Defective ALDOB does not cleave Fru 1-P to GA and DHAP

Stable Identifier
Reaction [transition]
Homo sapiens
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

Mutations in ALDOB that cause deficiency of aldolase B block the cleavage of fructose 1-phosphate (Fru 1-P) to glyceraldehyde (GA) and dihydroxyacetone phosphate (DHAP) and cause hereditary fructose intolerance (HFI). The links between the enzyme deficiency and pathology are unclear at present, but may involve depletion of the cellular phosphate pool and increased levels of Fru 1-P (Oberhaensli et al, 1987; Bouteldja & Timson, 2010). Affected individuals can develop severe hypoglycemia, lactic acidosis, and other metabolic abnormalities when fed fructose; the disease can be effectively managed by complete exclusion of fructose from the diet. A large number of ALDOB variants have been described in affected individuals (e.g. Tolan 1995); the two missense mutant alleles annotated here are the most common (53% of those with HFI have one of these alleles) (Cross et al. 1988; Cross et al. 1990; Coffee et al. 2010), and encode full length aldolase B proteins whose catalytic activity is sharply reduced due to considerable loss of stability (Malay et al., 2002; Malay et al. 2005; Rellos et al., 2000 - see also PDB structures 1XDL and 1XDM). Other less common variants, not annotated here, retain activities and thermal stabilities similar to the wild-type (Esposito et al, 2010). The physiological role of aldolase B has been established from metabolic and DNA sequencing studies of patients with HFI (Ali et al. 1998) and in a mouse model for this disease (Oppelt et al. 2015).

Literature References
PubMed ID Title Journal Year
2889861 Study of hereditary fructose intolerance by use of 31P magnetic resonance spectroscopy

Oberhaensli, RD, Rajagopalan, B, Taylor, DJ, Radda, GK, Collins, JE, Leonard, JV, Schwarz, H, Herschkowitz, N

Lancet 1987
8535439 Molecular basis of hereditary fructose intolerance: mutations and polymorphisms in the human aldolase B gene

Tolan, DR

Hum Mutat 1995
15733923 Structure of the thermolabile mutant aldolase B, A149P: molecular basis of hereditary fructose intolerance

Malay, AD, Allen, KN, Tolan, DR

J. Mol. Biol. 2005
10625657 Expression, purification, and characterization of natural mutants of human aldolase B. Role of quaternary structure in catalysis

Rellos, P, Sygusch, J, Cox, TM

J. Biol. Chem. 2000
1967768 Molecular analysis of aldolase B genes in hereditary fructose intolerance

Cross, NC, de Franchis, R, Sebastio, G, Dazzo, C, Tolan, DR, Gregori, C, Odièvre, M, Vidailhet, M, Romano, V, Mascali, G, Romano, C, Musumeci, S, Steinmann, B, Gitzelmann, R, Cox, TM

Lancet 1990
20033295 Increased prevalence of mutant null alleles that cause hereditary fructose intolerance in the American population

Coffee, EM, Yerkes, L, Ewen, EP, Zee, T, Tolan, DR

J. Inherit. Metab. Dis. 2010
12464284 The temperature dependence of activity and structure for the most prevalent mutant aldolase B associated with hereditary fructose intolerance

Malay, AD, Procious, SL, Tolan, DR

Arch. Biochem. Biophys. 2002
20848650 Hereditary fructose intolerance: functional study of two novel ALDOB natural variants and characterization of a partial gene deletion

Esposito, G, Imperato, MR, Ieno, L, Sorvillo, R, Benigno, V, Parenti, G, Parini, R, Vitagliano, L, Zagari, A, Salvatore, F

Hum. Mutat. 2010
3383242 Catalytic deficiency of human aldolase B in hereditary fructose intolerance caused by a common missense mutation

Cross, NC, Tolan, DR, Cox, TM

Cell 1988
9610797 Hereditary fructose intolerance

Ali, M, Rellos, P, Cox, TM

J. Med. Genet. 1998
25637246 Aldolase-B knockout in mice phenocopies hereditary fructose intolerance in humans

Oppelt, SA, Sennott, EM, Tolan, DR

Mol. Genet. Metab. 2015
Catalyst Activity

fructose-1-phosphate aldolase activity of ALDOB mutant proteins [cytosol]

Normal reaction
Functional status

Loss of function of ALDOB mutant proteins [cytosol]

Name Identifier Synonyms
hereditary fructose intolerance syndrome DOID:9869 Fructosemia, Fructose-1,6-bisphosphate aldolase B deficiency, Fructosaemia
Cite Us!