COLLAGEN & ITS SYNTHESIS

DR SAKINA ,MBBS,M.D SENIOR LECTURER ,MSU

COLLAGEN

Objectives

1.Definition2.Basic information of

collagen3.Different Types of collagen4.Molecular Structure 5.synthesis of collagen6.Functions of collagen6.Abnormalities associated

with Collagen

DEFINITION Derived from Greek word “kolla”

meaning Glue Producer” Major structural protein found in

connective tissue Is collagen

It is a fibrous element of tissues like bone teeth,tendon,cartilage &blood vessel

It Yield gelatin and glue upon boiling with water

BASIC INFORMATION ABOUT COLLAGEN

It is long, rigid structure in which three polypeptides are wound around one another in a rope like fashion.

These polypeptides are called α-helix Example:1. Gel- extracellular matrix or vitreous humor

of eye.2. Tight bundles- Tendons3. Stacked- as in Cornea4. Fibers arranged at an angle- Bones

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COLLAGEN

Organised into 3 groups based on location & function in the body

1.FIBRIL FORMING COLLAGEN – include type I,II,III

2.NETWORK FORMING COLLAGEN-include type IV ,VII

3.FIBRIL ASSOCIATED COLLAGEN – include type IX ,XII

DIFFERENT TYPES OF COLLAGEN

•This classification is taken from Harper’s illustrated biochemistry-27th edition which describes 19 different types. •As per latest research 29 types of collagen have been found.•Over 90% of the collagen in the body, however, are of type I, II, III, and IV.

The types of collagen are designated by Roman numerals.

Constituent procollagen chains, called pro α chain For instance, Type I procollagen is assembled

from two pro α 1 (I) and one pro α 2 (I) chain. It is thus a heterotrimer.

Whereas Type 2 procollagen is assembled

from three pro α 1 chains and is thus a homotrimer.

STRUCTURE OF COLLAGEN Collagen has a most unusual amino acid

composition in which Glycine, Proline, Hydroxyproline, Lysine & Hydroxylysine are dominant.

Glycine

Proline

3-Hydroxyproline 4-Hydroxyproline

NH2 | NH2 – CH2 – CH – CH2 – CH2 - C – H | COOHLysine

5-Hydroxylysine

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These amino acids are arranged in a repetitious tripeptide sequence, Gly-X-Y, in which X can be any amino acid but is frequently a Proline and Y is frequently a Hydroxyproline or Hydroxylysine.

Individual collagen polypeptide chains (each with about 1000 amino acid residues) assume a left-handed helical conformation (with 3 amino acids per turn) and aggregate into 3 stranded cables with a right-handed twist.

The Glycine at every third residue is required because there is no room for any other amino acid inside the triple helix where the glycine R-group is located.

SYNTHESIS OF COLLAGEN

SYNTHESIS OF COLLAGENPrecursors: Collagen is one of the proteins that

functions outside the cell.

Polypeptide Precursors of the collagen molecule are formed in Fibroblast, osteoblasts and chondroblasts.

These are secreted into the extracellular matrix.

1.Formation of Pro- α-chains: Pre-pro α-chains- contain a special amino acid sequence at their

N-terminal.This sequence acts as a signal peptide

This sequence facilitate the binding of ribosomes to the rough endoplasmic reticulum (RER), and direct the Pre-pro α-chain into the lumen of the RER

This sequence is cleaved in the lumen of RER and after its cleavage Precursor of collagen is formed.

This precursor is called Pro α-chain

2. Hydroxylation: Processing of Pro α-chains occur by a number of

enzymic steps in the lumen of RER.

Proline and lysine residues are hydroxylated intracellularly by prolyl & lysyl hydroxylase,(contain ferrous iron at active site) O2 and vitamin C

It is a post translational modification

Vit C deficiency, Leads to poor hydroxylation- and tensile strength is decreased (scurvy).

