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. Four ALDOC-specific residues (N90, V92, R96 and D100) may be key for ALDOC-specific functions.
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. As an aldolase, ALDOC putatively also contributes to other "moonlighting" functions, though its exact involvements remain unclear. For instance, it binds less tightly to the cytoskeleton than the other isozymes do, likely due to its more acidicpI. In addition, ALDOC participates in the stress-response pathway for lung epithelial cell function during hypoxia and in the resistance of cerebellarPurkinje cells against excitotoxic insult.
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
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
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^Slemmer JE, Haasdijk ED, Engel DC, Plesnila N, Weber JT (August 2007). "Aldolase C-positive cerebellar Purkinje cells are resistant to delayed death after cerebral trauma and AMPA-mediated excitotoxicity". The European Journal of Neuroscience. 26 (3): 649–56. doi:10.1111/j.1460-9568.2007.05708.x. PMID17686042. S2CID46706309.
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^Martins-de-Souza D, Schmitt A, Röder R, Lebar M, Schneider-Axmann T, Falkai P, Turck CW (October 2010). "Sex-specific proteome differences in the anterior cingulate cortex of schizophrenia". Journal of Psychiatric Research. 44 (14): 989–91. doi:10.1016/j.jpsychires.2010.03.003. PMID20381070.
Rocchi M, Vitale E, Covone A, Romeo G, Santamaria R, Buono P, Paolella G, Salvatore F (June 1989). "Assignment of human aldolase C gene to chromosome 17, region cen----q21.1". Human Genetics. 82 (3): 279–82. doi:10.1007/BF00291170. PMID2731939. S2CID7980799.
Rottmann WH, Deselms KR, Niclas J, Camerato T, Holman PS, Green CJ, Tolan DR (February 1987). "The complete amino acid sequence of the human aldolase C isozyme derived from genomic clones". Biochimie. 69 (2): 137–45. doi:10.1016/0300-9084(87)90246-X. PMID3105602.
Kim JH, Lee S, Kim JH, Lee TG, Hirata M, Suh PG, Ryu SH (March 2002). "Phospholipase D2 directly interacts with aldolase via Its PH domain". Biochemistry. 41 (10): 3414–21. doi:10.1021/bi015700a. PMID11876650.