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Structure of human brain fructose 1,6-(bis)phosphate aldolase: Linking isozyme structure with function

¹ Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts 02118-2394, USA
² Department of Biology, Boston University, Boston, Massachusetts 02215, USA
³ Department of Pharmacology, University of South Alabama, Mobile, Alabama 36688, USA

(RECEIVED June 8, 2004; FINAL REVISION August 20, 2004; ACCEPTED August 20, 2004)

Fructose-1,6-(bis)phosphate aldolase is a ubiquitous enzyme that catalyzes the reversible aldol cleavage of fructose-1,6-(bis)phosphate and fructose 1-phosphate to dihydroxyacetone phosphate and either glyceral-dehyde-3-phosphate or glyceraldehyde, respectively. Vertebrate aldolases exist as three isozymes with different tissue distributions and kinetics: aldolase A (muscle and red blood cell), aldolase B (liver, kidney, and small intestine), and aldolase C (brain and neuronal tissue). The structures of human aldolases A and B are known and herein we report the first structure of the human aldolase C, solved by X-ray crystallography at 3.0 Å resolution. Structural differences between the isozymes were expected to account for isozyme-specific activity. However, the structures of isozymes A, B, and C are the same in their overall fold and active site structure. The subtle changes observed in active site residues Arg42, Lys146, and Arg303 are insufficient to completely account for the tissue-specific isozymic differences. Consequently, the structural analysis has been extended to the isozyme-specific residues (ISRs), those residues conserved among paralogs. A complete analysis of the ISRs in the context of this structure demonstrates that in several cases an amino acid residue that is conserved among aldolase C orthologs prevents an interaction that occurs in paralogs. In addition, the structure confirms the clustering of ISRs into discrete patches on the surface and reveals the existence in aldolase C of a patch of electronegative residues localized near the C terminus. Together, these structural changes highlight the differences required for the tissue and kinetic specificity among aldolase isozymes.

Keywords: isozyme specificity; structural enzymology; protein–protein interactions; isozyme-specific residues; structure/function

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.04915904.

Reprint requests to: Karen N. Allen, Department of Physiology and Biophysics, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118-2394, USA; e-mail: allen{at}med-xtal.bu.edu; fax: (617) 638-4273; or Dean R. Tolan, Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215, USA; e-mail: tolan{at}bu.edu; fax: (617) 358-0338.

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