Sorbitol dehydrogenase (or SDH) is a cytosolic

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

. In humans this protein is encoded by the ''SORD''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. Sorbitol dehydrogenase is an enzyme in

carbohydrate metabolism Carbohydrate metabolism is the whole of the biochemistry, biochemical processes responsible for the metabolic anabolism, formation, catabolism, breakdown, and interconversion of carbohydrates in life, living organisms. Carbohydrates are central t ...

converting

sorbitol Sorbitol (), less commonly known as glucitol (), is a sugar alcohol with a sweet taste which the human body metabolizes slowly. It can be obtained by reduction of glucose, which changes the converted aldehyde group (−CHO) to a primary alco ...

, the

sugar alcohol Sugar alcohols (also called polyhydric alcohols, polyalcohols, alditols or glycitols) are organic compounds, typically derived from sugars, containing one hydroxyl group attached to each carbon atom. They are white, water-soluble solids that c ...

form of

glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...

, into

fructose Fructose (), or fruit sugar, is a Ketose, ketonic monosaccharide, simple sugar found in many plants, where it is often bonded to glucose to form the disaccharide sucrose. It is one of the three dietary monosaccharides, along with glucose and gal ...

. Together with

aldose reductase In enzymology, aldose reductase (or aldehyde reductase) () is an enzyme in humans encoded by the gene AKR1B1. It is an cytosolic NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monos ...

, it provides a way for the body to produce fructose from glucose without using ATP. Sorbitol dehydrogenase uses

NAD NAD or Nad may refer to: Geography * Nad, County Cork, a village in Ireland * North American Datum, a series of geographic coordinate systems * North Atlantic Drift, an Atlantic Ocean current * Hobli, a subdivision of a taluka in southern Ind ...

⁺ as a cofactor; its reaction is sorbitol + NAD⁺ → fructose + NADH + H⁺. A

zinc Zinc is a chemical element; it has symbol Zn and atomic number 30. It is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic tabl ...

ion is also involved in catalysis. Organs that use it most frequently include the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

and

seminal vesicle The seminal vesicles (also called vesicular glands or seminal glands) are a pair of convoluted tubular accessory glands that lie behind the urinary bladder of male mammals. They secrete fluid that largely composes the semen. The vesicles are 5 ...

; it is found in various organisms from

bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...

humans Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...

. A secondary use is the

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

of dietary

, though

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 A sugar substitute or artificial sweetener, is a food additive that provides a sweetness like that of sugar while containing significantly less food energy than sugar-based sweeteners, making it a zero-calorie () or low-calorie sweetener. Arti ...

Structure

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).; MolProbit
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 Alcohol dehydrogenases (ADH) () are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+) to N ...

, 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. Monomer Dimer Tetramer SDH

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 Retinopathy is any damage to the retina of the eyes, which may cause vision impairment. Retinopathy often refers to retinal vascular disease, or damage to the retina caused by abnormal blood flow. Age-related macular degeneration is technically in ...

cataract A cataract is a cloudy area in the lens (anatomy), lens of the eye that leads to a visual impairment, decrease in vision of the eye. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colours, blurry or ...

formation,

nephropathy Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipap ...

, and

peripheral neuropathy Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...

seen in diabetes are partly due to this phenomenon.

References

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