9.1.2 Cutaneous Biochemistry

Review:
2021

C.C. Zouboulis, Dessau

Biochemistry of the Epidermis

Keratin intermediate filament (KIF): Keratinocytes contain KIF that are fashioned into filament collections (tonofilaments) to construct the cytoskeleton. The different epidermal layers contain varying amounts of keratin (K); ranging from 30% in the stratum basale to 80% in the stratum corneum. Ks occur in acidic (type I)-neutral/basic (type II) pairs with more important among them

  • K5 and K14, associated with normal cell proliferation
  • K6 and K16, associated with with hyperproliferation in the epidermis
  • K1 and K10 as well as K2 and K11 indicative of terminal keratinocyte differentiation (maturation).
  • Some Ks such as K7 or K20 stain specific cells like Merkel cells or other benign clear cells or tumor cells (extramammary Paget's disease).

 

Keratinocyte differentiation: Major proteins involved in keratinocyte differentiation include involucrin, transglutaminase (TGase) and integrins, which lead to keratinocyte detachment from the basement membrane and interruption of proliferation. The transition of keratinocytes from the stratum spinosum to stratum granulosum is mediated by protein kinase C and the induction of the late differentiation markers loricrin and profilaggrin. Stratum granulosum keratinocytes contain protein- and lipid-rich granules (keratohyalin granules). Profilaggrin-containing granules mature to filaggrin (Odland granules), which contain  lipids that form the sheets of the epidermal permeability barrier (EPB). EPB function in human epidermis depends on TGase-mediated cross-linking of structural proteins and lipids during the terminal stages of keratinocyte differentiation. Several mutations in genes that encode for the EPB structural components can result in skin diseases.

 

EPB quality also depends on the presence of epidermal lipids, whereas abnormalities in the following lipids induced disease:

  • ceramides, dominant in atopic dermatitis
  • cholesterol (50% of stratum corneum lipids), dominant in aged and photo-aged skin
  • free fatty acids, dominant in psoriasis

 

EPB repair may be initiated by loss of its regulators Ca2+ and K+. There is a 4-fold increase in extracellular Ca2+ from basal layer to stratum corneum.

 

Topical application of solvents to the skin removes lipids from the stratum corneum and increases trans-epidermal water loss (TEWL) (Please also see chapters aging skin, dry skin, infantile skin), followed by induction of a rapid barrier repair through epidermal metabolic changes.

 

Skin fatty acids: The permeability of human skin is largely based on the quality and quantity of the lamellar lipids packed between corneocytes and forming the cornified envelope. Both the epidermal cell membranes and the corneocyte layers contain endogenous fatty acids.

 

Modification of skin fatty acids can lead to disease, like atopic dermatitis. Photo-aged and intrinsically aged epidermis exhibit abnormal EPB homeostasis.

 

Epidermal fatty acids can also derive from the diet. Diet fatty acids (polyunsaturated fatty acids -PUFA) can be actively metabolized by the skin. PUFA-deficient diets (e.g. linoleic acid) can result in both increased TEWL and scaly skin.

 

Skin absorption of xenobiotics: Xenobiotics are  chemical substances foreign to the biological system (natural compounds, drugs, environmental agents), which can be transported across the stratum corneum in a controlled manner based on their physicochemical traits (partition, diffusion and solubility). The skin is constantly exposed to xenobiotics by  occupational, environmental, therapeutic and systemic exposure.

 

Skin-own metabolizing enzymes, like cytochrome P450 (CYP), are involved in their percutaneous penetration. Specially relevant to the skin is the role of CYPs in mediating photosensitivity, and reactions to drugs.

 

Keratinocyte differentiation can be modulated by hormones (thyroid hormone and steroid hormones), vitamins (vitamin D3, retinoic acid, vitamin A/retinol from diet) and electrolytes (mostly calcium and potassium).

 

Defensins - refer to the chapter on Microbiology and Immunology.

