Retinoic acid (used simplified here for all-''trans''-retinoic acid) is a

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

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 ...

₁ (all-''trans''-

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 ...

) that mediates the functions of vitamin A₁ required for growth and development. All-''trans''-retinoic acid is required in

chordate A chordate () is an animal of the phylum Chordata (). All chordates possess, at some point during their larval or adult stages, five synapomorphies, or primary physical characteristics, that distinguish them from all the other taxa. These fiv ...

animals, which includes all higher animals from fish to humans. During early

embryonic development An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...

, all-''trans''-retinoic acid generated in a specific region of the embryo helps determine position along the embryonic anterior/posterior axis by serving as an

intercellular signaling In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...

molecule that guides development of the posterior portion of the embryo. It acts through

Hox gene Hox genes, a subset of homeobox genes, are a group of related genes that specify regions of the body plan of an embryo along the head-tail axis of animals. Hox proteins encode and specify the characteristics of 'position', ensuring that the cor ...

s, which ultimately control anterior/posterior patterning in early developmental stages. All-''trans''-retinoic acid (ATRA) is the major occurring retinoic acid, while isomers like 13-''cis''- and 9-''cis''-retinoic acid are also present in much lower levels. The key role of all-''trans''-retinoic acid in embryonic development mediates the high

teratogenicity Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The related t ...

of retinoid pharmaceuticals, such as

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 ...

(13-''cis''-retinoic acid) used for treatment of cancer and

acne Acne, also known as ''acne vulgaris'', is a long-term Cutaneous condition, skin condition that occurs when Keratinocyte, dead skin cells and Sebum, oil from the skin clog hair follicles. Typical features of the condition include comedo, black ...

. Oral megadoses of preformed vitamin A (

retinyl palmitate Retinyl palmitate, or vitamin A palmitate, is the ester of retinol (vitamin A) and palmitic acid, with formula C36H60O2. It is the most abundant form of vitamin A storage in animals. An alternate spelling, retinol palmitate, which violates the - ...

), and all-''trans''-retinoic acid itself, also have teratogenic potential by this same mechanism.

Mechanism of biological action

All-''trans''-retinoic acid acts by binding to the

retinoic acid receptor The retinoic acid receptor (RAR) is a type of nuclear receptor which can also act as a ligand-activated transcription factor that is activated by both all-trans retinoic acid and 9-cis retinoic acid the retinoid active derivatives of Vitamin A ...

(RAR), which is bound to DNA as a heterodimer with the

retinoid X receptor The retinoid X receptor (RXR) is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9-''cis''-13,14-dihydroretinoic acid, which is likely to be the major e ...

(RXR) in regions called retinoic acid response elements (RAREs). Binding of the all-''trans''-retinoic acid ligand to RAR alters the conformation of the RAR, which affects the binding of other proteins that either induce or repress

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

of a nearby gene (including Hox genes and several other target genes). RARs mediate transcription of different sets of genes controlling differentiation of a variety of cell types, thus the target genes regulated depend upon the target cells. In some cells, one of the target genes is the gene for the retinoic acid receptor itself ( RAR-beta in mammals), which amplifies the response. Control of retinoic acid levels is maintained by a suite of proteins that control synthesis and degradation of retinoic acid. The molecular basis for the interaction between all-''trans''-retinoic acid and the Hox genes has been studied by using deletion analysis in

transgenic mice A genetically modified mouse or genetically engineered mouse model (GEMM) is a mouse (''Mus musculus'') that has had its genome altered through the use of genetic engineering techniques. Genetically modified mice are commonly used for research or ...

carrying constructs of GFP reporter genes. Such studies have identified functional RAREs within flanking sequences of some of the most 3′ Hox genes (including Hoxa1, Hoxb1, Hoxb4, Hoxd4), suggesting a direct interaction between the genes and retinoic acid. These types of studies strongly support the normal roles of retinoids in patterning vertebrate embryogenesis through the Hox genes.

