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©ÖĿĿĀĞÊÑ

Group Members:-Presenter:- Khan Abdul Rizwan

Lai Ching

Group Leader:- Magtanong Glenda

Mante Geoffrey

Presenter:- Modi Durgesh

Group5

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Objectives1. Definition2. Different Types & their

Functions3. Molecular Structure &

Synthesis4. Role of vitamin C in Collagen

synthesis

I. Role of Collagen in wound repair

II. Structural and Chemical changes in Collagen as grows older

III. Abnormal Collagen synthesis: Diseases and genetic disorders

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DEFINITION

Derived from Greek word “kolla” meaning Glue Producer”

: any of a group of fibrous proteins that occur in vertebrates as the chief constituent of connective tissue fibrils and in bones and yield gelatin and glue upon boiling with water

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BASIC INFORMATION ABOUT COLLAGEN

Most abundant Fibrous protein (structural protein) in vertebrates

25% or more(up to 35%) of total body protein Major component of connective tissue Provides an extracellular framework for

Strength & Flexibility At least 25 distinct types of Collagen 30 distinct types PP chains (each encoded by

separate gene)

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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.

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The types of collagen are designated by Roman numerals.

Constituent procollagen chains, called pro α chains, are numbered using Arabic numerals, followed by the collagen type in parentheses. 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 (II) chains and is thus a homotrimer.

The collagen genes are named according to the collagen type, written in Arabic numerals for the gene symbol, followed by an A and the number of the pro α chain that they encode. Thus, the COL1A1 and COL1A2 genes encode the α1 and α2 chains of type I collagen, respectively.

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STRUCTURE OF COLLAGEN

Collagen has a most unusual amino acid composition in which Glycine, Proline, Hydroxyproline, Lysine & Hydroxylysine are dominant.

Glycine

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Proline

3-Hydroxyproline 4-Hydroxyproline

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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.

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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.

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The three collagen chains do not form Hydrogen bonds among residues of the same chain.

Instead, the collagen chains within each three stranded cable form interchain Hydrogen bonds.

This produces a highly interlocked fibrous structure that is admirably suited to its biological role, which is to provide rigid connections between muscles and bones as well as structural reinforcement for skin and connective tissue.

From the book:-Analytical Biochemistry - David Holme, Hazel Peck

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Collagen fibrils consist of recurring three-stranded polypeptide units called tropocollagen, arranged head to tail in parallel bundles.

Between the polypeptide strands of the triple helix covalently bonded molecular bridges are erected by a series of reactions that cause Lysine side chains to link together. Part of the toughness of collagen is due to the cross linking of tropocollagen molecules to one another via a reaction involving lysine side chains. These cross links form through the lysyl oxidase.

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This process (of forming cross links through the action of Lysyl oxidase) is continuous throughout the life leading to the accumulation of cross links.

This accumulation is usually associated with changes seen in aging like brittle bones and loss of elasticity of the skin.

In addition to this, collagen as one ages, becomes less organized and causes loss of skin turgor.

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SYNTHESIS OF COLLAGEN

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Collagen is initially synthesized as a larger precursor polypeptide, procollagen.

Numerous prolyl and lysyl residues of procollagen are hydroxylated by prolyl hydroxylase and lysyl hydroxylase, enzymes that require ascorbic acid (vitamin C). Hydroxyprolyl and hydroxylysyl residues provide additional hydrogen bonding capability that stabilizes the mature protein.

In addition, glucosyl and galactosyl transferases attach glucosyl or galactosyl residues to the hydroxyl groups of specific hydroxylysyl residues.

Registration peptides on amino and carboxyl ends of the alpha chain which serves as extensions (contains Cys)

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The central portion of the precursor polypeptide then associates with other molecules to form the characteristic triple helix.

This process is accompanied by the removal of the globular amino terminal and carboxyl terminal extensions of the precursor polypeptide by selective proteolysis (Procollagen peptidase/Procollagen aminoproteinase/Procollagen carboxyproteinase).

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Certain lysyl residues are modified by lysyl oxidase, a copper-containing protein that converts ε-amino groups to aldehydes.

The aldehydes can either undergo an Aldol condensation to form a C=C double bond

or to form a Schiff base (eneimine) with the ε-amino group of an unmodified lysyl residue, which is subsequently reduced to form a C-N single bond.

These covalent bonds cross-link the individual polypeptides and imbue the fiber with exceptional strength and rigidity.

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SUMMARY OF COLLAGEN SYNTHESIS

Glucosyl & Galactosyl added by glycosyl transfarase & galactosyl transfarase.

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Primary structure peptide chain (made up of amino

acids) (Gly –X - Y)n Gly – every 3rd residue (to ensure

tight packing due to its small R group) 1000 + residues

Secondary Structure Brought about by intrachain H-bonds HydroxyPro and HydroxyLys-

participate in the intrachain H-bonds which stabilizes the entire molecule.

Three residues per turn

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Tertiary Structure Interchain H-bonds Hydrophobic interaction Disulfide bonds Triple helix

Quaternary structure Cross linking between tropocollagen

units Schiff base and aldol residues further

increases the cross linking (covalent bonds).