 

Biochemistry of the Dermis

The main cell type of the dermis is the fibroblast that produces and degrades extracellular matrix (ECM) components.

 

Collagens are the principal ECM component (90% of total dermal proteins), accounting for about 75% of skin total dry weight. At least 25 collagens exist, half are present in skin:

  • collagen type I (85–90%)
  •  collagen type III (8–11%
  • collagen type V (2–4%)
  • Collagen type VII forms part of the so-called anchoring fibrils that attach the basement membrane to the ECM of the upper dermis
  • Collagen type XVII contributes to the so-called anchoring filaments that link the basal keratinocytes with the basement membrane

 

Collagen abnormalities lead to several scarring or fibrotic diseases, such as congenital bullous diseases, scleroderma and collagenoma.

 

Collagen biosynthesis involves the synthesis of procollagen polypeptides followed by both their intracellular and extracellular processing to generate a mature and functional collagen fiber.

 

Elasticity of skin: The other major ECM fibrous protein is elastin, which is produced by fibroblasts and provides the skin with its elasticity. Elastin is stretchable by more than its full resting length. Elastin is included in an amorphous portion. Elastin changes lead to both genetic and acquired diseases of the skin (cutis laxa and actinic elastosis).

 

Extrafibrillar matrix: Extrafibrillar matrix, the dermal material lying outside the cells, not consisting of either collagen or elastic fibers, is an amorphous and hydroscopic material consisting of proteoglycans, glycoproteins, water and hyaluronic acid (mucopolysaccharoidosis).

 

Biochemistry of Adnexal Structures

Eccrine sweat glands: They produce a watery perspiration that serves principally to cool and maintain the body core temperature at 37.5°C. At maximal output the eccrine glands of an adult human  can be up to 2-4 liters per hour or 10-14 liters per day (10–15 g/min·m2), but is less in children prior to puberty).  Eccrine gland activity with secretory and dark cells is regulated through neural stimulation using sympathetic nerve fibers distributed around the gland (neurotransmitter: acetylcholine). Sweat produced by clear cells is a clear, odor-free, colorless, slightly acidic fluid that consists of water (99.0–99.5%), the electrolytes NaCl, K+ and HCO3, and lactate, urea, ammonia, calcium, heavy metals. The dark cells produce macromolecules mixed with the sweat. There are significant regional variations in the composition of sweat, which also is modulated by psycho-emotional and environmental factors.

 

Apocrine sweat glands: They secrete their sterile, odor-free, weakly acidic product via exocytosis from secretory cells. Its viscous, milky consistency is due to its high content of lipids (fatty acids, cholesterol, squalene, triglycerides), androgens, ammonia, sugars, Fe2+. Some of these are odoriferous, especially so after their decomposition on the skin surface by bacteria. Myoepithelial cells are arranged spirally along the tubule.

 

Sebaceous glands: Their product, sebum, is released after sebocytes burst by DNA degradation   (holocrine secretion by programmed cell death). There is a remarkable variation in the composition of sebum through human life and human sebum is unique, with no similarity to other species. Human sebaceous glands not only produce sebum but also regulate steroidogenesis, local androgen synthesis, contribute to skin barrier function, interaction with neuropeptides, potential production of both anti- and pro-inflammatory compounds and synthesis of anti-microbial lipids (sapienate, oleic acid).

 

The sebaceous gland contains all enzymes needed for transformation of cholesterol to steroids. Moreover, it expresses beside others the 5α-reductase isoenzymes, needed for the intracellular conversion of testosterone, or even the adrenal androgen dehydroepiandrosterone directly, to the more potent 5α-dihydrotestosterone. Sebaceous glands are part of the skin neuroendocrine system as they produce and release corticotropin-releasing hormone in response to systemic or local stress. Abnormal sebaceous gland function leads to several skin diseases, the most common among them is acne.

 

Sebum is a yellowish viscous fluid containing lipids, such as triglycerides, free sterols and sterol esters, squalene, wax and free fatty acids, and cell debris.