Biosynthesis

All''-trans''-retinoic acid can be produced in the body by two sequential oxidation steps that convert all-''trans''-retinol to

retinaldehyde 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 ...

to all-''trans''-retinoic acid, but once produced it cannot be reduced again to all-''trans''-retinol. The enzymes that generate retinoic acid for

regulation of gene expression Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA). Sophisticated programs of gene expression are wide ...

include

retinol dehydrogenase In enzymology, a retinol dehydrogenase (RDH) () is an enzyme that catalyzes the chemical reaction :retinol + NAD+ \rightleftharpoons retinal + NADH + H+ Sometimes, in addition to or along with NAD+, NADP+ can act as a preferred cofactor in the ...

(Rdh10) that metabolizes retinol to retinaldehyde, and three types of

retinaldehyde dehydrogenase In enzymology, a retinal dehydrogenase, also known as retinaldehyde dehydrogenase (RALDH), catalyzes the chemical reaction converting retinal to retinoic acid. This enzyme belongs to the family of oxidoreductases, specifically the class acting on ...

, i.e.

ALDH1A1 Aldehyde dehydrogenase 1 family, member A1, also known as ALDH1A1 or retinaldehyde dehydrogenase 1 (RALDH1), is an enzyme that is encoded by the ''ALDH1A1'' gene. Function This protein belongs to the aldehyde dehydrogenases family of proteins ...

(RALDH1),

ALDH1A2 Aldehyde dehydrogenase 1 family, member A2, also known as ALDH1A2 or retinaldehyde dehydrogenase 2 (RALDH2), is an enzyme that in humans is encoded by the ''ALDH1A2'' gene. This protein belongs to the aldehyde dehydrogenase family of proteins. Th ...

(RALDH2), and

ALDH1A3 Aldehyde dehydrogenase 1 family, member A3, also known as ALDH1A3 or retinaldehyde dehydrogenase 3 (RALDH3), is an enzyme that in humans is encoded by the ''ALDH1A3'' gene, Function Aldehyde dehydrogenase isozymes are thought to play a major r ...

(RALDH3) that metabolize retinaldehyde to retinoic acid. Enzymes that metabolize excess all-''trans''-retinol to prevent toxicity include

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 ...

and

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

(cyp26).

Function in the absence of precursors

All''-trans''-retinoic acid is responsible for most of the activity of vitamin A₁, save visual pigment effects that require

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 ...

(retinaldehyde), and cell metabolism effects that may require

itself. Also, some biochemical functions necessary for fertility in vitamin A deficient male and female mammals originally appeared to require all-''trans''-retinol for rescue, but this is due to a requirement for local conversion of all-''trans''-retinol to all-''trans''-retinoic acid, as administered all-''trans''-retinoic acid does not reach some critical tissues unless given in high amounts. Thus, if animals are fed only all-''trans''-retinoic acid but no vitamin A₁ (all-''trans''-retinol or retinal), they suffer none of the growth-stunting or epithelial-damaging effects of lack of vitamin A₁ (including no

xerophthalmia Xerophthalmia (from Ancient Greek "xērós" (ξηρός) meaning "dry" and "ophthalmos" (οφθαλμός) meaning "eye") is a medical condition in which the eye fails to produce tears. It may be caused by vitamin A deficiency, which is someti ...

—dryness of the cornea). They do suffer retina degeneration and blindness, due to retinal deficiency. In addition, vitamin A₁-deprived but all-''trans''-retinoic acid-supplemented male rats exhibit

hypogonadism Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estrogen ...

and

infertility Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal state ...

due to lack of local retinoic acid synthesis in the testis; similar treatment of female rats causes infertility due to

fetal resorption Fetal resorption (also known as fetus resorption) is the disintegration and assimilation of one or more fetuses in the uterus at any stage after the completion of organogenesis, which, in humans, is after the ninth week of gestation. Before organog ...

caused by a lack of local retinoic acid synthesis in the embryo. The retinoic acid synthesis in testes is catalyzed primarily by the ALDH1A2 (RALDH2) aldehyde dehydrogenase. Suppressing this enzyme has been proposed as a possible way to make a male contraceptive pill, because retinoic acid is necessary for

spermatogenesis Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubule ...

in humans, much as in rats.

