ALDOB (aldolase B, fructose-bisphosphate)

2008-11-01   Shian-Yang Peng , Hey-Chi Hsu 

Department of General Education, National Taipei College of Nursing, Taipei 100, Taiwan, ROC (SYP); Department of Pathology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan, ROC (HCH)

Identity

HGNC
LOCATION
9q31.1
LOCUSID
ALIAS
ALDB,EC 4.1.2.13,OTTHUMP00000021803
FUSION GENES

DNA/RNA

Note

Locus Tag: RP11-490D19.1.
Atlas Image
Genomic organization of ALDOB gene on chromosome 9q21.3 - q22.2. Exons are represented by boxes on the diagram.

Description

ALDOB encompasses 14,448 base pairs of genomic DNA on the long arm of chromosome 9 in the telomere- to- centromere orientation. (NCBI Entrez Gene, NC-000009.10, 19-Nov-2008.)
The gene consists of 9 exons, with 115, 122, 212, 55, 161, 84, 193, 200, 526 base pairs, respectively.

Transcription

ALDOB encodes a 1669 bp mRNA, the coding region is from 126bp to 1220bp of the mRNA.
Exon 1 and the 3 part of exon 9 of the ALDOB gene are non-coding.

Pseudogene

None.

Proteins

Note

Names : aldolase B, Fructose-bisphosphate.
Other Names : aldolase 2, Liver-type aldolase.

Description

The 1095 bps open reading frame of ALDOB encodes a 364 amino acids protein with a calculated molecular weight of 39.3kDa.
The functional Aldolase B is a homotetramer. According to the three-dimensional structures of aldolase B homotetramers, the active sites of each monomer locate at the center of the alpha/beta barrels, while the C terminus of the protein is involed in determining the isozyme-specific activity of aldolase. Four isozyme specific regions (ISR) of aldolase B were determined, the first three are expressed by exon 3 of the human aldolase gene, the fourth locates at the C-terminal region.

Expression

There are three genetically distinct and tissue-specific isozymes of fructose-biphosphate aldolase (EC-Number 4.1.2.13 ) class-I in mammals. The A isozyme(aldolase A) is expressed mainly in muscle, the B isozyme(aldolase B) in the liver, kidney, stomach and intestine, and the C isozyme (aldolase C) in the brain, heart and ovary. Aldolase B is the only expressed isoform in highly differentiated hepatocytes. The high level of gene expression results from cooperation between a liver-specific promoter and an intronic enhancer.

Localisation

Cytoplasm and perinuclear membrane of hepatocytes.

Function

All the three aldolase isozymes catalyze the reversible cleavage of fructose-1,6-(bis) phosphate (FBP) or fructose 1-phosphate (F1P) to dihydroxyacetone phosphate and either glyceraldehyde- 3-phosphate or glyceraldehyde, respectively. Aldolase B has equal activity toward substrate F1P and FBP, and is involved in the two opposite metabolic pathways, glycolysis and gluconeogenesis. Aldolase isozymes utilize covalent catalysis through a Schiff base in the active site of the enzyme, but exhibit distinct catalytic properties. The Schiff-base lysine is located in the central cavity of the barrel. The enzymatic active sites at aldolose B protein sequence are: Arg 55 and Lys146 for binding of c-1-phosphate group of the substrate; Lys 299, the Schiff base for dihydroxyacetone-p; Try 363 for enzymatic activity toward fructose 1,6- bisphosphate site; Asp33, Glu187 and Lys229 residues for catalytic function.

Homology

The three human aldolase isozymes are similar in sequence with 66% identity between human A and B, 68% identity between B and C, and 78% identity between A and C. Aldolase molecules have seven major conserved common sequence (CCS-1 to -7), that are the constituents forming a basal alpha/beta barrel structure, are conserved in all aldolase molecules beyond isozyme groups. All isozymes have strictly conserved residues in the active site consisting of Asp33, Arg42, Lys107, Lys146, Glu187, Ser271, Arg303, and Lys229.
The identities of aldolase B between human and other animal species are shown bellow. Protein sequences of the mammalian aldolase B are highly conserved.
[Pongo abelii] aldolase B, fructose-bisphosphate (364/364, 100%)
[Pan troglodytes] aldolase B, fructose-bisphosphate (363/364, 99% identity)
[Rattus norvegicus] Aldob, aldolase B fructose-bisphosphate (349/364, 95% identity)
[Mus musculus] Aldob, aldolase B, fructose-bisphosphate (349/364, 95% identity)
[Bos taurus] aldolase B, fructose-bisphosphate (334/364, 91% identity)
[Canis lupus familiaris] aldolase B, fructose-bisphosphate (334/364, 91% identity)
[Ovis aries] aldolase B (333/364, 91% identity)
[Macaca mulatta] aldolase B (333/364, 91% identity)
[Gallus gallus] aldolase B, fructose-bisphosphate (294/364, 80% identity)
[Danio rerio] aldob, aldolase b, fructose-bisphosphate (277/364, 76% identity)
[Salmo salar] aldolase B (266/365, 72% identity)

