Aldolase A

Template:Short description Template:Cs1 config Template:Infobox gene Template:Infobox enzyme 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.<ref name="entrez">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

StructureEdit

ALDOA is a homotetramer and one of the three aldolase isozymes (A, B, and C), encoded by three different genes.<ref name=pmid24465716>Template:Cite journal</ref><ref name=pmid14615364>Template:Cite journal</ref> The ALDOA gene contains 8 exons and the 5' UTR IB.<ref name=pmid14615364/> 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.<ref name=pmid25267444>Template:Cite journal</ref> Though ALDOA localizes to the nucleus, it lacks any known nuclear localization signals (NLS).<ref name=pmid23886627>Template:Cite journal</ref>

MechanismEdit

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. Template:Citation needed

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;

Template:Complex enzymatic reaction

Template:KEGG compound Template:KEGG enzyme Template:KEGG compound Template:KEGG compound

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

FunctionEdit

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.<ref name=pmid24465716/><ref name=pmid25267444/><ref name=pmid23886627/><ref name=pmid21307348>Template:Cite journal</ref><ref name=pmid20511553>Template:Cite journal</ref> 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.<ref name=pmid24465716/><ref name=pmid23886627/><ref name=pmid21307348/> ALDOA likely regulates actin cytoskeleton remodeling through interacting with cytohesin-2 (ARNO) and Arf6.<ref name=pmid21307348/>

ALDOA is ubiquitously expressed in most tissues, though it is predominantly expressed in developing embryo and adult muscle.<ref name=pmid24465716/><ref name=pmid20511553/> In lymphocytes, ALDOA is the predominant aldolase isoform.<ref name=pmid20511553/> 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.<ref name=pmid23886627/> ALDOA has also been found in mitochondria.<ref name=pmid20511553/>

ALDOA is regulated by the energy metabolism substrates glucose, lactate, and glutamine.<ref name=pmid23886627/> 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.<ref name=pmid20511553/>

Clinical significanceEdit

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.<ref name=pmid24465716/>

Aldolase A deficiency is a rare, autosomal recessive disorder that is linked to hemolysis and accompanied by weakness, muscle pain, and myopathy.<ref name=pmid14615364/>