Aldolase C

Structure

ALDOC is one of the three aldolase isozymes (A, B, and C), encoded by three different genes. The amino acid sequence of ALDOC is highly similar to those of the other isozymes, sharing a 68% identity with ALDOB and 78% identity with ALDOA. In particular, the residues Asp33, Arg42, Lys107, Lys146, Glu187, Ser271, Arg303, and Lys229 are all conserved in the active sites of the three isozymes. This active site is located in the center of the homotetrameric αβ-barrel structure of these aldolases. However, several structural details set ALDOC apart. For instance, the Arg303 residue in ALDOC adopts an intermediate conformation between the liganded and unliganded structures observed in the other isozymes. Also, the C-terminal region between Glu332 and Lys71 forms a salt bridge with the barrel region that is absent in the A and B isoforms. Moreover, the electrostatic surface of ALDOC is more negatively charged, which may serve as an acidic binding site or as a docking site to accommodate the C-terminal conformations.

Function

ALDOC 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 (G3P), or glyceraldehyde, and dihydroxyacetone phosphate (DHAP) by aldol cleavage. As a result, it is a crucial player in ATP biosynthesis.

ALDOC is ubiquitously expressed in most tissues, though it is predominantly expressed in brain, smooth muscle, and neuronal tissue. However, since the ALDOA isoform is co-expressed with ALDOC in the central nervous system (CS), it is suggested that ALDOC contributes to CNS function outside of glycolysis. Moreover, its presence within other cell types, such as platelets and mast cells (MCs), may serve as a failsafe in the case that the other predominant aldolase isozymes become inactivated. Within cells, it localizes to the cytoplasm.

Clinical significance

This aldolase has been associated with cancer.

ALDOC is found to be upregulated in the brains of schizophrenia (SCZ) patients. Notably, while ALDOC is differentially expressed in the anterior cingulate cortex (ACC) of male SCZ patients, it displays no significant changes in female SCZ patients, indicating that different regulatory mechanisms may be involved in male versus female SCZ patients. It is likely that ALDOC is involved in SCZ through its role in glycolysis, which is a central biochemical pathway in SCZ.

Furthermore, ALDOC is reported to undergo oxidation in brains affected by mild cognitive impairment (MCI) and Alzheimer's disease (AD). This oxidative modification inhibits ALDOC activity, causing the accumulation of fructose 1,6- bisphosphate and driving the reverse reaction, in the direction of gluconeogenesis rather than glycolysis, thus halting ATP production.

Interactive pathway map

References

References

1. "Entrez Gene: ALDOC aldolase C, fructose-bisphosphate".
2. (June 1989). "Assignment of human aldolase C gene to chromosome 17, region cen----q21.1". Human Genetics.
3. (2014). "Fructose-bisphosphate aldolase a is a potential metastasis-associated marker of lung squamous cell carcinoma and promotes lung cell tumorigenesis and migration". PLOS ONE.
4. (December 2004). "Structure of human brain fructose 1,6-(bis)phosphate aldolase: linking isozyme structure with function". Protein Science.
5. (2014). "A novel anti-aldolase C antibody specifically interacts with residues 85-102 of the protein". mAbs.
6. (December 2013). "Nuclear localization of aldolase A correlates with cell proliferation". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research.
7. (July 2009). "Proteomic analysis of dorsolateral prefrontal cortex indicates the involvement of cytoskeleton, oligodendrocyte, energy metabolism and new potential markers in schizophrenia". Journal of Psychiatric Research.
8. (October 2010). "Sex-specific proteome differences in the anterior cingulate cortex of schizophrenia". Journal of Psychiatric Research.
9. (March 2010). "Redox proteomic analysis of carbonylated brain proteins in mild cognitive impairment and early Alzheimer's disease". Antioxidants & Redox Signaling.