INTEGUMENT LEVEL 200

(Biochemistry)
OCK HAGAN

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 Objectives

• The process of keratinization

• Learn about the extracellular matrix composition of the human

integument

• Learn about the biochemical basis of integument pigmentation

• Learn about the biochemistry of photoaging

• Understand the clinical correlations

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 Structure and the cellular composition of the skin
◆ Epidermis- provides waterproofing
and serves as a barrier to infection;
Main cellular components –
keratinocytes (produces keratin)
Melanocytes (produces melanin)
Dermis is responsible for the tensile
strength of skin. Its main functions are
to regulate temperature and to supply the
epidermis with nutrient-saturated blood
Main cell type is fibroblast
(responsible for laying down the
connective tissue).

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 Keratinocytes, keratin and keratinisation
Keratinocytes
• Formed from stem cells of basal layer
• Make up about 95% of the cells within the epidermis
• Regenerating stratified squamous epithelium that differentiate from cuboidal cells in basal
layer to flat anucleated cells in the stratum corneum.
• Produces the intermediate filament protein called keratin
• Has a life cycle of 28 days

Keratinisation
Process of keratinocytes dividing from
the basal layer, differentiating,
maturing and migrating to the skin
surface

✔Cell division - Basal progenitor cells

divide continuously
✔Differentiation - maturing cells lay
down keratin filaments
✔Maturation - keratin laden
keratinocytes lose nucleus and die
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✔Cells flatten towards the surface and
 Keratinocytes, keratin and keratinisation

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 Keratinocytes, keratin and keratinisation
Keratin
◆ Main protein in the epidermis of
human skin, hair, nails

◆ Intermediate filaments constituted

from keratin polypeptides

◆ Two main types of keratin

polypeptides
◆ Basic/neutral
◆ Acidic

◆ A heterodimer of a basic/neutral and

acidic keratin is the basic unit of
keratin intermediate

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 Keratinocytes, keratin and keratinisation
Genetic disorders

Bullous congenital
ichthyosis

Epidermolysis
Bullosa
simplex Ichthyosis bullosa
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of Siemens
 Skin Extracellular matrix
• Secreted by fibroblast
• Collagen- type I makes about 90%. Type 3 makes up about 9%. Others include type
V and VI
• Collagen is responsible for skin tensile strength and tissue integrity
• Elastin- Provides the skin with elasticity and resilience. Glycosaminoglycans-
predominantly chondroitin sulfate, dermatan sulfate, keratin sulfate, heparan
sulfate, and heparin
• Proteoglycans- Predominantly vesicans and perlecans

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 Collagen synthesis
1. Synthesis of a chains of pre-procollagen on
ribosomes.  α-chain structure Gly-X-Y
repeats in a left handed
turn
3. Hydroxylation of lysine and proline in X frequently a proline
rER/Golgi by lysyl-5-hydroxylase and Y frequently a
prolyl-4-hydroxylase. hydroxylysine or
hydroxyproline (mostly)
4. Glycosylation: addition of galactose and
glucose to some hydroxylysine residues
(galactosyl transferase and glycosyl
transferase).

5. Assembly of α-chains to form procollagen.

Reaction needs the formation of disulphide
bonds between registration peptides, at both
ends of the prepro- collagen.

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 Collagen synthesis
• 5. Secretion of procollagen molecules by
exocytosis into the extracellular space.

• 6. Cleavage of registration peptides is catalysed

by procollagen peptidases. The resulting
molecule is called tropocollagen.

• 7. Oxidation – deamination of the

hydroxylysine, the removal of (NH2) group has a
net oxidative effect and the formation of
covalent cross-links.  Reaction is catalyzed by
lysine oxidase (or catalase). 

• 8. Self-assembly or polymerization of
tropocollagen molecules form collagen fibrils.
Cross-linkage between adjacent tropocollagen
molecules stabilizes the fibrils. 

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 Skin disorders of collagen and elastin

Ehlers-Danlos disease
✔Genetic disorders resulting from collagen gene
mutations
✔Classic = Mutation in COL5 gene; Hyper extensible
skin, abnormal wound healing, easy bruising

Scurvy
✔Acquired from vitamin C deficiency
✔Impairs wound healing, easy bruising, gum swelling
and bruising

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 Elastin

12

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 Elastin
◆ It is secreted by connective tissue cells as soluble tropoelastin into EC matrix
◆ Composed maily of hydrophobic amino acids like valine, glycine, proline and alalnine
◆ Topoeleastins are laid on meshwork of microfibrils (Fibrillin and fibulin)
◆ Polypeptide chains are cross-linked together by lysil oxidase to form allysine.
◆ Allysine and lysine from different microfibrils to form desmosomes and isodesmosomes to
cross-link them
◆ Forms an extensive network of elastin fibres and sheets
◆ Elastin fibres associate with microfibrils made up of glycoproteins including fibrillin

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 Disorders of elastin
Marfans disease
✔Autosomal dominant inheritable syndrome
✔Mutation in fibrillin-1 which is important for elastin
function
✔Causes ocular, skeletal and cardiovascular disorders
✔Skin = Striae (stretch marks)

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 Proteoglycans
Proteins linked covalently to
glycosaminoglycans (GAGs).
Carbohydrates make up about 95% of its
weight

Proteins bound covalently to GAGs are

called core proteins

Many have been classified; they vary in

tissue of origin, function, core protein
types

Examples include aggrecans, syndecan,

betaglycan, serglycan

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 Integument Pigmentation

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 Melanocytes

• Specialised cells for producing

melanin derived from neural crest

• Precursor-melanoblast

• Found in association with

keratinocytes in the skin and some
other organs.

