Sorbitol dehydrogenase

The structure of human sorbitol dehydrogenase was determined through crystallization experiments and X-ray diffraction (with a resolution of 2.20 Å). The method used for crystallization was “Vapor Diffusion, Hanging Drop” at pH 6.2 and at a temperature of 295.0 K. Sorbitol dehydrogenase consists of four identical chains (A, B, C, D), each of which being 31% helical (14 helices) and 26% beta sheet (23 strands). MolProbity Ramachandran analysis was conducted by Lovell, Davis, et al. The results were that 97.1% of all residues were in favored regions and 100.0% of all residues were in allowed regions, with no outliers. All four chains have 356 residues each and a catalytic site. The catalytic sites contain both a serine and a histidine residue, which are hydrophilic sidechains. The residues require NAD+ and a zinc ion to be present for catalytic activity. Sorbitol dehydrogenase belongs to the oxidoreductase family, which means that it helps catalyze oxidation reduction reactions. As stated above, the enzyme helps in the pathway of converting glucose into fructose. ==Subunit interactions in SDH==

The interactions between subunits forming a tetramer in SDH is determined by non-covalent interaction. These non-covalent interactions consists of a hydrophobic effect, hydrogen bonds, and electrostatic interactions between the four identical subunits. For homotetrameric proteins such as SDH, the structure is believed to have evolved going from a monomeric to a dimeric and finally toward a tetrameric structure in evolution. The SDH proteins have a close evolutionary relationship with alcohol dehydrogenase, which also belongs to the protein superfamily of medium-chain dehydrogenase/reductase enzymes (MDRs). Mammalian ADHs are all dimeric enzymes but certain bacterial ADHs also share a tetrameric quaternary structure. SDH from silver leaf whitefly and that from yeast ADH1 both lack a structural zinc site and share a tetrameric quaternary structure, thus showing a close evolutionary relationship from a structural viewpoint between the two classes of proteins (ADH and SDH). The general binding process in SDH is described by the gain in free energy, which can be determined from the rate of association and dissociation between subunits. A hydrogen-bonding network between subunits has been shown to be important for the stability of the tetrameric quaternary protein structure. For example, a study of SDH that used diverse methods such as protein sequence alignments, structural comparisons, energy calculations, gelfiltration experiments, and enzyme kinetics experiments could reveal an important hydrogen-bonding network that stabilizes the tetrameric quaternary structure in mammalian SDH. ==Clinical significance==

In tissues where sorbitol dehydrogenase is low or absent, such as in the retina, lens, kidney, and nerve cells, sorbitol can accumulate under conditions of hyperglycemia. In uncontrolled diabetes, large amounts of glucose enter these tissues and is then converted to sorbitol by aldose reductase. Sorbitol then accumulates, causing water to be drawn into the cell due to the increased osmotic pressure, impairing tissue function. Retinopathy, cataract formation, nephropathy, and peripheral neuropathy seen in diabetes are partly due to this phenomenon. ==References==