Biosynthesis of Collagen
Azizah Hikma Safitri
Biochemistry Department
Medical Faculty of UNISSULA
Topics
01 Introduction 02 Structure of Collagen
Genetic & Deficiency Diseases
03 Synthesis of Collagen 04 Result From Abnormalities in the
Synthesis of Collagen
Introduction
§ Most mammalian cells are located in tissues where they are
surrounded by a complex Extracelullar Matrix (ECM) often
referred to as “connective tissue,” which protects the
organs and also provides elasticity where required (eg, in
blood vessels, lungs, and skin).
§ The ECM contains three major classes of biomolecules:
structural proteins (1), for example, collagen, elastin, and
fibrillin, certain specialized proteins (2) such as fibronectin
and laminin, which form a mesh of fibers that are embedded
in proteoglycans (3).
Introduction
§ ECM represent specifically organized networks of collagen, elastin, glycoproteins and proteoglycans that
have distinct structural roles and specific functional properties in all tissues.
§ ECM are biologically active, interact with cells, and regulate cellular functions during development,
regeneration and normal tissue turnover.
§ Several diseases (eg, osteogenesis imperfecta and a number of types of the Ehlers-Danlos syndrome) are
due to genetic disturbances of the synthesis of collagen. Changes occur in the ECM during the aging
process.
Structure of Collagen
§ Collagen is protein molecules provide
structural support to extracellular spaces
of connective tissues
§ Collagen is synthesized by amino acids,
therefore its constitute of protein
§ Collagen consists of amino acids bound
together to form a triple helix of elongated
fibril known as a collagen helix
Structure of Collagen
§ All collagen types have a triple helical structure.
§ A striking characteristic of collagen is the
occurrence of glycine residues at every third
position of the triple helical portion of the alpha
chain.
§ Glycine is the only amino acid small enough to be
accommodated in the limited space available in
the central core of the triple helix.
§ Repeating structure, represented as (Gly-X-Y)n,
is an absolute requirement for the formation of
the triple helix.
§ X and Y can be any other amino acids, about 100
of the X positions are proline and about 100 of
the Y positions are hydroxyproline
Structure of Collagen
§ Repeating structure,
represented as (Gly-X-Y)n, is an
absolute requirement for the
formation of the triple helix.
§ X and Y can be any other amino
acids, about 100 of the X
positions are proline and about
100 of the Y positions are
hydroxyproline.
Types of Collagen
ü Collagen can be further divided into several
groups depending on the type of structures
they form. There are 28 various types of
collagen that have been discovered, but by
far, the most common are types I through
IV, with type I comprising over 90% of the
collagen in the human body.
Classification of Collagen
Biosynthesis of Collagen
ü The process of collagen
synthesis occurs mainly in
the cells of fibroblasts
which are specialized cells
with the main function of
synthesizing collagen and
stroma.
ü Collagen synthesis occurs
both intracellularly and
extracellularly.
Biosynthesis of Collagen
Biosynthesis of Collagen
1. Intracellular
a. Transcription of mRNA in the nucleus
ü Genes for pro-a1 and pro-a2 chains
are transcribed
b. Translation
ü mRNA moves into the cytoplasm
and interacts with ribosomes for
translation.
ü After translation, it is referred to as
pre-pro-polypeptide chain; this
chain then travels to the
endoplasmic reticulum (ER) for
post-translational modification.
Biosynthesis of Collagen
1. Intracellular
c. Post-translational modification
Once in the ER, the pre-pro-polypeptide undergoes post-
translational processing where three major modifications are
made to the pre-pro-polypeptide for it to become pro-
collagen.
1. The signal peptide on the N-terminal is removed
2. The lysine and proline residues get additional hydroxyl groups added
to them via hydroxylase enzymes which require vitamin C as a
cofactor
3. Glycosylation of the selected hydroxyl groups on lysine with galactose
and glucose b
§ Three of the hydroxylated and glycosylated pro-a-chains assemble by twisting into a
triple helix by zipper-like folding. The triple helix configuration is 3 left-handed
helices twisted into a right-handed coil
§ Now the pro-collagen molecule is ready to move to the Golgi apparatus for final
modifications and assembled into secretory vesicles to enter the extracellular space
Biosynthesis of Collagen
1. Intracellular
c. Post-translational modification
Once in the ER, the pre-pro-polypeptide undergoes post-
translational processing where three major modifications are
made to the pre-pro-polypeptide for it to become pro-
collagen.
