enzymology Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

, a retinol dehydrogenase (RDH) () is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

that catalyzes the

chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...

:retinol + NAD⁺

\rightleftharpoons

retinal + NADH + H⁺ Sometimes, in addition to or along with NAD⁺, NADP⁺ can act as a preferred cofactor in the reaction as well. The substrate of the enzyme can be all-''trans''- or -''cis''- retinol. There are at least over 20 different isolated enzymes with RDH activity to date. Thus, the two substrates of this enzyme are

retinol Retinol, also called vitamin A1, is a fat-soluble vitamin in the vitamin A family found in food and used as a dietary supplement. As a supplement it is used to treat and prevent vitamin A deficiency, especially that which results in xerophtha ...

and NAD⁺, whereas its 3

products Product may refer to: Business * Product (business), an item that serves as a solution to a specific consumer problem. * Product (project management), a deliverable or set of deliverables that contribute to a business solution Mathematics * Produ ...

are

retinal Retinal (also known as retinaldehyde) is a polyene chromophore. Retinal, bound to proteins called opsins, is the chemical basis of visual phototransduction, the light-detection stage of visual perception (vision). Some microorganisms use retin ...

NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...

(or NADPH in the case where NADP⁺ is a cofactor), and H⁺. This enzyme belongs to the family of

oxidoreductase In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule, the reductant, also called the electron donor, to another, the oxidant, also called the electron acceptor. This group of enzymes usually ut ...

s, specifically those acting on the CH-OH group of donor with NAD⁺ or NADP⁺ as acceptor. The

systematic name A systematic name is a name given in a systematic way to one unique group, organism, object or chemical substance, out of a specific population or collection. Systematic names are usually part of a nomenclature. A semisystematic name or semitrivial ...

of this enzyme class is retinol:NAD⁺ oxidoreductase. Other names in common use include retinol (vitamin A1) dehydrogenase, MDR, microsomal retinol dehydrogenase, all-trans retinol dehydrogenase, retinal reductase, and retinene reductase. This enzyme participates in retinol metabolism. Occasionally, the literature refers to retinol dehydrogenase as an enzyme that oxidizes retinol in general, such as class IV

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 ...

(ADH4), which reportedly is the most efficient

oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...

in the human

(ADH) family.

Structure

As one of the most important RDH, 11-''cis''-retinol dehydrogenase catalyzes the 11-''cis'' retinaldehyde (the most common visual pigments in higher animals) formation. The enzyme is mainly expressed in the

retinal pigment epithelium The pigmented layer of retina or retinal pigment epithelium (RPE) is the pigmented cell layer just outside the neurosensory retina that nourishes retinal visual cells, and is firmly attached to the underlying choroid and overlying retinal visual ce ...

( RPE) and is part of short-chain

dehydrogenase A dehydrogenase is an enzyme belonging to the group of oxidoreductases that oxidizes a substrate by reducing an electron acceptor, usually NAD+/NADP+ or a flavin coenzyme such as FAD or FMN. Like all catalysts, they catalyze reverse as well as f ...

(SDR) / reductase superfamily. The integral membrane enzyme is anchored to the

membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. B ...

s by its two

hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, th ...

chains. The

catalytic Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

domain of 11-''cis''-retinol dehydrogenase is restricted to the lumenal compartment, suggesting its origin from compartmentalized process. 11-''cis''-retinol dehydrogenase is also mainly associated to the

smooth endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

of RPE cells. The 32-kDa integral membrane protein protein (p32) was found to act as the stereospecific 11-''cis''-retinol dehydrogenase in the presence of NAD⁺ cofactor, and p32 catalyzes the

biosynthesis Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. ...

of 11-''cis'' retinal commonly found visual

chromophore A chromophore is the part of a molecule responsible for its color. The color that is seen by our eyes is the one not absorbed by the reflecting object within a certain wavelength spectrum of visible light. The chromophore is a region in the molec ...

. One of the widely studied genes of retinol dehydrogenase ''RDH12'', which encodes retinol dehydrogenase is part of the

superfamily SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilies. Domains are functional, str ...

of short-chained alcohol dehydrogenases and reductases. ''RDH12'' is mainly expressed in neuroretina and is composed of 7 exons encoding a 360-amino acid peptide.

Zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc 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 periodi ...

molecules serve as the ligand cofactor with the cofactor NAD. The retinol will interact with the enzyme at the area between those two cofactors. However, not all retinol dehydrogenases in

visual cycle The visual cycle is a process in the retina that replenishes the molecule retinal for its use in vision. Retinal is the chromophore of most visual opsins, meaning it captures the photons to begin the phototransduction cascade. When the proton i ...

are identified, and this remains challenging to scientists due to the overlapping expressions and activity redundancy among two large RDH and RDH-like producing classes: microsomal short-chain

/ reductase and

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

ic medium-chain

s. In Bovine, retinol dehydrogenase is found as a part of retinal rod outer segments and shows difficulty when separating from

. Its

Stokes radius The Stokes radius or Stokes–Einstein radius of a solute is the radius of a hard sphere that diffuses at the same rate as that solute. Named after George Gabriel Stokes, it is closely related to solute mobility, factoring in not only size but also ...

is 8.5 nm in Lubrol 12A9 mixed

micelle A micelle () or micella () (plural micelles or micellae, respectively) is an aggregate (or supramolecular assembly) of surfactant amphipathic lipid molecules dispersed in a liquid, forming a colloidal suspension (also known as associated collo ...

