enzyme was identified by Nishimura et al. (1990) and is a potential target for treatment of diabetic neuropathy (Oates, 2008). The active enzyme is a monomer (Ruiz et al. 2004) whose amino-terminal methionine residue has been removed (Jacquinod et al. 1993). Under physiological conditions, formation of D-sorbitol is strongly favored (Grimshaw 1992).
R-HSA-5652195 (Reactome) Cytosolic SORD (sorbitol dehydrogenase) catalyzes the reaction of D-sorbitol and NAD+ to form fructose (Fru) and NADH + H+. This reaction was first described by Hers (1960) in sheep seminal vesicles; the human enzyme was identified by O'Brien et al. (1983). The active enzyme is a tetramer with four associated Zn2+ ions (Pauly et al. 2003) whose amino-terminal methionine residue has been removed (Karlsson et al. 1989).
R-HSA-6799495 (Reactome) D-glyceric acid (DGA) is an intermediate of serine catabolism and of a minor pathway of fructose metabolism. The only known fate of DGA is phosphorylation to 3-phospho-D-glyceric acid (3PDGA) by cytosolic glycerate kinase (GLYCTK) (Gou et al. 2006). Defects in GLYCTK can cause D-glyceric aciduria (D-GA; MIM:220120), a rare inborn error of serine and fructose metabolism where DGA is excreted in large amounts in the urine. A variable phenotype is observed, ranging from severe mental retardation and death to milder speech delays and normal development (Van Schaftingen 1989, Sass et al. 2010).
R-HSA-6813749 (Reactome) Retinal dehydrogenase 1 (ALDH1A1 tetramer) is a cytosolic aldehyde dehydrogenase that can oxidise glyceraldehyde (GA) to D-glycerate (DGA) (Yoval-Sanchez et al. 2013). DGA is a metabolite in a minor pathway of fructose catabolism and serine catabolism.
R-HSA-70333 (Reactome) Cytosolic ketohexokinase (KHK, also known as fructokinase) catalyzes the reaction of D-fructose (Fru) and ATP to form D-fructose 1-phosphate (Fru 1-P) and ADP. Two isoforms of the enzyme, A and C, are encoded by alternatively spliced forms of the gene; both form catalytically active dimers. The C isoform is predominant in liver and kidney tissues, has high affinity for fructose, and is probably responsible for the bulk of fructose phosphorylation in vivo (Asipu et al. 2003; Trinh et al. 2009). The A isoform is found in lower levels in many other tissues and may serve a role in fructose metabolism outside of liver and kidney (Funari et al. 2005). The physiological role of KHK has been established from metabolic and DNA sequencing studies of patients with essential fructosuria (Bonthron et al. 1994) and in mouse models for this disease (Diggle et al. 2010; Ishimoto et al. 2012).
R-HSA-70342 (Reactome) Cytosolic aldolase B (ALDOB) catalyzes the reaction of D-fructose 1-phosphate (Fru 1-P) to form dihydroxyacetone phosphate (DHAP) and D-glyceraldehyde (GA) (Hers & Kusaka 1953; Schapira 1975). The active form of the enzyme is a tetramer (Dalby et al. 2001). Deficiencies in the enzyme are associated with hereditary fructose intolerance in vivo (e.g., Tolan 1995; Ali et al. 1998).
ALDOB is the same aldolase isoform that catalyzes the reversible cleavage of fructose-1,6-bisphosphate in glycolysis. This isoform, found in liver, kidney, and intestine, is approximately equally active with fructose 1 phosphate and fructose 1,6 bisphosphate as substrates at saturating concentrations, while the muscle and brain isoforms (ALDOA and ALDOC, respectively), have little activity with fructose-1-phosphate (Lebherz & Rutter 1969; Penhoet et el. 1969).
R-HSA-70349 (Reactome) Cytosolic dihydroxyacetone kinase (DAK) catalyzes the reaction of ATP and D-glyceraldehyde (GA) to form ADP and D-glyceraldehyde 3-phosphate (GA3P). This reaction was originally characterized in studies of guinea pig liver and human erythrocytes (Hers & Kusaka 1953; Beutler & Guinto 1973). The human enzyme has been cloned and studied (Cabezas et al. 2005; Rodrigues et al. 2014). DAK/TKFC also catalyzes the phosphorylation of dihydroxyacetone (DHA) to dihydroxyacetone phosphate (DHAP), not a necessary step in fructose catabolism, but possibly functional on exogenous DHA. Triokinase activities on GA and DHA require homodimeric enzyme formed by two-domain subunits, where triose binds to one subunit and ATP to the other, each in a different domain.
DAK/TKFC is a bifunctional enzyme which, besides the ATP/Mg-dependent phosphorylation of GA and DHA, also catalyses, in presence of Mn2+, a unisubstrate reaction splitting flavin-adenine dinucleotide (FAD) into riboflavin cyclic 4',5'-phosphate (cyclic FMN) and AMP (Cabezas et al. 2005; Rodrigues et al. 2014).
In addition, DAK/TKFC protein binds to MDA5 and acts as a negative regulator of MDA5-mediated induction of IFN-alpha/beta pathways (Diao et al. 2007). Potentially related to this TKFC effect are the observations that hepatic DAK/TKFC levels correlate with outcome in chronic hepatitis C patients treated with interferon (Perdomo et al. 2012), and that a DAK/TKFC serum peptide is a predictor of disease severity in hepatitis B patients (Xu et al. 2013).
SORD tetramermim-catalysisR-HSA-5652195 (Reactome)
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