Aldolase A

Aldolase A, fructose-bisphosphate
250px PDB rendering based on 4ALD.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1ALD, 2ALD, 4ALD
Identifiers
Symbols	ALDOA ; ALDA; GSD12; HEL-S-87p
External IDs	OMIM: 103850 MGI: 87994 HomoloGene: 141054 ChEMBL: 2106 GeneCards: ALDOA Gene
EC number	4.1.2.13
Gene ontology Molecular function • actin binding • fructose-bisphosphate aldolase activity • protein binding • cytoskeletal protein binding • tubulin binding • identical protein binding • poly(A) RNA binding • fructose binding Cellular component • extracellular region • extracellular space • nucleus • cytosol • actin cytoskeleton • membrane • platelet alpha granule lumen • M band • I band • extracellular exosome Biological process • platelet degranulation • carbohydrate metabolic process • fructose metabolic process • glucose metabolic process • gluconeogenesis • glycolytic process • ATP biosynthetic process • striated muscle contraction • actin filament organization • blood coagulation • regulation of cell shape • platelet activation • fructose 1,6-bisphosphate metabolic process • small molecule metabolic process • muscle cell cellular homeostasis • protein homotetramerization • canonical glycolysis Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE ALDOA 200966 x at tn.png
File:PBB GE ALDOA 214687 x at tn.png
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	226	11674
Ensembl	ENSG00000149925	ENSMUSG00000030695
UniProt	P04075	P05064
RefSeq (mRNA)	NM_000034	NM_001177307
RefSeq (protein)	NP_000025	NP_001170778
Location (UCSC)	Chr 16: 30.05 – 30.07 Mb	Chr 7: 126.8 – 126.8 Mb
PubMed search	[1]	[2]

fructose-bisphosphate aldolase
Identifiers
EC number	4.1.2.13
CAS number	Template:CAS
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search PMC articles PubMed articles NCBI proteins

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 and dihydroxyacetone phosphate. 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]

Structure

ALDOA is a homotetramer and one of the three aldolase isozymes (A, B, and C), encoded by three different genes. The ALDOA gene contains 8 exons and the 5' UTR IB. 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. Though ALDOA localizes to the nucleus, it lacks any known nuclear localization signals (NLS).

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.

File:ALDO reaction.png 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. 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. ALDOA likely regulates actin cytoskeleton remodeling through interacting with cytohesin-2 (ARNO) and Arf6.

ALDOA is ubiquitously expressed in most tissues, though it is predominantly expressed in developing embryo and adult muscle. In lymphocytes, ALDOA is the predominant aldolase isoform. 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. ALDOA has also been found in mitochondria.

ALDOA is regulated by the energy metabolism substrates glucose, lactate, and glutamine. 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.

Clinical Significance

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.

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

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.

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|{{{bSize}}}px|alt=Glycolysis and Gluconeogenesis edit]]

File:WP534.png

Glycolysis and Gluconeogenesis edit

Interactions

Aldolase A has been shown to interact with:

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

See also

• Fructose-bisphosphate aldolase
• ALDOB
• ALDOC

External links

• http://pdbdev.sdsc.edu:48346/pdb/molecules/pdb50_5.html
• Fructose-Bisphosphate Aldolase at the US National Library of Medicine Medical Subject Headings (MeSH)
• ALDOA
• EC 4.1.2.13