Function in embryonic development

Al-''trans''-retinoic acid (ATRA) is a

morphogen A morphogen is a substance whose non-uniform distribution governs the pattern of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental biology, establishing positions of the various ...

signaling molecule, which means it is concentration dependent; malformations can arise when the concentration of ATRA is in excess or deficient. Other molecules that interact with ATRA are

FGF8 Fibroblast growth factor 8 (FGF-8) is a protein that in humans is encoded by the ''FGF8'' gene. Function The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and ...

Cdx The Cdx gene family, also called caudal genes, are a group of genes found in many animal genomes. Cdx genes contain a homeobox DNA sequence and code for proteins that act as transcription factors. The gene after which the gene family is named (the ...

and Hox genes, all participating in the development of various structures within the embryo. For example, ATRA plays an important role in activating Hox genes required for

hindbrain The hindbrain or rhombencephalon or lower brain is a developmental categorization of portions of the central nervous system in vertebrates. It includes the medulla, pons, and cerebellum. Together they support vital bodily processes. Metencephalo ...

development. The hindbrain, which later differentiates into the

brain stem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is conti ...

, serves as a major signaling center defining the border of the head and trunk. A double-sided retinoic acid gradient, that is high in the trunk and low at the junction with the head and tail, represses FGF8 in the developing trunk to allow normal

somitogenesis Somitogenesis is the process by which somites form. Somites are bilaterally paired blocks of paraxial mesoderm that form along the anterior-posterior axis of the developing embryo in segmented animals. In vertebrates, somites give rise to skeleta ...

, forelimb bud initiation, and formation of the atria in the heart. During exposure to excess ATRA, the hindbrain becomes enlarged, hindering the growth of other parts of the brain; other developmental abnormalities that can occur during excess ATRA are missing or fused

somites The somites (outdated term: primitive segments) are a set of bilaterally paired blocks of paraxial mesoderm that form in the embryonic stage of somitogenesis, along the head-to-tail axis in segmented animals. In vertebrates, somites subdivide in ...

, and problems with the aorta and large vessels within the heart. With an accumulation of these malformations, an individual can be diagnosed with

DiGeorge syndrome DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent in ...

. However, since ATRA partakes in various developmental processes, abnormalities associated with loss of ATRA are not just limited to sites associated with DiGeorge syndrome. Retinoic acid is essential throughout an individual's lifetime, but it is most critical during pregnancy. Without the proper concentrations of ATRA, severe abnormalities can be present and even fatal to the growing fetus. Genetic loss-of-function studies in mouse and zebrafish embryos that eliminate ATRA synthesis or ATRA receptors (RARs) have revealed abnormal development of the somites, forelimb buds, heart, hindbrain, spinal cord, eye, forebrain basal ganglia, kidney, foregut

endoderm Endoderm is the innermost of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer). Cells migrating inward along the archenteron form the inner layer of the gast ...

, etc.

Related pharmaceuticals

Tretinoin Tretinoin, also known as all-''trans'' retinoic acid (ATRA), is a medication used for the treatment of acne and acute promyelocytic leukemia. For acne, it is applied to the skin as a cream, gel or ointment. For leukemia, it is taken by mouth f ...

/ all-trans-retinoic acid (Tradename: Retin-A) *

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 ...

/ 13-cis-retinoic acid (Tradename: Accutane(US), Roaccutane)

References

External links

Retinoic acid bound to proteins
in the PDB {{Retinoid receptor modulators Carboxylic acids Cell communication Cell signaling Apocarotenoids Cyclohexenes