 

Hair follicle: Hair fiber growth occurs in a highly time-resolved manner. Glucose (and glutamine) is the principal energy source. The hair follicle can react to most hormones of the human body. Hair follicles in different regions of the body respond differently to androgens. Drug-induced inhibition of the testosterone-metabolizing enzyme to 5α-dihydrotestosterone 5α-reductase type II induces hair regrowth in some balding men.

 

The hair fiber includes “hard” K, water, lipids, pigment, and trace elements (in order of decreasing amount). Neither the chemical composition of hair proteins nor its amino acid composition shows any difference between different ethnicities.

 

Hair fibers have a coating of long-chain fatty acids bonded covalently to the protein membrane of the epicuticle (which may be interrupted in disease processes such as Netherton syndrome, ectodermal dysplasia, dystrophic hairs, atopic hair, brittle hair).

 

Nails: Corneocytes of the nail plate (onychocytes) are also filled with K filaments. Low-sulfur K form α-helical filaments running parallel to the nail surface and are embedded in a non-K matrix of high sulfur,  glycine and  tyrosine proteins. Up to 90% of nail Ks are of the hard “hair” K type. Water, lipids and trace elements including iron, zinc, and calcium are present in the nail plate. The nail low lipid content contributes to their 1000-fold greater water permeability than the epidermis.
Exogenous factors, dissolving lipids out of the nail plate lead to brittle nails, onychodystrophy and superinfection.

Skin endocrinology

Vitamin D production: Vitamin D3 (cholecalciferol) belongs to the group of fat-soluble secosteroids, which has an important impact in the intestinal absorption of calcium, magnesium, and phosphate. Besides oral ingestion it is photochemically induced in the epidermis through UVB radiation (290–315 nm). Sun exposure to face, arms and legs  for 30 minutes twice per week, or approximately 25% Minimal Erythema Dose (MED) is enough to transform 7-dehydrocholesterol into  cholecalciferol (vitamin D3).

 

Steroidogenesis and neurohormones: Skin and its appendages respond to central hormone regulation but also act as a neuroendocrine organ in a manner largely independent of body central control systems. It includes the production of corticotropin-releasing hormone and downstream proopiomelanocortin peptides.

 

Pigmentation of skin and hair follicle: Despite the variations in skin and hair color, skin and hair pigmentation is derived from the pigment melanin, synthesized via a phylogenetically ancient biochemical process termed melanogenesis. Synthesis occurs within melanosomes, which are specialized organelles unique to highly dendritic, neural crest-derived, cells called melanocytes.

 

Melanogenesis starts by the formation of  melanosomes, whose size markedly differs between skin types, and continues through the biochemical pathway that converts L-tyrosine into melanin. Both processes are under complex genetic control.

 

Melanin is a family of polymorphous and multifunctional biopolymers that include:

  • Eumelanin: brown-black melanin
  • Pheomelanin: red/yellow melanin
  • mixed melanins (containing both eumelanin and pheomelanin)
  • neuromelanin

 

Both eumelanin and pheomelanin can be produced within the same melanocyte. Pheomelanins are photo-labile with photolysis products including superoxide, hydroxyl radicals and hydrogen peroxide. Genetic and immunological abnormalities of melanin production can lead to significant diseases such as albinism and vitiligo, respectively.

 

The conversion of L-tyrosine to melanin follows three steps:

  • Hydroxylation of L-phenylalanine/L-tyrosine to L-dihydroxy-phenylalanine (L-DOPA)
  • Dehydrogenation/oxidation of L-DOPA to dopaquinone, which is the precursor for both eumelanin and pheomelanin and the limiting step in melanogenesis
  • Dehydrogenation of dihydroxyindole to yield melanin pigment

 

The conversion of dopaquinone to leuko-dopachrome signals eumelanin production, while the addition of cysteine to dopaquinone to yield cysteinyl-DOPA occurs in pheomelanin production.

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