Aldolase B

Aldolase B also known as fructose-bisphosphate aldolase B or liver-type aldolase is one of three

The generic fructose bisphosphate aldolase enzyme cleaves a 6-carbon fructose sugar into two 3-carbon products in a reverse

The ΔG°’ of this reaction is +23.9 kJ/mol. Though the reaction may seem too uphill to occur, it is of note that under physiological conditions, the ΔG of the reaction falls to close to or below zero. For example, the ΔG of this reaction under physiological conditions in erythrocytes is -0.23 kJ/mol.[10]

Structure

Aldolase B is a homotetrameric enzyme, composed of four subunits with molecular weights of 36 kDa with local 222 symmetry. Each subunit has a molecular weight of 36 kDa and contains an eight-stranded α/β barrel, which encloses lysine 229 (the Schiff-base forming amino acid that is key for catalysis).^[11][12]

Isozyme specific regions

Though the majority of the overall structure of the aldolase enzyme is conserved amongst the three isozymes, four regions of the generic aldolase enzyme have been identified to be highly variable among isozymes. Such regions have been denoted isozyme-specific regions (ISR1-4). These regions are thought to give isozymes their specificities and structural differences. ISRs 1-3 are all found in exon 3 of the ALDOB gene. ISR 4 is the most variable of the four and is found at the c-terminal end of the protein.^[5]

ISRs 1-3 are found predominantly in patches on the surface of the enzyme. These patches do not overlap with the active site, indicating that ISRs may change specific isozyme substrate specificity from a distance or cause the C-terminus interactions with the active site.^[12] A recent theory suggests that ISRs may allow for different conformational dynamics in the aldolase enzyme that account for its specificity.^[13]

Physiology

Aldolase B plays a key role in

Though the mechanism aldolase B regulation is unknown, increased ALDOB gene transcription in animal livers has been noticed with an increase in dietary carbohydrates and decrease in glucagon concentration.^[15][16]

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".

Pathology

Genetic mutations leading to defects in aldolase B result in a condition called hereditary fructose intolerance. Due to the lack of functional aldolase B, organisms with HFI cannot properly process F1P, which leads to an accumulation of F1P in bodily tissues. In addition to being toxic to cellular tissues, high levels of F1P traps phosphate in an unusable form that does not return to the general phosphate pool, resulting in depletion of both phosphate and ATP stores. The lack of readily available phosphate causes the cessation of glycogenolysis in the liver, which results in hypoglycemia.^[17] This accumulation also inhibits gluconeogenesis, further reducing the amount of readily available glucose. The loss of ATP leads to a multitude of problems including inhibition of protein synthesis and hepatic and renal dysfunction. Patient prognosis, however, is good in cases of hereditary fructose intolerance. By avoiding foods containing fructose, sucrose, and sorbitol, patients can live symptom-free lives.^[14]

HFI is recessively inherited autosomal disorder. Approximately 30 mutations that cause HFI have been identified, and these combined mutations result in a HFI frequency of 1 in every 20,000 births.^[14][18] Mutant alleles are a result of a number different types of mutations including base pair substitutions and small deletions. The most common mutation is A149P, which is a guanine to cytosine transversion in exon 5, resulting in the replacement of alanine at position 149 with proline. This specific mutant allele is estimated to account for 53% of HFI alleles.^[19] Other mutations resulting in HFI are less frequent and often correlated with ancestral origins.^[20]

References