Biochemistry-Connective Tissue Disorders Flashcards Preview

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Flashcards in Biochemistry-Connective Tissue Disorders Deck (40)
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1
Q

What are the two major components of the extra-cellular matrix?

A

Collagen and proteoglycans

2
Q

What special cells would you expect to find in extra cellular skin tissue? Bone?

A

Fibroblasts and Macrophages. Osteocytes/osteoclasts/osteoblasts are found in bone.

3
Q

What connective tissues are used in the body to give tissue strength?

A

Elastin (gives elasticity due to hydrophobic region), collagen (hard strength) and laminin (adhesion molecule).

4
Q

What clinical signs will you observe in someone who is deficient in laminin?

A

Blistering. Laminin is responsible for anchoring of epithelial cells to the extra-cellular matrix.

5
Q

What gives cartilage its strength and elasticity, respectively?

A

Strength = collagen Elasticity = elastin

6
Q

What protein classification does collagen fall into?

A

Fibrous glycoproteins. It is made of 3 polypeptide chains wound together to form a triple-helix with varying amounts of carbohydrate.

7
Q

How would you use proper nomenclature to describe a three-chain a2b structure made up of type I collagen? How do the other collagen types differ from type I?

A

The other collagen types are homotrimers

8
Q

What type of collagen makes up 90% of our body’s collagen? Where is it found?

A

Type I. It is found in skin, bone, tendons, cornea, soft tissue and scars. It also has the least amount of carbohydrate.

9
Q

What is the main type of collagen made by chondrocytes in cartilage?

A

Type II. It has about 10% carbohydrate

10
Q

What type of collagen is very important in hollow organs and blood vessels? Where is it not found?

A

Type III. It is not found in bone or tendons unless there is scarring.

11
Q

What type of collagen is not fiber-forming, forms a mesh and is responsible for adhesion in basement membranes?

A

Type IV. Has the highest carbohydrate content and utilizes disulfide bonds.

12
Q

How are fibrillar collagens genetically similar?

A

They all contain 42 exons with varying intron length. They all have a central encoding region that generates a 1014 AA stretch with repeating [Gly-X-Y] units

13
Q

What are the primary amino acids found in fibrillar collagen? How is this beneficial to collagen strength and stability?

A

Glycine, Proline and Hydroxyproline. Glycine is found in the middle of the helix because it is small. Glycines and prolines hydrogen bond for increased strength.

14
Q

Which way do the helices go in collagen? How is this beneficial to collagen strength and stability?

A

Left-handed helical strands coiled in a right-handed super-helix. If you try to pull the helix out, the left-handed helices will counteract the right-handed super helix

15
Q

In a study of someone’s tissue who has a collagen disorder, it is found that their collagen is only stable at a temperature below 27* C. What could be different about their collagen?

A

They may be missing hydroxyproline. The hydroxyl group on the outer surface of collagen is what allows for stability at higher temperatures.

16
Q

How is collagen formed from preprocollagen?

A

Procollagen is formed after signal peptides are removed in the ER. Procollagen wraps up to form three domains: globular N & C domains at the ends, a triple helical domain and a non-triple helical domain. Proline and lysine are hydroxylated. Procollagen is secreted. Extracellularly, amino and carboxyl-procollagen peptidases cleave the globular ends to form tropocollagen. Tropocollagen then assembles into fibrils and the lysyl oxidase stabilizes the fibrils via lysine residue cross-linkages.

17
Q

What condition is a consequence of a loss of collagen strength due to defective amino-procollagen peptidases?

A

Ehlers-Danlos type VII

18
Q

What enzyme deficiency can cause a type of Ehlers-Danlos due to instability of intermolecular cross-linking in collagen fibrils?

A

Lysyl oxidase

19
Q

What is needed for preservation of prolyl/lysyl hydroxylase?

A

Ascorbic acid. Every once in a while prolyl/lysyl hydroxylase will oxidize alpha-ketoglutarate instead of proline/lysine which causes Fe2+ to become Fe3+. Ascorbic acid reduces the Fe3+ and protects the enzyme from destruction and it can continue hydroxylating proline/lysine residues.

20
Q

A patient comes to your clinic complaining of poor wound healing after a simple appendectomy. Physical exam shows easily bruised skin, hyperextensible skin and joint hypermobility. What is your diagnosis?

