Lysosomes
Lysosomes (derived from the Greek words
lysis, meaning "to separate", and soma,
"body") are the cell's waste disposal system
and can digest some compounds.
Characteristic:
- Heterogeneous subcellular organelles in
cytosol, bounded by cell membrane
- Minute bodies, spherical or ellipsoidal
(0.8-0.9 μm)
-found in cells having greater metabolic
activity and in phagocytes.
The lysosomal membrane protects the
cytosol, and therefore the rest of the cell,
from the degradative enzymes within the
lysosome
At pH 4.8, the interior of the lysosomes is
acidic compared to the slightly basic
cytosol (pH 7.2).
The lysosome maintains this pH
differential by pumping protons (H+ ions)
from the cytosol across the membrane via
proton pumps and chloride ion channels
Lysosomal production involves ongoing
synthesis of enzymes more than 40 in
number, which are acid hydrolases:
i. Proteinases
ii. Lipases
iii. Carbohydrases
iv. Estrases
v. Nucleases
Enzymes are heavily glycosylated,
maintained at low pH
Lysosomal contents are first formed
• in rough endoplasmic reticulum, here
some CHO is added to enzymes
• They then pass on Golgi complex for
further changes and packaging in
vesicular form.
• Final processing is fusion of vesicles with
endosome
Enzymes to enter lysosomes possess
mannose at their end and can not move
into lysosome.
A change in mannose moiety occurs to
mannose-6-phosphate , which can be
recognized by specific receptors on
lysosomal membrane
Mannose 6 phosphate-enzyme complex
readily pass into lysosomes.
Functions of lysosomes:
A. Autophagy: hydrolytic digestion of
cells own worn out, damaged or unwanted
cytoplasmic material.
The material is segregated within a
membrane-vacuole which becomes fused
with lysosomes for digestion.
B.Hetrophagy:
Digestion of exogenous material
i. Phagocytosis
ii. Pinocytosis
iii. Endocytosis
Phagocytosis: cells take up large particles
e.g bacteria( vesicle containing phagocytosed material is called phagosomes)
Pinocytosis: taking up of fluid materil
(pinosome:
Endocytosis: taking up of smaller
particulate material (endosomes)
After digestion residual, insoluble digested
contents are ejected from cell by
exocytosis OR may remain in cell as
residual bodies.
Residual bodies stay in non-dividing cells
throughout life, become prominent in old
age in form of lipofuscin (lipid rich pigment)
within cell.
C. Role in protein degradation:
The protein that undergo turn over
(replaced by new) is digested. It is
completed by proteinases and require no
ATP.
D. Role during embryonic life:
Lysosomes help in causing APOPTOSIS
( programmed death of cell)
Relationship of
lysosomes with
diseases
Lysosomal membranes may
1. Release their hydrolases in response to
i. Asbestos dust
ii. Ion. radiation
iii. Hypoxia
iv. Silica particles
v. Heat
vi. Drugs
Cell death may take place of mutations in
genome occur.
2. Uric acid (hyperuricemia) enter
lysosomal membrane and release enzymes
lead to gouty arthritis
3. Osteoclasts of bone may release
hydrolases cause erosion of bones.
More than 50 lysosomal diseases,
classified on nature of stored
material
Salient features are involvement of
Kidneys, muscles, liver, spleen, heart and
bones
Specific deficiencies of lysosomal enzymes
result in non-digestion of their substrate
that accumulate in lysosomes in large
amount
Classification of LSDs
A. Diseases affecting carbohydrate
metabolism
a. Mucopolysaccharidoses
b. Glycoproteinases
B. Lipid storage diseases
a. Gangliosidoses
b. Neutral glycosphingoliiposes
c. Mucolipidoses
d. Disorders of neutral lipids
e. leukodystrophies
GlycosAminoGlycans (GAGs)
heteropolysaccharides having
i. amino sugar: (N-acetylglucosamine or Nactylgalactosamine)
ii. Uronic acid: (D-glucuronic acid or Liduronic acid)
Both of these sugar acids may be present.
iii. Amino sugars may have sulfate group.
Attached to –OH group.
Examples :
1. Hyaluronic acid -jelly like ,lubrication of
joints of animals. skin, blood vessels,
Connective tissues,corneas,tendon.
2. Chondroitin sulfate:
cartilages,ligaments,tendons, aortic
wall.
3. Heparin: anti-coagulant found in mast
cells lining liver, spleen,lungs, thymus,
blood
4. Others : keratan sulfate, dermatan
sulfate, heparan sulfate,
Proteoglycans
Glycosaminoglycans (GAG) are degraded in
lysosomes by acid hydrolases, pH 5.0
Low optimum pH required to prevent
enzymes leaking into cytosol and causing
cell death.
GAGS have shorter half life except keratan
(120 days)
They are engulfed by phagocytosis forming
vesicle which fuses with lysosome for
degradation.
Enzymes cleave polysaccharide chain –
endoglycosidases, producing
oligosaccharides. Further degradation
occurs and last groups SO4 or sugars are
removed.
A. Mucopolysaccharidoses
hereditary diseases,
Caused by deficiency of hydrolases
enzymes involved in hydrolysis of heparan
and dermatan sulfates.
Progressive disorders –accumulation of
GAGs in cells causing
i. Skelatal and extra-cellular deformities
ii. Mental retardation
All are autosomal except Hunter disease
which is X-linked
Homozygous children are normal at birth
but later deteriorate and in severe cases
death result.