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ROLE OF VITAMIN C IN COLLAGEN SYNTHESIS

Vitamin C is involved at every stage of synthesis of collagen.

The first step is the synthesis of Procollagen, from which collagen is ultimately formed.

Procollagen is 3-D stranded structure made up mainly of the amino acid glycine and proline.

Procollagen: the precursor molecule of collagen, synthesized in the fibroblast, osteoblast etc. and cleaved to form collagen extracellulary.

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The conversion involves a reaction that substitutes a hydroxyl group, OH, for a hydrogen atom, H, in the proline residues at certain points in the polypeptide chains, converting those residues to hydroxyproline. This hydroxylation reaction secures the chains in the triple helix of collagen. The hydroxylation, next, of the residues of the amino acid lysine, transforming them to hydroxylysine, is then needed to permit the cross-linking of the triple helices into the fibers and networks of the tissues. These hydroxylation reactions are catalyzed by two different enzymes: prolyl-4-hydroxylase and lysyl-hydroxylase. Vitamin C also serves with them in inducing these reactions.

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Elemis Pro-Collagen Marine Cream 100ml

Elemis Pro-Collagen Marine Cream 100ml is clinically proven to reduce the appearance of wrinkle depth by 78% and increase hydration and moisture levels by up to 45%

£125.00

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Ascorbic acid can also stimulate collagen synthesis by other mechanisms, it can induce lipid peroxidation and reactive aldehydes, which is a step required for collagen expression. Collagen gene expression is probably influenced by lipid peroxidation, or through acetaldehyde formation, which consequently increases collagen gene transcription in cultured human fibroblasts

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USES OF COLLAGEN

History:-From the Greek for glue, kolla, the word

collagen means "glue producer". Collagen adhesive was used by Egyptians

about 4,000 years ago, and Native Americans used it in bows about 1,500 years ago. The oldest glue in the world, carbon-dated as more than 8,000 years old, was found to be collagen — used as a protective lining on rope baskets and embroidered fabrics, and to hold utensils together; also in crisscross decorations on human skulls.

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Industrial uses If collagen is partially hydrolyzed, the three

tropocollagen strands separate into globular, random coils, producing gelatin, which is used in many foods, including flavored gelatin desserts. Besides food, gelatin has been used in pharmaceutical, cosmetic, and photography industries.

Animal glues are thermoplastic, softening again upon reheating, and so they are still used in making musical instruments such as fine violins and guitars.

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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)

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Collagen is also used to make the pennis bigger. Collagen is also sold commercially as a joint

mobility supplement. This lacks supportive research as the proteins would just be broken down into its base amino acids during digestion, and could go to a variety of places besides the joints depending upon need and DNA orders. 

Collagen is now being used as a main ingredient for some cosmetic makeup.

Recently an alternative to animal-derived collagen has become available. Although expensive, this human collagen, derived from donor cadavers, placentas and aborted fetuses, may minimize the possibility of immune reactions.

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COLLAGEN IN WOUND HEALING

Vital role in hemostasis Attracts thrombocytes Activates thrombocytes to secrete serotonin,

ADP and Thromboxane A2

Platelet plug is formed

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CHANGES IN COLLAGEN DUE TO AGEING

Increase in pyridinoline and deoxypyridinoline

Increase in the thickness of collagen fiber Increase in length

CHARACTERISTICS Hair whitening Wrinkling and toughening of nails Wrinkling and toughening of skin

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ABNORMALITIES ASSOCIATED WITH COLLAGEN

EHLERS-DANLOS SYNDROME - group of inherited disease - collagen involved III-

- Different types :- VII, IV, VICharacteristics - hyper extensibility of skin. - abnormal tissue fragility -increase joint mobility

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ALPORT SYNDROME

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

Characteristics- - Hematuria - renal diseases

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OSTEOGENESIS IMPERFECTA

Caused due to abnormal (less) Collagen type I

Characteristics - weak bones - fragile bones

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EPIDERMOLYSIS BULLOSA

Due to alteration of Collagen type VII

Characteristics - skin breaks - blister formation

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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 and lysyl hydroxylases)Characteristics- - bleeding gum - delayed wound healing

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GENETIC DISEASES DUE TO COLLAGEN SYNTHESIS ABNORMALITIES-DUE TO

GENE MUTATIONGene or Enzyme

Disease

COL1A1,COL1A2

Osteogenesis imperfecta, osteoporosis, ehlers-danlos syndrome type VII

COL2A1 Severe chondrodysplasia osteoarthritis

COL3A1 Ehlers-danlos syndrome type IV

COL4A3-COL4A6

Alport syndrome (including both autosomal and X-linked forms)

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COL7A1 Epidermolysis bullosa, dystrophic

COL10A1 Schmid metaphysial chondrodysplysia

Lysyl hydroxylase

Ehlers-danlos syndrome type VI

Propcollagen N-proteinase

Ehlers-danlos syndrome type VII autosomal recessive

Lysyl hydroxylase

Menkes disease

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