Aldolase A

Aldolase A (ALDOA, or ALDA), also known as fructose-bisphosphate aldolase, is an enzyme that in humans is encoded by the ALDOA gene on chromosome 16.

ALDOA
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesALDOA, ALDA, GSD12, HEL-S-87p, aldolase, fructose-bisphosphate A, Aldolase A
External IDsOMIM: 103850 MGI: 87994 HomoloGene: 141054 GeneCards: ALDOA
Gene location (Human)
Chr.Chromosome 16 (human)[1]
Band16p11.2Start30,064,164 bp[1]
End30,070,457 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

226

11674

Ensembl

ENSG00000149925

ENSMUSG00000030695

UniProt

P04075

P05064

RefSeq (mRNA)

NM_001177307
NM_001177308
NM_007438

RefSeq (protein)

NP_001121089
NP_001230106
NP_908930
NP_908932

NP_001170778
NP_001170779
NP_031464

Location (UCSC)Chr 16: 30.06 – 30.07 MbChr 7: 126.8 – 126.8 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
fructose-bisphosphate aldolase
Identifiers
EC number4.1.2.13
CAS number9024-52-6
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

The protein encoded by this gene is a glycolytic enzyme that catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP). Three aldolase isozymes (A, B, and C), encoded by three different genes, are differentially expressed during development. Aldolase A is found in the developing embryo and is produced in even greater amounts in adult muscle. Aldolase A expression is repressed in adult liver, kidney and intestine and similar to aldolase C levels in brain and other nervous tissue. Aldolase A deficiency has been associated with myopathy and hemolytic anemia. Alternative splicing and alternative promoter usage results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 3 and 10. [provided by RefSeq, Aug 2011][5]

Structure

ALDOA is a homotetramer and one of the three aldolase isozymes (A, B, and C), encoded by three different genes.[6][7] The ALDOA gene contains 8 exons and the 5' UTR IB.[7] Key amino acids responsible for its catalytic function have been identified. The residue Tyr363 functions as the acid–base catalyst for protonating C3 of the substrate, while Lys146 is proposed to stabilize the negative charge of the resulting conjugate base of Tyr363 and the strained configuration of the C-terminal. Residue Glu187 participates in multiple functions, including FBP aldolase catalysis, acid–base catalysis during substrate binding, dehydration, and substrate cleavage.[8] Though ALDOA localizes to the nucleus, it lacks any known nuclear localization signals (NLS).[9]

Mechanism

In mammalian aldolase, the key catalytic amino acid residues involved in the reaction are lysine and tyrosine. The tyrosine acts as an efficient hydrogen acceptor while the lysine covalently binds and stabilizes the intermediates. Many bacteria use two magnesium ions in place of the lysine.

The reaction mechanism of aldolase.
The enzyme's reactive site amino acid's side-chains are shown in blue.
Abbreviations: DHAP - dihydroxyacetone phosphate; Fru1,6bP - Fructose-1,6-bisphosphate; GAD - glyceraldehyde 3-phosphate;
β-D-fructose 1,6-phosphate fructose-bisphosphate aldolase D-glyceraldehyde 3-phosphate dihydroxyacetone phosphate
+

Compound C05378 at KEGG Pathway Database. Enzyme 4.1.2.13 at KEGG Pathway Database. Compound C00111 at KEGG Pathway Database. Compound C00118 at KEGG Pathway Database.

The numbering of the carbon atoms indicates the fate of the carbons according to their position in fructose 6-phosphate.

Function

ALDOA is a key enzyme in the fourth step of glycolysis, as well as in the reverse pathway gluconeogenesis. It catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehydes-3-phosphate and dihydroxyacetone phosphate by aldol cleavage of the C3–C4 bond. As a result, it is a crucial player in ATP biosynthesis.[6][8][9][10][11] ALDOA also contributes to other "moonlighting" functions such as muscle maintenance, regulation of cell shape and motility, striated muscle contraction, actin cytoskeleton organization, and regulation of cell proliferation.[6][9][10] ALDOA likely regulates actin cytoskeleton remodeling through interacting with cytohesin-2 (ARNO) and Arf6.[10]

ALDOA is ubiquitously expressed in most tissues, though it is predominantly expressed in developing embryo and adult muscle.[6][11] In lymphocytes, ALDOA is the predominant aldolase isoform.[11] Within the cell, ALDOA typically localizes to the cytoplasm, but it can localize to the nucleus during DNA synthesis of the cell cycle S phase. This nuclear localization is regulated by the protein kinases AKT and p38. It is suggested that the nucleus serves as a reservoir for ALDOA in low glucose conditions.[9] ALDOA has also been found in mitochondria.[11]