Incomplete hydrolysis of GAGs cause
accumulation of oligo-saccharides in urine
and thus specific diseases can be
diagnosed.
Diagnosis: measuring cellular level of
hydrolases.
Bone marrow and blood cord transplant is
treatment.
Transplanted macrophages produce
hydrolases
Enzymes replacement is also available R/
a. Hurler Syndrome: MPS-1
Α-L Iduronidase deficiency
Corneal clouding, dwarfism, mental
retardation, coarse facial features, hearing
loss
Degradation of heparan and dermatan
sulfate affected.
b. Hunter syndrome: MPS-II
The syndrome has X-linked recessive
Iduronate-2-sulfatase deficiency
wide range of severity
No corneal clouding but physical and
mental -2replacement treatment
Degradation of heparan and dermatan
sulfate affected.
Sanfilippo syndrome: MPS-III
severe nervous disorder and mental
retardation
Defect in removal of N-sulfate or N-acetylglucosamine residues.
Symptoms appear after the first year of life
Behavioral problems
Coarse facial features
Heavy eyebrows that meet in the middle of the face
above the nose
Sleep difficulties, full lips
Stiff joints that may not extend fully
Walking problems
d. SLY syndrome: MPS-VII
Β-glucuronidase deficiency
Hepato-spleno-megaly
Skeletal derormity
Short strature
Corneal clouding
Mental retardation
B. Glycoproteinosis :
Acid hydrolysis are specific for removal of
one component of glyco-proteins
Hydrolases in these respect are exoenzymes remove respective groups in
sequence reverse of incorporation
If any degrative enzyme is missing,
degradation by other enzymes stop.
C. Glycoprotein storage
disease (oligosacchadoses) is caused by
deficiency of any enzyme
α -mannosidosis type-I is progressive
deficiency of α-mannosidase
Mannose rich oligosaccharides fragments
appear in urine. Diagnosis is by enzyme
assays.
Lipidoses
are those in which certain lipids
accumulate within cells of various tissues.
A. Neutral glycosphingolipidoses
1. Niemann Pick Disease
Autosomal recessive ,
affected cells contain sphingomyelin and
cholesterol, occur in many organs chiefly
in brain. Tissues are deficient in
sphingomyelinase(sphingomyelin--ceramide+phosphocholine
Autosomal recessive
disease
2. Gaucher disease:
Genetic disorder. Autosomal recessive
Affects fewer than 10,000 people
worldwide.
Gaucher affects all racial and ethnic
groups; prevalence is higher among
Ashkenazi Jews. More common than TaySachs disease.
Cells laden with cerebrosides which
contain glucose.
Spleen, liver are much enlarged
,lungs,lymph nodes and bones are also
affected (phagocytic cells affected)
Deficiency : Enzyme β-glucosidase
Ceramide-glucose---- ceramide+glucose
Ceramide-glucose is is glucocerebroside
Gaucher is a progressive, debilitating and
sometimes life-threatening disease.
Symptoms can include:
easy bleeding and bruising, fatigue,
anemia, weak bones, bone and joint pain,
and enlargement of the spleen or liver.
Symptoms can appear at any age.
3. Fabry’s disease:
Transmitted by X-chromosome
Skin,CNS, Heart,muscles,kidneys involved
Death due to heart/kidneys
defect lies in Trihexosylceramide αgalactosidaseA.
Ceramide-glucose-galactose-galactose
(ceramide trihexoside) ------ceramideglucose-galactose+galactose (ceramide
dihexoside)
Symptoms:
i. Pain whole body
ii. Proteinuria
iii. Cardiomyopathy
iv. Angiokeratoma
v. ocular involvement showing cornea
verticillata (also known as vortex keratopathy),
i.e. clouding of the corneas
B .Gangliosidoses:
1. Tay-Sach’s Disease:
Prevalant in jews, affects young
Autosomal recessive
Features- optic atrophy and idiocy
Due to deficiency β-hexoseminidase A
Enzyme responsible for breakdown of
gangliosides.
Gangliosides in large amount deposits in
cells.
(CNS, Liver,heart) but symptoms confined to
CNS
Optic
atrophy
2. Sandhoff’s disease:
Due to deficiency β-hexoseminidase A but
in addition B type is deficient.
Disease affects infants
C. Mucolipidoses:
i- I.cell disease:
Inclusion cell disease
Deficiency of UDP-N-Acetylglucosamine-1phosphotransferase
Glycolipids accumulate in cells alongwith
glycoproteins
such as abnormal skeletal development,
coarse facial features,
restricted joint movement, may be present at birth.
enlargement of certain organs, such as the liver
(hepatomegaly) or spleen (splenomegaly), and
sometimes even the heart valves
D. Disorders of neutral fats:
1. Wolman disease:
deficiency of acid lysosome lipase
accumulation of cholestero esters, and Tgs in
the cells
Feeding difficulties with frequent vomiting
Diarrhea (loose frequent stools)
Swelling of the abdomen (abdominal
distention)
Enlargement of the liver (hepatomegaly) and
spleen (splenomegaly)
Failure to gain weight or sometimes weight loss
2. Cholesterol ester storage disease
deficiency of acid lysosome lipase
accumulation of cholestero esters
E. Leukodystrophies:
1. Krabbe’s Disease:
Deficiency of galactosylceramidase
Accumulation of galactosylceramide and
galactosphingosine