Biochemistry of skin (barrier function, vitamin D, cytokeratins, intercellular junctions, melanin biosynthesis)

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Introduction

The skin, as the largest organ of the human body, serves crucial roles in protection, sensory perception, thermoregulation, and biochemical synthesis. Understanding its biochemical components helps in elucidating dermatological disorders and improving therapeutic approaches. This article explores the skin's barrier function, vitamin D metabolism, cytokeratins, intercellular junctions, and melanin biosynthesis. Skin is strategically placed at the interface between external and internal environments, so it serves as a barrier and a shield against various stressors (mechanical, chemical, biological) while also creating the peripheral sensing system. For this reason some may call it "brain on the outside"

Skin layers

Histological composition of skin

Histological layers of epidermis

1. Epidermis (Outer Layer)

• Stratum corneum – Dead, flattened keratinized cells (corneocytes) embedded in a lipid matrix.
• Stratum lucidum – Present only in thick skin (palms, soles), contains eleidin.
• Stratum granulosum – Keratohyalin granules, lamellar bodies contribute to skin barrier.
• Stratum spinosum – Polyhedral keratinocytes with desmosomes (prickle cells).
• Stratum basale – Basal keratinocytes, melanocytes, Merkel cells, and mitotically active stem cells.

2. Dermis (Middle Layer)

• Papillary dermis – Loose connective tissue, fibroblasts, immune cells, capillaries, and Meissner’s corpuscles.
• Reticular dermis – Dense irregular connective tissue, collagen (type I), elastic fibers, sweat glands, sebaceous glands, hair follicles, blood vessels, and Pacinian corpuscles.

3. Hypodermis (Subcutaneous Tissue)

• Composed of adipose tissue, connective tissue, larger blood vessels, and lymphatics.

Skin as a barrier

The epidermis, particularly the stratum corneum, acts as a selective permeability barrier, preventing excessive water loss and providing defense against microbial invasion. The primary biochemical components responsible for this function include:

• Lipids: Ceramides account for 50% of S. corneum followed by cholesterol and free fatty acids. They form the intercellular lipid matrix that maintains hydration and barrier integrity.
• Proteins: Involucrin, loricrin, and filaggrin contribute to the formation of the cornified envelope, a protein-lipid complex that enhances mechanical resistance.
• Natural Moisturizing Factor (NMF): Comprising amino acids and metabolites like pyrrolidone carboxylic acid (PCA), NMF retains water within the skin and prevents dehydration.
• Acidic pH: provides an optimal pH for enzymes involved in extracellular processing of bilayer lipids

Vitamin D biosynthesis

The skin is a primary site for vitamin D synthesis, a critical hormone for calcium homeostasis and immune regulation. The process includes:

1. UVB radiation (290–315 nm) converts 7-dehydrocholesterol in the epidermis to previtamin D3 via a photochemical reaction in keratinocytes.
2. Thermal isomerization in the skin leads to the formation of cholecalciferol (vitamin D3).
3. Hydroxylation in the liver by 25-hydroxylase (CYP2R1, CYP27A1) converts cholecalciferol into 25-hydroxyvitamin D3 (25(OH)D3), the major circulating form.
4. Activation in the kidneys by 1α-hydroxylase (CYP27B1) results in the formation of 1,25-dihydroxyvitamin D3 (calcitriol), the biologically active form.

Vitamin D biosynthesis

Calcitriol binds to the vitamin D receptor regulating gene expression involved in calcium absorption, keratinocyte differentiation, and immunomodulation. Deficiency in vitamin D is associated with conditions such as rickets, osteoporosis, psoriasis, and atopic dermatitis.

Cytokeratins

Cytokeratins are intermediate filaments that provide structural integrity to epidermal cells. They are classified based on their expression:

• Basal layer keratins: K5 and K14 maintain basal cell integrity and function.
• Differentiation-associated keratins: K1 and K10 are expressed in suprabasal layers and contribute to the mechanical resilience of keratinocytes.
• Wound-healing and stress-induced keratins: K6, K16, and K17 play a role in epidermal repair and hyperproliferative skin conditions.
• Keratin mutations: Defects in keratin genes can cause disorders like epidermolysis bullosa simplex (K5, K14 mutations) and pachyonychia congenita (K6, K16 mutations).

Cytokeratins also serve as diagnostic markers for various skin diseases, with altered expression patterns observed in conditions such as psoriasis, atopic dermatitis, and skin cancers.

Intercellular junctions

Cell-cell adhesion is critical for maintaining skin integrity and function. The primary intercellular junctions include:

• Tight Junctions (TJs): Claudins and occludins form a selective barrier to regulate water and ion passage.
• Desmosomes: Composed of desmogleins and desmocollins, desmosomes provide mechanical strength and are disrupted in pemphigus vulgaris.
• Gap Junctions: Connexins facilitate intercellular communication, with Cx26 mutations leading to keratitis-ichthyosis-deafness (KID) syndrome.

Melanin

Melanin is polymorphous and multifunctional biopolymer that include the cutaneous melanin and neuromelanin. Of all our phenotypic traits skin and hair color communicate more immediate information to the observer than any other. Skin and hair color depends principally on relative amounts of eumelanin (brown/ black) and pheomelanin (red/yellow), two variations derived from the pigment melanin, which is synthesized via a phylogenetically ancient process termed melanogenesis. Synthesis occurs within melanosomes - specialized organelles with melanocytes.

Melanin pathway

The process of melanogenesis can be divided into:

1. the formation of the melanosome in which melanogenesis occurs
2. the biochemical pathway that converts L-tyrosine into melanin

Both processes are under complex genetic control.

The biosynthesis of melanin is based on the conversion of the amino acid L-tyrosine into a complex and heterogeneous group of compounds. This reaction can be broadly divided into the following steps:

1) hydroxylation of L-phenylalanine/L-tyrosine to L-dihydroxy-phenylalanine (L-Dopa)

2) The dehydrogenation/oxidation of L-Dopa to dopaquinone—the precursor for both eu/pheomelanins and the limiting step in melanogenesis.

3) The dehydrogenation of DHI (dihydroxyindole) to yield melanin pigment.

4) The conversion of dopaquinone to leuko-dopachrome signals eumelanin production, while the addition of cysteine to dopaquinone to yield cysteinyldopa occurs in pheomelanin production

References

Biochemistry of human skin, Desmond J Tobin

Lippincotts illustrated reviews 6th edition

Marks Basic medical biochemistry 5th edition (2018)