A

The patient has Ehlers-Danlos type I connective tissue disorder

21
Q

A patient comes to visit you complaining of hearing loss. While taking this patient’s history, you find that he had lots of bone fractures as a child. You also note bluish sclera in your physical exam. His mother has a similar condition. What is connective tissue is mutated in this patient?

A

This is a mild case of autosomal dominant type I osteogenesis imperfecta. This results from a decrease in the amount of type I collagen.

22
Q

What is the biochemical mechanism responsible for the lethal type II form of osteogenesis imperfecta?

A

Glycine substitutions in the collagen helix that destabilizes the collagen.

23
Q

Development of what specific enzyme makes malignant melanoma a highly metastatic cancer?

A

Type IV collagenases eat through basal lamina and allow for tumor spread

24
Q

What inorganic ion plays a role in defense against newly developed tumor cells?

A

Zn2+. Matrix metalloproteases (collagenases) release endostatin when they degrade collagen. Endostatin plays a role in the prevention of angiogenesis and thus prevents blood supply to tumors.

25
Q

What were proteoglycans formerly known as?

A

Mucopolysaccharides

26
Q

Why are most structural polysaccharides linked via beta linkages?

A

It creates a tighter linkage so digestive enzymes can’t chop it up.

27
Q

What makes up the proteoglycans in higher mammals?

A

Uronic acid + “osamine” with beta 1,3 and beta 1,4 linkages

28
Q

How do engineer mimic the structure of our extracellular ground substance when building bridges?

A

They use steel (collagen) for tensile strength and concrete (proteoglycans) for resilience.

29
Q

What are the different glycosaminoglycans?

A
30
Q

Why do glycosaminoglycans make great molecules for smooth articulation of joint surfaces?

A

They have a high negative charge that makes them highly hydrated and great for lubrication.

31
Q

How is hyaluronic acid different from the other glycosaminoglycans?

A

It does not have sulfer and does not covalently bond with molecules in the ECM

32
Q

What is the difference between heparan sulfate and heparin?

A

Heparin has much more iduronic acid, sulfates and has a lower molecular weight. It is an anticoagulant where heparan sulfate is a glycosaminoglycan found in many connective tissues.

33
Q

A 7 year old child sustains a tear to his cartilage during a soccer game. What proteoglycan will be laid down first in healing? What will be laid down thereafter?

A

Hyaluronic acid is usually laid down first, but does not covalently bind to anything. Chondroiton is the main proteoglycan of cartilage and has a core protein covalently bound to repeating disaccharides.

34
Q

What transferases “leap frog” over eachother once the initial carbohydrates have been added to a serine/threonine in the protein in proteoglycan synthesis?

A

Transferases that add Glucuronic acid to N-acetylglucosamine and transferases that add N-acetylglucosamine to glucuronic acid.

35
Q

How are sulfates transfered onto the polymer during proteoglycan synthesis?

A

PAPS

36
Q

How does iduronic acid get into proteoglycan chains during synthesis?

A

Epimerases convert glucuronic acid to iduronic acid after glucuronic acid has already been incorporated into the chain.

37
Q

How do chondrocytes recycle material for proteoglycan synthesis?

A

Every 100 days or so the proteoglycans are taken up by the chondrocytes and degraded by the lysosomes.

38
Q

What is the biochemical basis of the different mucopolysaccharidoses?

A

Defect in degradation of proteoglycans. Degradation must go stepwise otherwise these osmotically active polymers aggregate in the lysosomes and cause cell death.

39
Q

A concerned mother brings her 6 month old baby in to see you with a concern of mental retardation. You note coarse facial features, skeletal abnormalities, corneal clouding and organomegaly. What proteoglycans are possibly accumulating in this child?

A

Dermatan and heparan sulfate due to alpha-L-iduronidase deficiency causing Hurler’s syndrome (MPS I)

40
Q

Why do patients with Hurler’s syndrome typically have smaller stature? How can you confirm diagnosis of Hurler’s syndrome?

A

Premature closure of the growth plate due to early death of chondrocytes. In order to diagnose it you need to add alpha-L-iduronidase to a tissue sample and see if it fixes the chondrocytes.