1. The signal peptide on the N-terminal is removed
2. The lysine and proline residues get additional hydroxyl groups added
to them via hydroxylase enzymes which require vitamin C as a
cofactor
3. Glycosylation of the selected hydroxyl groups on lysine with galactose
and glucose b
§ Three of the hydroxylated and glycosylated pro-a-chains assemble by twisting into a triple helix by zipper-like
folding. The triple helix configuration is 3 left-handed helices twisted into a right-handed coil
§ Now the pro-collagen molecule is ready to move to the Golgi apparatus for final modifications and assembled
into secretory vesicles to enter the extracellular space
Biosynthesis of Collagen
2. Extracellular
a. Propeptide cleavage
ü Enzymes known as collagen peptidases perform propeptide
cleavage and remove the ends of the procollagen molecule and
the molecule becomes tropocollagen
b. Collagen Fibril Assembly
ü Lysyl oxidase a copper-dependent enzyme acts on lysine and
hydroxylysines, and covalent bonding between tropocollagen
molecules form a collagen fibril
Biosynthesis of
Collagen
Biosynthesis of Collagen
Biosynthesis of Collagen
Genetic & Deficiency Diseases
Result From Abnormalities in the
Synthesis of Collagen
Errors of collagen synthesis can present with clinical manifestations.
A few notable diseases are scurvy, osteogenesis imperfecta, and
Ehlers–Danlos syndrome.
ü Osteogenesis imperfecta which is an autosomal dominant
disorder of type 1 collagen, which can present with a
spectrum of findings from mild to lethal.
ü Ehlers-Danlos syndrome which is also an inherited collagen
disorder with at least 6 different subtypes with different
mutations of different collagen types.
ü Lastly, Vitamin C deficiency is a nutritional deficiency which
leads to altered hydroxylase enzyme function which requires
Vitamin C as a cofactor.
1. Scurvy
§ A nutritional deficiency of water-soluble vitamin C or ascorbic acid most
commonly causes scurvy.
§ Scurvy is rare in the developing world and is mostly seen in infants, the elderly,
and alcoholics, all who may have inadequate nutritional intake and malnutrition.
§ Patients may present with general fatigue, weakness, poor wound healing,
anemia, and gum disease. Clinically, one of the first signs of scurvy occurs on the
skin and manifests as perifollicular hemorrhage where follicles of the skin are
plugged with keratin. These areas appear as bruise-like spots around the hair
follicles.
§ There can also be fragile hairs arranged in a corkscrew confirmation.
§ Scurvy is diagnosed clinically with a dietary history, and x-rays may show subperiosteal
hemorrhage or cortical thinning. Ascorbic acid levels less than 11 micromols/L can help
confirm the diagnosis. Treatment is vitamin C supplementation and a diet that includes
tomatoes, citrus fruits, and other vegetables high in vitamin C.
2. Osteogenesis Imperfecta (OI)
§ This is a family of genetic disorders that affect the
bones making them weak and easily breakable.
Inheritance is autosomal dominant, and most cases are
due to mutations in the COL1A1 or COL1A2genes.
§ There are 8 types, each with differing degrees of
severity with type 1 the mildest and type II the most
severe.
§ Gene mutations affect procollagen formation in which the small glycine amino acid is
substituted for bulkier amino acids which alter the collagen triple helix structure.
§ OI affects 1 in 15,000 people, and diagnosis is made clinically and can be confirmed by DNA or
collagen testing. Prognosis depends on the type of OI.
§ There is no cure and treatment is supportive and based on the prevention of fractures.
Bisphosphonates, surgery, and physiotherapy have been shown to help.
3. Ehlers-Danlos Syndrome (EDS)
§ This is a group of inherited connective tissue
disorders that affect about 1 in 5000
individuals globally.
§ There are 13 EDSs, and signs and symptoms
vary based on the type of EDS. Most forms
of EDS are autosomal dominantly inherited,
and mutations are in the COL1A1, COL1A2,
COL1A2, COL3A1, COL5A1.
§ Mutations in genes affect extracellular peptide cleavage and alter collagen fibril cross-
linking and aggregation, which causes altered stability and functionality of the fibers
3. Ehlers-Danlos Syndrome (EDS)
References
[Link]
Terima Kasih
