Sorbitol dehydrogenase
| sorbitol dehydrogenase | |||||||
|---|---|---|---|---|---|---|---|
 Sorbitol dehydrogenase tetramer, Human | |||||||
| Identifiers | |||||||
| Symbol | SORD | ||||||
| NCBI gene | 6652 | ||||||
| HGNC | 11184 | ||||||
| OMIM | 182500 | ||||||
| RefSeq | NM_003104 | ||||||
| UniProt | Q00796 | ||||||
| Other data | |||||||
| EC number | 1.1.1.14 | ||||||
| Locus | Chr. 15 q15-q21.1 | ||||||
| |||||||
Sorbitol dehydrogenase (or SDH) is a cytosolic enzyme. In humans this protein is encoded by the SORD gene.[1]
Sorbitol dehydrogenase is an enzyme in carbohydrate metabolism converting sorbitol, the sugar alcohol form of glucose, into fructose.[2] Together with aldose reductase, it provides a way for the body to produce fructose from glucose without using ATP. Sorbitol dehydrogenase uses NAD+ as a cofactor; its reaction is sorbitol + NAD+ → fructose + NADH + H+. A zinc ion is also involved in catalysis. Organs that use it most frequently include the liver and seminal vesicle; it is found in various organisms from bacteria to humans. A secondary use is the metabolism of dietary sorbitol, though sorbitol is known not to be absorbed as well in the intestine as its related compounds glucose and fructose, and is usually found in quite small amounts in the diet (except when used as an artificial sweetener).
Structure
[edit]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).[3] 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.[4] 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.[3]
Subunit interactions in SDH
[edit]The interactions between subunits forming a tetramer in SDH is determined by non-covalent interaction.[5] 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).[5]
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.[5]
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.[5]
Clinical significance
[edit]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.[6]
References
[edit]- ^ Iwata T, Popescu NC, Zimonjic DB, Karlsson C, Höög JO, Vaca G, Rodriguez IR, Carper D (March 1995). "Structural organization of the human sorbitol dehydrogenase gene (SORD)". Genomics. 26 (1): 55–62. doi:10.1016/0888-7543(95)80082-W. PMID 7782086.
- ^ El-Kabbani O, Darmanin C, Chung RP (February 2004). "Sorbitol dehydrogenase: structure, function and ligand design". Curr. Med. Chem. 11 (4): 465–76. doi:10.2174/0929867043455927. PMID 14965227. Archived from the original on April 14, 2013.
{{cite journal}}: CS1 maint: unfit URL (link) - ^ a b PDB: 1pl7; Pauly TA, Ekstrom JL, Beebe DA, Chrunyk B, Cunningham D, Griffor M, Kamath A, Lee SE, Madura R, Mcguire D, Subashi T, Wasilko D, Watts P, Mylari BL, Oates PJ, Adams PD, Rath VL (September 2003). "X-ray crystallographic and kinetic studies of human sorbitol dehydrogenase". Structure. 11 (9): 1071–85. doi:10.1016/S0969-2126(03)00167-9. PMID 12962626.
- ^ Lovell D, et al. (2003). "Ramachandran Plot" (PDF). Proteins. 50 (3): 437–450. doi:10.1002/prot.10286. PMID 12557186. S2CID 8358424.
- ^ a b c d Hellgren M, Kaiser C, de Haij S, Norberg A, Höög JO (2007). "A hydrogen-bonding network in mammalian sorbitol dehydrogenase stabilizes the tetrameric state and is essential for the catalytic power". Cell. Mol. Life Sci. 64 (23): 3129–3138. doi:10.1007/s00018-007-7318-1. PMC 11136444. PMID 17952367. S2CID 22090973.
- ^ Harvey, Richard; Ferrier, Denise (2011). Lippincott's Illustrated Reviews: Biochemistry Fifth Edition. Lippincott Williams & Wilkins. p. 140. ISBN 9781608314126.
