Card Set Information
Path chapter 5
Role of lysosomes?
Key component in the intercellular digestive tract.
Contain many hydrolytic enzymes.
Route of production of lysosomal enzymes?
Synthesized the the endoplasmic reticulum
Transported to the golgi.
In the golgi they undergo many post transcriptional modifications, attachment of mannose-6-phosphate to some oligosaccharide side chains.
The mannose, address labels, bind to receptors on the internal golgi membrane and are segregated from other enzymes. They then are pinched off in vesicles and moved to lysosomes.
The mannose-6-phosphate receptors are shuttled back to the golgi.
Function of lysosomal acid hydrolyses?
catalyze the breakdown of a variety of macromolecules.
Can be derived from the turnover of intercellular organelles or acquired form outside the cell.
With a deficiency of any of these enzymes the partially degraded by products can collect in the cell and inhibit normal cell function.
5 routes of difunctional lysosomal enzymes?
1. synthesis of a catalytically inactive protein that will cross link with normal enzyme. Immunoassays will look normal but functional enzyme will be low.
2. Defect in post translational processing.
3. Lack of enzyme activator protein.
4. Lack of substrate activator protein. Proteins that bind with the substrate and facilitate its hydrolysis.
5. Lack of transport protein required to remove material from the lysosome.
-Lysosomal storage disorders can result from the lack of any preteen essential for the normal function of lysosomes.
What organs are effected?
1. The tissue where most of the material to be degraded is found.
2. The location of degradation.
Ex. The brain is rich in gangliosides and hence defective hydrolysis of gangliosides results primarily in the storage within neurons and neurologic symptoms.
7 subgroups of lysosomal storage diseases.
4. Mucopolysaccharidoses MPS
6. Other complex carb diseases.
7. Other lysosomal storage diseases.
Type 2 glycogenosis
type 1 infantile, generalized
Tyoe 2 Juvenile
GM1 ganglioside b-galactosidase
GM1 galctoside, galactose containing oligosaccharides
Multiple sulfatase deficiency
arylsulfitase A,B,C; steroid sulfatase; iduronate sulfatase; heparin N-sulfatase
sulfide, steroid sulfide, heparin sulfide, dermatan sulfide
Dermatan sulfate, heparin sulfate
Dermatan sulfate, heparin sulfate
deficiency of phosphoralating enzymes essential for the synthesis of mannose-6-phosphate recognition marker. Enzymes are secreted extracellularly.
fucose containing sphingolipids
mannose containing oligpsaccharides
Cholesterol esters, triglycerides
Acid phosphate deficiency
Lysosomal acid phosphate
Degradation of GM2 gangliodides?
requires three polypeptides.
Morphology of tay sachs
GM2 accumulates in many tissues, heart, liver, spleen.
Clinical dominance is the involvement of neurons of the central and autonomic nervous system and retina.
Neurons are ballooned with cytoplasmic vacuoles
Stains for fats are positive
Whorled onion skin layers of membranes in lysosomes.
Progressive distraction of neurons
Retina ganglion cells are swollen with GM2, a cherry red spot appears in the macula.
Appears normal at birth and begins to manifest symptoms at 6 months.
motor and mental deterioration
death at 2-3
Niemann-Pick disease: Types A and B
: severe infantile form eight extensive neurological involvement, marked visceral accumulation of sphingomylen, progressive wasting and death within 3 years.
: Organomegaly but no CNS involvement
Symptoms evident by 6 months
: protuberant abdomen because of hepatosplenomegly.
Once manifestations appear, they are followed by failure to thrive, vomiting, fever and lymphadenopathy.
sphingomyelinase activity is in the liver and bone marrow.
Morphology of Neimann-Pick
accumulation of sphingomylin in lysosomes, particularly on the mononuclear phagocyte system.
enlarged cells with sphingomyelin and cholesterol in them
Stain positive for fat
lysosomes take the form of parallel palisaded, zebra bodies
spleen, live, lymph nodes, bone marrow, tonsils, gastrointestinal tract, and lungs.
Large spleen and slightly large liver.
1/2 of patients have cherry red spot.
Neimann-pick type C
protein involved in cholesterol trafficking, cholesterol accumulates within the cell
present in astrocytes, terminal axons and dendrites degenerate.
Can present at hydrous fetal and still birth, neonatal hepatitis, chronic progressive neurologic disease.
Childhood ataxia, suprnuclear palsy, psychomotor regression, hepatosplenomegaly and dysarthria.
Most common lysosomal storage disorder.
Cleaves glucose molecules from ceramide
accumulates in phagocytic cells
glucocerebrosides are continually formed from the catabolism of glycolipids derived mainly from the cell membranes of senescent leukocytes and erythrocytes.
detectible but low enzyme
Gaucher cells look like tissue paper, fibrous
Storage of lipids is toxic
Expansion of marrow space leads to bone pain.
Where to measure glucocerebrosidase?
leukocytes of cultured skin fibroblasts
What is a mucopolysaccharide?
long chain complex carb linked with a protein to form a proteoglycan
What GAGs accumulate in MPS
dermatan sulfate, heparin sulfate, keratan sulfate, and chondrotin sulfate
General features of MPS
includes liver spleen and blood vessels and heart
coarse fascial features, clouding of cornea, joint stiffness, mental retardation
mucopolysaccharide is often excreted in the urine.
Hepatospleenomegaly 6-24 months
Hunters, type 2, differs from hurlers in that it is X linked and has clear corneas
mucopolysaccharide are found accumulated in mononuclear cells, endothelial cells, smooth muscle cells, and fibroblasts.
spleen, liver, heart, and blood vessels
cells are distended and have clearing of cytoplasm to create balloons.
Zebra bodies in neurons
Hepatospleenomegaly, skeletal deformaties, valvular lesions, subendothelial arterial depostits (leads to MI) brain lesions.
Glycogen storage diseases
enzymes involved in the synthesis or degradation of glycogen
different enzyme in each tissue
Formation of glycogen
glucose to glucose-6-phosphate by hexokinase
G6p to G1P by phosphoglucomutase
G1P TO URIDINE DIPHOSPHATE, highly branched polymer
aplpha 1,4 linkage
breakdown of glycogen
G1P is split in the liver and muscle by distance phosphorylases until about 4 glucoses remain, limit dextran
then need a debranching enzyme
Three principle types of glycogenoses
1. Hepatic type
Von Gierke disease, Type 1, glucose-6-phosphatase, hepato and reno-megaly.
convolutions, failure to thrive hypoglycemia, gout
2. Myopathic type
McArdle syndrom Type V, muscle phosphorylase, skeletal muscle accumulates glycogen
painful cramps with strenuous activity
3, misc type
Pompe type II, acid maltase, heart muscle and liver.
lack of hemogentisis oxadase
build up of hemogentisis acid
deposit of pigment in articular cartilage of joints. Cartilage becomes brittle and fibrillated.