ALDOA
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1ALD, 2ALD, 4ALD
Identifiers
Aliases	ALDOA, ALDA, GSD12, HEL-S-87p, aldolase, fructose-bisphosphate A, Aldolase A
External IDs	OMIM: 103850 MGI: 87994 HomoloGene: 141054 GeneCards: ALDOA
Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16p11.2 Start 30,064,164 bp[1] End 30,070,457 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7|7 F3 Start 126,394,406 bp[2] End 126,399,923 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gastrocnemius muscle skeletal muscle tissue superior frontal gyrus prefrontal cortex left ventricle Brodmann area 9 nucleus accumbens caudate nucleus hypothalamus putamen Top expressed in ankle vastus lateralis muscle triceps brachii muscle sternocleidomastoid muscle temporal muscle digastric muscle masseter muscle tibialis anterior muscle knee joint extensor digitorum longus muscle More reference expression data BioGPS n/a
Gene ontology Molecular function cytoskeletal protein binding tubulin binding fructose binding protein binding catalytic activity lyase activity actin binding fructose-bisphosphate aldolase activity identical protein binding RNA binding cadherin binding Cellular component cytoplasm M band membrane I band extracellular region actin cytoskeleton extracellular exosome platelet alpha granule lumen nucleus extracellular space cytosol secretory granule lumen tertiary granule lumen ficolin-1-rich granule lumen sperm head Biological process gluconeogenesis glycolytic process muscle cell cellular homeostasis canonical glycolysis actin filament organization fructose metabolic process platelet degranulation fructose 1,6-bisphosphate metabolic process ATP biosynthetic process regulation of cell shape protein homotetramerization striated muscle contraction neutrophil degranulation binding of sperm to zona pellucida Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 226 11674 Ensembl ENSG00000149925 ENSMUSG00000030695 UniProt P04075 P05064 RefSeq (mRNA) NM_000034 NM_001127617 NM_001243175 NM_001243177 NM_184041 NM_184043 NM_001355562 NM_001355563 NM_001355564 NM_001355565 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 Mb Chr 7: 126.39 – 126.4 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.

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.^{[citation needed]}

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 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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|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:

• PLD2,^[12]
• actin,^[11]
• GLUT4,^[13]
• phospholipase D2,^[13]
• light chain 8 of dynein,^[13]
• erythrocyte anion exchanger Band 3 protein,^[13]
• ryanodine receptor,^[11]
• Cytohesin-2,^[10] and
• V-ATPase (vacuolar-type H+-ATPase).^[10]