ALDOA is regulated by the energy metabolism substrates glucose, lactate, and glutamine.[9] In human mast cells (MCs), ALDOA has been observed to undergo post-translational regulation by protein tyrosine nitration, which may alter its relative affinity for FBP and/or IP3. This change then affects IP3 and PLC signaling cascades in IgE-dependent responses.[11]

Clinical significance

Aldolase A (ALDOA) is a highly expressed in multiple cancers, including lung squamous cell carcinoma (LSCC), renal cancer, and hepatocellular carcinoma. It is proposed that ALDOA overexpression enhances glycolysis in these tumor cells, promoting their growth. In LSCC, its upregulation correlates with metastasis and poor prognosis, while its downregulation reduces tumor cell motility and tumorigenesis. Thus, ALDOA could be a potential LSCC biomarker and therapeutic drug target.[6]

Aldolase A deficiency is a rare, autosomal recessive disorder that is linked to hemolysis and accompanied by weakness, muscle pain, and myopathy.[7]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.[§ 1]

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|{{{bSize}}}px|alt=Glycolysis and Gluconeogenesis edit]]
Glycolysis and Gluconeogenesis edit
  1. The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".

Interactions

Aldolase A has been shown to interact with:

See also

References

  1. GRCh38: Ensembl release 89: ENSG00000149925 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000030695 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: ALDOA aldolase A, fructose-bisphosphate".
  6. Du, S; Guan, Z; Hao, L; Song, Y; Wang, L; Gong, L; Liu, L; Qi, X; Hou, Z; Shao, S (2014). "Fructose-bisphosphate aldolase a is a potential metastasis-associated marker of lung squamous cell carcinoma and promotes lung cell tumorigenesis and migration". PLOS ONE. 9 (1): e85804. Bibcode:2014PLoSO...985804D. doi:10.1371/journal.pone.0085804. PMC 3900443. PMID 24465716.
  7. Yao, DC; Tolan, DR; Murray, MF; Harris, DJ; Darras, BT; Geva, A; Neufeld, EJ (15 March 2004). "Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr)". Blood. 103 (6): 2401–3. doi:10.1182/blood-2003-09-3160. PMID 14615364.
  8. Tittmann, K (December 2014). "Sweet siblings with different faces: the mechanisms of FBP and F6P aldolase, transaldolase, transketolase and phosphoketolase revisited in light of recent structural data". Bioorganic Chemistry. 57: 263–80. doi:10.1016/j.bioorg.2014.09.001. PMID 25267444.
  9. Mamczur, P; Gamian, A; Kolodziej, J; Dziegiel, P; Rakus, D (December 2013). "Nuclear localization of aldolase A correlates with cell proliferation". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1833 (12): 2812–22. doi:10.1016/j.bbamcr.2013.07.013. PMID 23886627.
  10. Merkulova, M; Hurtado-Lorenzo, A; Hosokawa, H; Zhuang, Z; Brown, D; Ausiello, DA; Marshansky, V (June 2011). "Aldolase directly interacts with ARNO and modulates cell morphology and acidic vesicle distribution". American Journal of Physiology. Cell Physiology. 300 (6): C1442-55. doi:10.1152/ajpcell.00076.2010. PMC 3118619. PMID 21307348.
  11. Sekar, Y; Moon, TC; Slupsky, CM; Befus, AD (1 July 2010). "Protein tyrosine nitration of aldolase in mast cells: a plausible pathway in nitric oxide-mediated regulation of mast cell function". Journal of Immunology. 185 (1): 578–87. doi:10.4049/jimmunol.0902720. PMID 20511553.
  12. Kim, Jong Hyun; Lee Sukmook; Kim Jung Hwan; Lee Taehoon G; Hirata Masato; Suh Pann-Ghill; Ryu Sung Ho (Mar 2002). "Phospholipase D2 directly interacts with aldolase via Its PH domain". Biochemistry. United States. 41 (10): 3414–21. doi:10.1021/bi015700a. ISSN 0006-2960. PMID 11876650.
  13. St-Jean, M; Izard, T; Sygusch, J (11 May 2007). "A hydrophobic pocket in the active site of glycolytic aldolase mediates interactions with Wiskott-Aldrich syndrome protein". The Journal of Biological Chemistry. 282 (19): 14309–15. doi:10.1074/jbc.m611505200. PMID 17329259.

Further reading


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