Mutations

Atlas Image
Types of mutation related to Hereditary fructose intolerance (HFI).
c. means cDNA coding region mutations, g. means genome mutations and p. refers to protein change after nucleotide mutation. IVS (intervening sequence) refers to introns.

Germinal

Recessively inherited mutations in the ALDOB gene, that caused catalytic deficiency of aldolase B, have been found in hereditary fructose intolerance (HFI). Many types of mutation in human ALDOB gene were reported, including missense mutations, nonsense mutations, deletions, insertions and mutation at the splicing regions (list in the diagram above). The mutations bring about reduced enzyme activity and affect structural stability. Mutants that retained tetrameric structure but with altered kinetic properties would reduce its catalytic activity. Mutants with homotetramers dissociated into subunits would have more severe impaired enzymatic activity. The three most common sites are: p.A150P (64%), p.A175D (16%) and p.N335K (5%).

Somatic

Human cancer result from the genetic mutation of ALDOB was not reported so far.

Implicated in

Entity name
Hereditary fructose intolerance (HFI)
Disease
An autosomal recessive disease that results in the inability to metabolize fructose and related sugars. When fructose, sucrose, or sorbitol was taken from the diet, affected patients suffer from vomiting, abdominal pain, hypoglycemia. Continued ingestion of noxious sugars leads to hepatic and renal injury, which eventually leads to liver cirrhosis and growth retardation.
Prognosis
Complete exclusion of fructose, sucrose, and sorbitol from the diet results in dramatic recovery if liver and kidney damage is not irreversible.
Oncogenesis
Not found
Entity name
Hepatocellular cellular carcinoma (HCC)
Note
Aldolase B is the only expressed isoenzymes of aldolase in highly differentiated hepatocytes.
The mRNA of aldolase B was downexpressed in HCC patients detected by northern blot or RT-PCR, and it was also undetectable or expressed at very low levels in the hepatocellular carcinoma (HA22T, SKHep, HCC36, PLC/PLZ/5 and Hep3B) and hepatoblastoma (HepG2) cell lines.
Disease
Hepatocellular carcinoma (HCC) is an aggressive malignancy with a poor prognosis.
Down-regulation of ALDOB was detected in patients of HCC and is associated with advanced disease, ETR and poor prognosis. A dramatic down-regulation of ALDOB was found in 116 of 203 HCCs (57%), while 43% of HCCs maintained the expression. The ALDOB down-regulation correlated with high-grade (grade II-IV) HCC (p
Prognosis
In stage II HCC which had no vascular invasion, the ALDOB down-regulation was associated with ETR (p

