Disease relevance of SORD

• SORD is thought to be involved in the etiology of diabetic complications, and its deficiency has been linked to congenital cataracts [1].
• In a family with red cell SORD deficiency and congenital cataracts, Km values for sorbitol and NAD+ as well as the effect of the enzymatic deficiency on sorbitol accumulation in red cells incubated in high-glucose or high-fructose media were determined [2].
• Human sorbitol dehydrogenase (SDH) was expressed in Escherichia coli BL21 cells and purified using ammonium sulfate precipitation and anion-exchange and dye-affinity chromatography [3].
• Sorbitol dehydrogenase from Bacillus subtilis. Purification, characterization, and gene cloning [4].
• The results indicate that sorbitol metabolism in oral actinomyces involve oxidation of sorbitol to fructose by an inducible enzyme, nicotinamide adenine dinucleotide-linked sorbitol dehydrogenase [5].

High impact information on SORD

• Sorbitol dehydrogenase activity was reduced in silenced fruit, but activities of neutral invertase, vacuolar invertase, cell wall-bound invertase, fructose kinase, and hexokinase were unaffected [6].
• The glutathione redox couple modulates zinc transfer from metallothionein to zinc-depleted sorbitol dehydrogenase [7].
• Enzymes with related structures (for example, sorbitol dehydrogenase and alcohol dehydrogenase, and possibly, aldehyde reductase and aldose reductase, respectively) are linked functionally by this scheme [8].
• In contrast, dose-dependent necrosis of periportal regions of the liver and increases in plasma levels of lactate dehydrogenase, sorbitol dehydrogenase and SGOT were observed in plasma from alcohol dehydrogenase-positive deermice (AdhF) 24 hr following administration of allyl alcohol (21 to 84 mg per kg) [9].
• Aldose reductase and sorbitol dehydrogenase protein levels in the patients with diabetic nephropathy were significantly increased in PBMCs cultured in high-glucose conditions [10].

Chemical compound and disease context of SORD

• Conclusion: Determination of galactose metabolising enzymes, sorbitol dehydrogenase and polyols in lenses may help in understanding the mechanism of formation of inexplicable congenital cataracts [11].

Biological context of SORD

• The deduced amino acid sequence of the SORD structure differs at a few positions from the directly determined protein sequence, suggesting allelic forms of the enzyme [12].
• The SORD gene was mapped by fluorescence in situ hybridization and found to occupy a single site on chromosome 15q15, indicating that it is a single-copy gene [1].
• The gene structure of SORD spans approximately 30 kb divided into 9 exons and 8 introns [12].
• Marmoset SORD, which appears to be a single gene in this species, shows significantly less homology with either SORD1 or SORD2 than they do with each other, suggesting that the human homologs represent a recent gene duplication event [13].
• However, knowledge of the presence of this highly similar sequence in the human genome is essential to ensure that sequence variations identified during genetic analysis of SORD are not attributed to polymorphisms within that gene itself [14].

Anatomical context of SORD

• Membrane-bound and soluble forms of erythrocyte sorbitol dehydrogenase (SORD) activity are compared in normal individuals [2].
• These findings can be explained either by the presence of two alleles at a different SORD locus determining the enzyme in seminal plasma or by the formation of secondary isozymes [15].
• Sorbitol dehydrogenase was below the detectable limit in pericytes and endothelial cells [16].
• We report here a novel sorbitol dehydrogenase inhibitor, 16, that shows very high oral potency (50 microg/kg) in normalizing elevated fructose levels in the sciatic nerve of chronically diabetic rats and sustained duration of action (>24 h) [17].
• In isolated hepatocytes in suspension, the effect of sorbitol but not that of fructose to increase the concentration of fructose 1-phosphate and to stimulate glucokinase was abolished by 2-hydroxymethyl-4-(4-N,N-dimethylamino-1-piperazino)-pyrimidine (SDI 158), an inhibitor of sorbitol dehydrogenase [18].

Associations of SORD with chemical compounds

• Linkage group 3 comprises PEP-B (peptidase B), MPI-1 (mannosephosphate isomerase), SORD (sorbitol dehydrogenase), and mIDH-2 (mitochondrial isocitrate dehydrogenase) [19].
• The mutation responsible for SORD deficiency did not modify the Km for sorbitol and NAD+ [2].
• In SORD-deficient patients, the enzymatic deficiency was observed in both crude haemolysate and SORD-M preparations with sorbitol, galactitol, xylitol or ribitol as substrates [2].
• The polyol pathway comprises the enzymes aldose reductase and sorbitol dehydrogenase which convert glucose to fructose via sorbitol [14].
• Purified SDH was crystallized from polyethylene glycol solutions using the hanging-drop vapour-diffusion method [3].

Physical interactions of SORD

• This study reports a molecular modelling investigation of human sorbitol dehydrogenase complexed with the substrate sorbitol and the inhibitor WAY135 706 based on the structures of human beta3 alcohol dehydrogenase, human sigma alcohol dehydrogenase and horse liver alcohol dehydrogenase [20].

Other interactions of SORD

• The related alcohol dehydrogenases and zeta-crystallin have the same gene organization split by 8 introns, but no splice points coincide between SORD and these gene types [12].
• It has also been suggested that polymorphism in either the aldose reductase or sorbitol dehydrogenase genes might contribute to sorbitol accumulation [14].
• Aldose reductase, sorbitol dehydrogenase, and glucose-6-phosphate dehydrogenase enzyme activities were studied in human foetal brain and liver at different periods of gestation [21].
• For hepatocellular evaluation, measurement of a minimum of two scientifically appropriate blood tests is recommended, e.g., alanine aminotransferase, aspartate aminotransferase, sorbitol dehydrogenase, glutamate dehydrogenase, or total bile acids [22].
• Chromatographic assays involving estrogen receptor-beta, sorbitol dehydrogenase, human alpha-thrombin, cholera toxin B subunit, beta-galactosidase, and Griffonia simplicifolia isolectin B(4) were established in microaffinity columns and operated in frontal analysis mode [23].

Analytical, diagnostic and therapeutic context of SORD

• High levels of SORD transcripts were observed in lens and kidney, as judged from Northern blot analysis [12].
• Detailed sequence analysis suggests that this SORD-related gene cannot be expressed as a full-length sorbitol dehydrogenase isoenzyme [14].
• This is the first crystallization report of human sorbitol dehydrogenase [3].
• Cloning of the sorbitol dehydrogenase gene (gutB) from Bacillus subtilis offers an excellent system for studying zinc binding, substrate specificity, and catalytic mechanism of this enzyme through protein engineering [4].
• Western blotting was used to measure aldose reductase and sorbitol dehydrogenase protein levels [10].

References