Function

Retinoid dehydrogenases/reductases (oxidoreductases), including retinol dehydrogenase, catalyze the key oxidation-reduction reactions in the

, converting

vitamin A Vitamin A is a fat-soluble vitamin and an essential nutrient for humans. It is a group of organic compounds that includes retinol, retinal (also known as retinaldehyde), retinoic acid, and several provitamin A carotenoids (most notably bet ...

to 11-''cis'' retinal, which is the chromophore of the rod and cone photoreceptors. It is believed that RDHs at rod and cone are different, but related and can catalyze the same reaction. RDH12 is the primary enzyme that reduces all-''trans'' retinal released from bleached photopigments during recovery phase in the

. The RDH12 enzyme can use either ''cis'' or ''trans'' retinoid isomers as substrates and can also function as both

(i.e. retinol to retinal) and reductase (i.e. retinal to retinol). The conversion of retinol to retinal is the rate-limiting step in the

retinoic acid Retinoic acid (used simplified here for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that mediates the functions of vitamin A1 required for growth and development. All-''trans''-retinoic acid is required in ...

biosynthesis. In vertebrates, the retinoic acid is the ligand that controls nuclear receptor signaling pathway, which is responsible for growth and development as well as epithelial maintenance, therefore can be used for cancer and acne treatment. In human, ADH4 can exhibit at least 10 folds higher V_max/K_m than other ADH. Visual cycle adapted v3

Some retinol dehydrogenases are in extra-

ocular Eyes are organs of the visual system. They provide living organisms with vision, the ability to receive and process visual detail, as well as enabling several photo response functions that are independent of vision. Eyes detect light and con ...

tissues, such as

human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...

retinol dehydrogenase-4 (RoDH-4), which converts retinol and 1-''cis''-retinol to different aldehydes in

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

and

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...

. It was also found that 13-''cis''-retinoic acid (isotretinoin), 3,4-didehydroretinoic acid, and 3,4-didehydroretinol can act as

competitive inhibitor Competitive inhibition is interruption of a chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for binding or bonding. Any metabolic or chemical messenger system can potentially be affected b ...

of the 3α-hydroxysteroid dehydrogenase

oxidative Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...

activity of the enzyme. This can potentially explain how

isotretinoin Isotretinoin, also known as 13-''cis''-retinoic acid and sold under the brand name Accutane among others, is a medication primarily used to treat severe acne. It is also used to prevent certain skin cancers (squamous-cell carcinoma), and in th ...

, the active ingredient is Roaccutane ( Accutane), can suppress

sebaceous gland A sebaceous gland is a microscopic exocrine gland in the skin that opens into a hair follicle to secrete an oily or waxy matter, called sebum, which lubricates the hair and skin of mammals. In humans, sebaceous glands occur in the greatest number ...

s and be used for severe acne treatment.

Disease relevance

The

missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

''rdh5'', which codes for microsomal 11-''cis''-retinol dehydrogenase (RDH5), causes fundus albipunctatus, whose

symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...

s include retinal white-spot accumulation, stationary

night blindness Nyctalopia (; ), also called night-blindness, is a condition making it difficult or impossible to see in relatively low light. It is a symptom of several eye diseases. Night blindness may exist from birth, or be caused by injury or malnutrition ( ...

caused by delay in

cone A cone is a three-dimensional geometric shape that tapers smoothly from a flat base (frequently, though not necessarily, circular) to a point called the apex or vertex. A cone is formed by a set of line segments, half-lines, or lines con ...

and rod

photopigment Photopigments are unstable pigments that undergo a chemical change when they absorb light. The term is generally applied to the non-protein chromophore moiety of photosensitive chromoproteins, such as the pigments involved in photosynthesis and p ...

regeneration Regeneration may refer to: Science and technology * Regeneration (biology), the ability to recreate lost or damaged cells, tissues, organs and limbs * Regeneration (ecology), the ability of ecosystems to regenerate biomass, using photosynthesis ...

, and elderly

cone dystrophy A cone dystrophy is an inherited ocular disorder characterized by the loss of cone cells, the photoreceptors responsible for both central and color vision. Presentation The most common symptoms of cone dystrophy are vision loss (age of onset r ...

. At least 20

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

s in ''rdh12''

, which encodes retinol dehydrogenase, can be associated to

disease A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...

s, including severe and early-onset

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

retinal dystrophy (arRD), or

Leber congenital amaurosis Leber congenital amaurosis (LCA) is a rare inherited eye disease that appears at birth or in the first few months of life. It affects about 1 in 40,000 newborns. LCA was first described by Theodor Leber in the 19th century. It should not be co ...

. Patients suffer from

and rod malfunction since

childhood A child (plural, : children) is a human being between the stages of childbirth, birth and puberty, or between the Development of the human body, developmental period of infancy and puberty. The legal definition of ''child'' generally refers ...

and develop

legal blindness Visual impairment, also known as vision impairment, is a medical definition primarily measured based on an individual's better eye visual acuity; in the absence of treatment such as correctable eyewear, assistive devices, and medical treatment� ...

when reaching

adulthood An adult is a human or other animal that has reached full growth. In human context, the term ''adult'' has meanings associated with social and legal concepts. In contrast to a " minor", a legal adult is a person who has attained the age of major ...

. This suggests that RDH12 might play a central role in the visual cycle and can be a promising

therapeutic A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis. As a rule, each therapy has indications and contraindications. There are many different ...

target. A possible mechanism of the accelerated degradation among RDH12 mutants is the

polyubiquitination Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fou ...

cytosolic The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...

ubiquitin ligase A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin ...

s and subsequent degradation by

proteosome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by whi ...

. Its conformation aberration provokes the aforementioned accelerated degradation.

References

{{Portal bar, Biology, border=no EC 1.1.1 NADH-dependent enzymes Enzymes of unknown structure