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]
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).
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 magnesiumions in place of the lysine.
The reaction mechanism of aldolase.
The enzyme's reactive site amino acid's side-chains are shown in blue.
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 ATPbiosynthesis. ALDOA also contributes to other "moonlighting" functions such as muscle maintenance, regulation of cell shape and motility, striated musclecontraction, actincytoskeleton 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 kinasesAKT 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.
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