Bibliography

Pubmed IDLast YearTitleAuthors
174576942007Transferrin hypoglycosylation in hereditary fructose intolerance: using the clues and avoiding the pitfalls.Adamowicz M et al
77173891995Diverse mutations in the aldolase B gene that underlie the prevalence of hereditary fructose intolerance.Ali M et al
88296341996A newly identified aldolase B splicing mutation (G-->C, 5' intron 5) in hereditary fructose intolerance from New Zealand.Ali M et al
84380461993DNA diagnosis of fatal fructose intolerance from archival tissue.Ali M et al
80693281994Identification of a novel mutation (Leu256-->Pro) in the human aldolase B gene associated with hereditary fructose intolerance.Ali M et al
80719801994Null alleles of the aldolase B gene in patients with hereditary fructose intolerance.Ali M et al
155377552004Structure of human brain fructose 1,6-(bis)phosphate aldolase: linking isozyme structure with function.Arakaki TL et al
84961481993Differential usage of the carboxyl-terminal region among aldolase isozymes.Berthiaume L et al
19280901991Identification of a splice-site mutation in the aldolase B gene from an individual with hereditary fructose intolerance.Brooks CC et al
82998831994A partially active mutant aldolase B from a patient with hereditary fructose intolerance.Brooks CC et al
179553892007Clinical and genetic analysis for a Chinese family with hereditary fructose intolerance.Chi ZN et al
82998921994Aldolase B and fructose intolerance.Cox TM et al
23499371990Partial aldolase B gene deletions in hereditary fructose intolerance.Cross NC et al
23363801990A new aldolase B variant, N334K, is a common cause of hereditary fructose intolerance in Yugoslavia.Cross NC et al
33832421988Catalytic deficiency of human aldolase B in hereditary fructose intolerance caused by a common missense mutation.Cross NC et al
19677681990Molecular analysis of aldolase B genes in hereditary fructose intolerance.Cross NC et al
116797162001The structure of human liver fructose-1,6-bisphosphate aldolase.Dalby AR et al
185414502008Hereditary fructose intolerance: frequency and spectrum mutations of the aldolase B gene in a large patients cohort from France--identification of eight new mutations.Davit-Spraul A et al
23397101990Molecular evidence for compound heterozygosity in hereditary fructose intolerance.Dazzo C et al
155320222004Six novel alleles identified in Italian hereditary fructose intolerance patients enlarge the mutation spectrum of the aldolase B gene.Esposito G et al
79099841994Localization of the gene for the nevoid basal cell carcinoma syndrome.Goldstein AM et al
120347482002In vivo functional characterization of the aldolase B gene enhancer.Gregori C et al
164066492006Aldolase B mutations and prevalence of hereditary fructose intolerance in a Polish population.Gruchota J et al
22032591990Hereditary fructose intolerance caused by a nonsense mutation of the aldolase B gene.Kajihara S et al
121430532002Underexpression of mRNA in human hepatocellular carcinoma focusing on eight loci.Kinoshita M et al
172925852007Semi-automated, reverse-hybridization detection of multiple mutations causing hereditary fructose intolerance.Kriegshäuser G et al
98548141998Role of isozyme group-specific sequence 4 in the isozyme-specific properties of human aldolase C.Kusakabe T et al
147312342004Radiation hybrid mapping of the pig ALDOA, ALDOB and ALDOC genes to SSC3, SSC1 and SSC12.Lin L et al
177863582007Identification of differential expression of genes in hepatocellular carcinoma by suppression subtractive hybridization combined cDNA microarray.Liu Y et al
180008792008Novel interaction partners of Bardet-Biedl syndrome proteins.Oeffner F et al
74862511995Sheep gene mapping: assignment of ALDOB, CYP19, WT and SOX2 by somatic cell hybrid analysis.Payen E et al
183573952008Aberrant expression of the glycolytic enzymes aldolase B and type II hexokinase in hepatocellular carcinoma are predictive markers for advanced stage, early recurrence and poor prognosis.Peng SY et al
126118902003Spatial clustering of isozyme-specific residues reveals unlikely determinants of isozyme specificity in fructose-1,6-bisphosphate aldolase.Pezza JA et al
75084151993Linkage mapping of the Aldo-2, Pax-5, Ambp, and D4h9S3E loci on mouse chromosome 4 in the region of homology with human chromosome 9.Pilz A et al
106256572000Expression, purification, and characterization of natural mutants of human aldolase B. Role of quaternary structure in catalysis.Rellos P et al
31056021987The complete amino acid sequence of the human aldolase C isozyme derived from genomic clones.Rottmann WH et al
150637622004Genetic variations in humans associated with differences in the course of hepatitis C.Saito T et al
88805831996Molecular basis of hereditary fructose intolerance in Italy: identification of two novel mutations in the aldolase B gene.Santamaria R et al
158807272005The spectrum of aldolase B (ALDOB) mutations and the prevalence of hereditary fructose intolerance in Central Europe.Santer R et al
87229131996Mapping functional chicken genes: an alternative approach.Smith EJ et al
149669072004Genes encoding Pir51, Beclin 1, RbAp48 and aldolase b are up or down-regulated in human primary hepatocellular carcinoma.Song H et al
106408061999Comparative FISH mapping on Z chromosomes of chicken and Japanese quail.Suzuki T et al
23411571990Assignment of 12 loci to rat chromosome 5: evidence that this chromosome is homologous to mouse chromosome 4 and to human chromosomes 9 and 1 (1p arm).Szpirer C et al
20815961990Syntenic conservation between humans and cattle. I. Human chromosome 9.Threadgill DW et al
85354391995Molecular basis of hereditary fructose intolerance: mutations and polymorphisms in the human aldolase B gene.Tolan DR et al
152217722004Proteomic profiling of proteins decreased in hepatocellular carcinoma from patients infected with hepatitis C virus.Yokoyama Y et al