• Involved in the production of melanin

which has different function in
different organs

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 Formation of melanosomes
• Melanosomes - elliptic membrane-bound
organelles (melanin synthesis).

• Synthesis of matrix proteins and tyrosinase

(TYR) on the rough endoplasmic reticulum.

• TYR undergoes post translational modification in

the form of glycosylation in the Golgi apparatus.

• Fusion of premelanosomes with coated vesicles

containing tyrosinase - formation of the
melanosome.

• Melanosome migrates into one of the dendrites of

the
melanocyte → transfer to a
neighboring keratinocyte.

• Melanin forms a shield on the sun-exposed

keratinocyte
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 Melanin synthesis
Enzymes

• Three enzymes in melanosomes which absolutely required for different melanin type
synthesis
– tyrosinase (TYR) – responsible for critical step of melanogenesis (tyrosine
hydroxylation)
– tyrosinase-related protein 1 (TYR1) and DOPAchrome tautomerase
(DHI = 5,6-dihydroxyindole; DHICA = 5,6-dihydroxyindole-2-carboxylic acid)

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 Melanin synthesis

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 Melanin in skin colour determination

Melanins are polymorphous and multifunctional polymers of eumelanin, pheomelanin, mixed

melanins (a combination of the two); and neuromelanin

◆ Brown-black eumelanin
✔ Black eumelanin produces black colour when in abundance and grey when rare.
✔ Found mainly in non-European
◆ Brown eumalanin.
✔ Mainly in people of European descent. Gives brown colour (hair) in abundance and in
small amounts light brown or blonds

Phaeomelanin
Produces reddish colour. In hair it is the main colouring agent in ginger hair. Protective to
the body by binding cation, anions, drugs and chemicals

Neuromelanin
is produced in dopaminergic neurons of substantia nigra. It can chelate toxin like Cd, Pb, Hg

Number of melanocytes in human skin of all types is essentially constant, the number, size, and
manner in which melanosomes are distributed within keratinocytes vary-leading colour
variations in humans and also different parts of the body
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 Factors involved in melanin production
• The melanin granules accumulate above the nuclei of keratinocytes and absorb
harmful UV-R before it can reach the nucleus and damage the DNA.

• Quick responds of the melanocyte-keratinocyte complex to a wide range of

environmental stimuli (paracrine and/or autocrine) - to UV-R, melanocyte-
stimulating hormone (MSH), endothelins, growth factors, cytokines, etc.

• UV-R exposure → melanocytes increase their expression of proopiomelanocortin

(POMC, the precursor of MSH) and its receptor melanocortin 1 receptor (MC1-R),
TYR and TYRP1

• Fibroblasts (possibly other cells in skin) - produce cytokines, growth factors, and
inflammatory mediators that can increase melanin production and/or stimulate
melanin transfer to keratinocytes by melanocytes.

• Certain drugs can cause hyperpigmentation of the skin eg chloroquine, levodopa

(parkinson’s), antibiotics (sulfonamides, tetracycline)
•
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 Melanin and Humans

When a human skin is exposed to sunlight-it initially turns reddish to

brownish as more melanin is synthesised. Tanning

Lack of melanin that result from lack of enzymes leads to a

recessively inherited oculocutaneous albinism

Freckles, birth and moles result from over concentration of melanin at

particular spots.

UV light causes mutations in DNA especially pyrimidine dimers

eg C-C, T-T, C-T. These mutations can lead to formation of melanomas
when unrepaired

Reduced levels of neuromelanin is found in Parkinson’s disease

Higher levels of eumelanin can cause Vitamin D deficiency

especially for dark skinned individuals in temperate regions

Vitliligo- Autoimmune destruction of the melanocytes

Results in patchy loss of skin colouration
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 Skin bleaching The usage of topical and oral agents to
achieve the ”lightening of the skin”

Common among Non-Caucasian population

of the world

Has deep psychosocial underpinnings

including social status, body perceptions

Agents used targets melanocyte reduction

and inhibition of melanin enzymes like
tyrosinase

Agents commonly utilised include

hydroxyquinones, mercury, steroids

Potential side effects include acne,

ochronosis (nansoben), dermatitis, skin
cancer, mercury poisoining, kidney damage

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 Aging and skin

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 Biochemistry of skin aging

●intrinsic factors (genetically programmed cell changes

○Reactive oxygen species

○Glycated proteins- Advance glycation end-products AGEs)

●Extrinsic
○ about 90% due to UV
○ others include pollutants

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 UV light and ROS

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 Matrix Metalloproteinases

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 AGEs

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 Effect of aging on the skin
1. Wrinkle. Due to loss of collagen in dermis. Increased fibroblast synthesis of MMP
which destroys collagen and elastin+reduced synthesis of collagen by senescent
fibroblast

2. Slackness- due to loss of skin elasticity+resilience due to elastin destruction

3. Increased transparency-reduced melanocytes= reduced melanin

4. Dehydration-reduction in synthesis of GAGs like hyaluronic acid (that bind

water). Also due to loss of subcutaneous fat

5. Increased susceptibility to tumours eg melanomas due to diminished protection

from UV

6. Reduced numbers of melanocytes, but the remaining becomes larger in size. They
also become erratic leading to hyperpigmentation

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 Additional reading

https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0000027

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4989561/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5917548/

https://onlinelibrary.wiley.com/doi/full/10.1111/j.1600-0625.2009.00912.x

https://link.springer.com/article/10.1007/s13555-016-0154-1

https://clinicalgate.com/integumentary-system-2/

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