Biochem Emphysema

8/8/2019 Biochem Emphysema

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ALPHA

Jao Levina

Lopez, J. Kalaw

Liao Lopez, A.


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CASE

A severe form of obstructive lung disease was found in several

members of a family. One brother had died earlier of lung disease.

Blood plasma from his surviving brother and sister showed

abnormally low concentrations of antitrypsin (3 5 The

plasma fraction also moved abnormally on isoelectric focusing

gel electrophoresis.


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OBJECTIVES

To define emphysema

To define 1-antitrypsin and its effects on the lungs

To identify the signs and symptoms of emphysema

To enumerate the different methods of treating emphysema


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EMPHYSEMA

Long-term, progressive disease of the

lungs

Included in a group of diseases called

C

hronic Obstructive PulmonaryDiseases

Causes:

Smoking

Exposure to air pollution and second handsmoke

Heriditary


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Signs and Symptoms

Shortness of breath

Barrel chest

Fatigue

Coughing (with or withour sputum)

Wheezing

Cyanosis

Excess Mucus production


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Particulates become lodged into alveoli causing an inflammatory

response

Enzymes released during inflammatory response causes

disintegration of alveolar walls Deformation of lungs

Reduced surface area for gas exchange


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To accomodate for decreased surface area:

Expansion of thoracic cage (Barrel Chest)

Diaphragm contraction

Hyperventilation

Vasoconstriction of vessels = Pulmonary Hypertension

Familial Emphysema

Caused by 1-antitrypsin deficiency

Autosomal

Decreased production of 1-antitrypsin


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1-ANTITRYPSINA. Description

A1AT is a single-chain glycoprotein consisting of 394

amino acids in the mature form and exhibits a number

of glycoforms.

The three N-linked glycosylations sites are mainly

equipped with so-called diantennary N-glycans


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However, one particular site shows aconsiderable amount of heterogeneity since

tri- and even tetraantennary N-glycans can

be attached to the Asparagine 107 (ExPASy

amino acid nomenclature).


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These glycans carry different amounts of negatively-charged sialic acids, thiscauses the heterogeneity observed on normal A1AT when analysed by isoelectric

focussing.

In addition, the fucosylated triantennary N-glycans were shown to have the

fucose as part of a so-called Sialyl Lewis x epitope, which could confer this

protein particular protein-cell recognition properties.

The single cysteine residue of A1AT in position 256 (ExPASy nomenclature) is

found to be covalently linked to a free single cysteine by a disulfide bridge.


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A1AT has a characteristic secondary structure of beta sheets and alpha

helices.


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1-antitrypsin 1 is produced in the

liver and

released into the blood, ultimately to

protect the lungs from attack by an

enzyme called neutrophil elastase.

Neutrophil elastase is produced bywhite blood cells in response to

infection or irritants to digest damaged

tissue in the lungs.


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B. FUNCTION

Hepatocytes synthesize alpha1-antiprotease serine protease inhibitor

Its principle function in the lung is to inactivate

neutrophil elastase, to protect the lungs from

protease-mediated tissue destruction

The major biochemical activity is inhibition of

several neutrophil-derived proteases (eg,

trypsin, elastase, proteinase 3, cathepsin G).


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C. MUTATION

AAT deficiency is caused by mutations in the SERPINA1 gene, located

on chromosome 14

Mutation: Substitution of Lys residue for a glutamate at position 342

(Z-variant)


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Mutation cause a shortage (deficiency) of the protein

Z protein polymerizes in the liver

serum AAT

AAT to lungs

inhibition of elastase activity in lungs

neutrophil elastase destroys small air sacs in the lungs (alveoli)

emphysema


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D. Methionine and serine residues: Effect of smoking


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DIAGNOSIS

Serum 1 antitrypsin level (20-48 m)

Serum protein electrophoresis

90% of the serum 1 -globulin

Alpha-1 genotyping


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TREATMENT

1 Antitrypsin Replacement Therapy

Replacement of 1 antitrypsin in the blood and increase it to its protective

levels

recommended for symptomatic persons with the PiZZ phenotype given when 1 antitrypsin is less than 11 mol/L or 310 mg/L


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1 Antitrypsin

from pooled human plasma

administered intravenously every week

Dose: 60 mg/kg

Pitfalls:

Risk for disease transmission

Costly

Difficulty of administration

Recent Advancements: Inhalation Therapy

Transgenic production


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Synthetic Chaperones

Chaperones -auxiliary proteinsthat assist in the folding and

assembly of growing proteins

4-phenyl-butyriuc acid

Gene Technology

insertion of normal human 1antitrypsin gene that has been

done in muscle and liver cells


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CONCLUSION

Emphysema can be caused by a rare genetic predisposition called 1antitrypsin deficiency.

The deficiency in 1 antitrypsin causes an imbalance in the protease

and antiprotease activity resulting to alveolar destruction byneutrophil elastase.

Probable treatment of emphysema includes 1 antitrypsin

replacement therapy, use of synthetic chaperones and gene

technology.

Documents

Biochem Emphysema