Other Information

Locus ID:

NCBI: 229
MIM: 612724
HGNC: 417
Ensembl: ENSG00000136872

Variants:

dbSNP: 229
ClinVar: 229
TCGA: ENSG00000136872
COSMIC: ALDOB

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000136872ENST00000616752A0A087WXX2
ENSG00000136872ENST00000647789P05062
ENSG00000136872ENST00000647789A0A024R145
ENSG00000136872ENST00000648064P05062
ENSG00000136872ENST00000648064A0A024R145
ENSG00000136872ENST00000648423A0A3B3ITZ0
ENSG00000136872ENST00000648758P05062
ENSG00000136872ENST00000648758A0A024R145
ENSG00000136872ENST00000649902A0A3B3IS80

Expression (GTEx)

0
500
1000
1500
2000
2500
3000

Pathways

PathwaySourceExternal ID
Glycolysis / GluconeogenesisKEGGko00010
Pentose phosphate pathwayKEGGko00030
Fructose and mannose metabolismKEGGko00051
Glycolysis / GluconeogenesisKEGGhsa00010
Pentose phosphate pathwayKEGGhsa00030
Fructose and mannose metabolismKEGGhsa00051
Metabolic pathwaysKEGGhsa01100
Glycolysis (Embden-Meyerhof pathway), glucose => pyruvateKEGGhsa_M00001
Gluconeogenesis, oxaloacetate => fructose-6PKEGGhsa_M00003
Glycolysis (Embden-Meyerhof pathway), glucose => pyruvateKEGGM00001
Gluconeogenesis, oxaloacetate => fructose-6PKEGGM00003
Biosynthesis of amino acidsKEGGhsa01230
Biosynthesis of amino acidsKEGGko01230
Carbon metabolismKEGGhsa01200
Carbon metabolismKEGGko01200
MetabolismREACTOMER-HSA-1430728
Metabolism of carbohydratesREACTOMER-HSA-71387
Glucose metabolismREACTOMER-HSA-70326
GlycolysisREACTOMER-HSA-70171
GluconeogenesisREACTOMER-HSA-70263
Fructose metabolismREACTOMER-HSA-5652084
Fructose catabolismREACTOMER-HSA-70350

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
175767702007Physical interaction between aldolase and vacuolar H+-ATPase is essential for the assembly and activity of the proton pump.64
149669072004Genes encoding Pir51, Beclin 1, RbAp48 and aldolase b are up or down-regulated in human primary hepatocellular carcinoma.22
249935272014Aldolase positively regulates of the canonical Wnt signaling pathway.17
297065652018Aldolase B-Mediated Fructose Metabolism Drives Metabolic Reprogramming of Colon Cancer Liver Metastasis.17
150637622004Genetic variations in humans associated with differences in the course of hepatitis C.16
253527372014Electronic medical records and genomics (eMERGE) network exploration in cataract: several new potential susceptibility loci.15
263768792015Aldolase B inhibits metastasis through Ten-Eleven Translocation 1 and serves as a prognostic biomarker in hepatocellular carcinoma.15
158807272005The spectrum of aldolase B (ALDOB) mutations and the prevalence of hereditary fructose intolerance in Central Europe.13
201623642010The biochemical basis of hereditary fructose intolerance.13
285583812017Aldolase B Overexpression is Associated with Poor Prognosis and Promotes Tumor Progression by Epithelial-Mesenchymal Transition in Colorectal Adenocarcinoma.12

Citation

Shian-Yang Peng ; Hey-Chi Hsu

ALDOB (aldolase B, fructose-bisphosphate)

Atlas Genet Cytogenet Oncol Haematol. 2008-11-01

Online version: http://atlasgeneticsoncology.org/gene/44287/aldob