N CH

CH2CH2

CH2

ON CH

CH2CH2

CH

O

OH

NH3

+

CH2CH2

CH2

CH2

CHNHO

NH3

+

CH2CH

CH2

CH2

CHNHO

OH

-ketogutarate succinate

-ketogutarate succinate

prolyl hydroxylase

lysyl hydroxylase

(ascorbate)

(ascorbate)

O2 + CO2 +

O2 + CO2 +

proline4-hydroxyproline

lysine 5-hydroxylysine

galactosyl transferase

glucosyltransferase

UDP-galactose UDP-glucoseNH3

+

CH2CH

CH2

CH2

CHNHO

OH

OCH2

O

OHOH

OH

OH

H

H

H HH

OCH2

O

O

OH

OH

OH

H

HH

H

H

CH

CH2

CH2

CH2

CH

NH3+

NH

O

3. Glycosylation: Modified by glycosylation with glucose or

galactose residues

4. Assembly and Secretion: After hydroxylation and glycosylation- Pro α-chains are

converted to Pro-collagen. Pro-collagen has a central region of triple helix and its ends have

non-helical regions of amino and carboxyl terminal extensions . These extensions are called Propeptides.

In the formation of procollagen interchain disulfide bonds are formed between the C- terminal extensions of the pro α-chains.

This alignment of pro α-

chains is favorable for helix formation.

Then pro-collagen chains are

translocated to Golgi- apparatus.

In the golgi apparatus they are packaged in secretory vesicles.

These vesicles fuse with the membrane and release the pro-collagen molecule into the extracellular space.

5. Extracellular cleavage of Procollagen molecules:

After their release, The Procollagen molecules are cleaved by N- and C- Procollagen peptidases.

These remove the terminal Propeptides.

Triple helical structure is released as Tropocollagen

6. Formation of collagen fibrils:Tropocollagen spontaneously

associate with each other and form collagen fibrils

7. Cross-link formation: The collagen fibres are strengthened by

covalent cross link between lysine & hydroxylysine residues by lysyl oxydase which converts these amino acid into Aldehyde ,which form into Aldol condensation near amino terminal

This enzyme contain copper at its active site,In copper deficiency collagen synthesis is Abnormal

These covalent bonds cross-link gives the fiber exceptional strength and rigidity.

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Degradation of collagen: Collagen highly stable molecule. Half life is several years. Breakdown- collagenases

Degradation of collagen is seen when there is bone and cartilage resorption, osteoporosis,tumour metastasis,paget’s disease,rickets,osteoarthritis etc

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FUNCTIONS OF COLLAGEN

1.To give support to organs2.To provide alignment of cells3.In blood vessels if collagen is

exposed,platelets adhere and thrombus formation is initiated

Medical uses:- Collagens are widely employed in the construction

of artificial skin substitutes used in the management of severe burns & beauty treatments.

(These collagens may be derived from bovine, equine or porcine, and even human sources and are sometimes used in combination with silicones, glycosaminoglycans, fibroblasts, growth factors and other substances)

ABNORMALITIES ASSOCIATED WITH COLLAGENEHLERS-DANLOS SYNDROME - group of inherited disease - collagen involved type III- - defective lysyl oxidase

Characteristics - hyper extensibility of skin. - abnormal tissue fragility -increase joint mobility

ALPORT SYNDROME

Collagen involved- type IV (found in the basement membrane of glomerulus)

Characteristics- - Hematuria - renal diseases

OSTEOGENESIS IMPERFECTACaused due to abnormal (less) Collagen type I

Characteristics - weak bones - fragile bones

EPIDERMOLYSIS BULLOSADue to alteration of Collagen type VII

Characteristics - skin breaks - blister formation

SCURVY Gly –X- Y (Y = 4-hydroxyproline)

Enzyme : propyl-4-hydroxylase

Co-factor: Vit. C. Due to Vit C deficiency(impaired synthesis of collagen due to

deficiencies of prolyl and lysyl hydroxylases)Characteristics- - bleeding gum - delayed wound healing

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