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Lysosome and Peroxisome
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Lysosome
Organelle contains digestive enzymes to
digest macromolecules.
Single membrane bound organelle The Golgi apparatus produces lysosomes by
budding.
Contains digestive enzymes synthesized inthe rough endoplasmic reticulum
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The digestive enzymes include:
a) lipase (digests lipids)b) Carbohydrases (digest carbohydrates)
c) Proteases (digest proteins)
d) Nucleases (digests nucleic acids)
The pH inside a lysosome is 4.8 (cytoplasmis 7.3)
Lysosome membrane pumps H+ (ATPase)
from cytoplasm into the vesicle tomaintain low pH.
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The lysosomes are used for the digestion ofmacromolecules from phagocytosis
(ingestion of food), Cellular recycling process (where old
components are continuously destroyedand replaced by new ones)
Autophagy, or autophagocytosisprogrammed cell death (apoptosis)
Illness caused by the malfunction of the
lysosomes or one of their digestiveproteins, e.g., Tay-Sachs disease or Pompe'sdisease
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Peroxisome
Single membrane bound organelle
Not formed in the Golgi complex instead self-replicate by dividing
Abundant in the liver Main function to detoxify cell by eliminating toxic
hydrogen peroxide
4H2O2 4H2O + 2O2Chemical reaction catalyzed by the enzymecatalase
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b-oxidation of long and very long chain fatty
acids into acetyl groups
bile acid synthesis
cholesterol synthesis
numerous genetic disorders associated with
defects in the peroxisome
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Properties of peroxisomes
Spherical, single membrane bound,
Diameter = 0.2 - 1 m, several hundred/cell
All eukaryotes
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>2000: Study of protein functions, pathophysiology,applications to management and therapy
1958: Peroxisomes 1st described
1964: Zellweger cerebro-hepato-renal syndrome
1973: Abnormal peroxisomes in ZS
1983: PBD, a paradigm for metabolicmalformation syndromes
1987: Complementation groups
reflect genetic heterogeneity in PBD
1990: Peroxisome biogenesis (PEX) genes identified in yeast
1994: Human genes identified by yeast homology
Timeline of discovery
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Px
Organelles
Benefits
concentrate enzymes andsubstrates
sequester toxic substances
Requirements
targeting systems
transporters, receptors Consequences
genetic diseases ofthe components
Nucleus
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Peroxisome assembly (PEX) genes
Encode proteins (peroxins) required for matrix
protein import, peroxisome division and
membrane formation
14 human PEX genes; 13 thus far responsible
for PBD
26 different PEX genes among eukaryotes
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Peroxisomes originate from ER membranes and byfission of existing peroxisomes
adapted from Annu Rev Genet. 2000;34:623-652.
Sacksteder KA, Gould SJ.
NEXT >>
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Role of peroxins in matrix protein
import
Gould, Raymond, Valle.In: Metab & Molec Basis of Inh Dis. Ch129 p. 3190.
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Enzymatic pathways in peroxisomes
Fatty acid oxidation (VLCFA, PA)
H2O2 detoxification (catalase)
Docohexanoic acid (DHA) synthesis
Bile acid synthesis
Plasmalogen (ether phospholipid) synthesis
Cholesterol synthesis
Glyoxylate detoxification
Lysine catabolism (pipecolic acid)
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J. Biol Chem. 2001; 276:38115-20.
Su HM, Moser AB, Moser HW, Watkins PA
Synthesis of docohexanoic acid (DHA) requires peroxisomal
-oxidation
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Plasmalogen
CH2-O-CH=CH-R
CH-O-C-CH2-R2
O
CH2-OPO3-ethanolamineor -choline
Vinyl ether-linkedalkyl chain at C-1
Plasmalogens are abundant in
nervous tissue and erythrocytemembranes as phosphatidyl-choline phosphatidyl-ethanolamine
Plasmalogens are glycerol-
based phospholipids with avinyl ether-linked alkyl groupin the C-1 position
Functions: antioxidant DHA storage lipid messengers (PAF) vesicle formation
Plasmalogen lipids
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Plasmalogen biosynthesis is initiated in
peroxisomes
Click to view animation >>
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Genetic disorders of peroxisomes
Multiple enzyme deficiencies: PeroxisomalBiogenesis Disorders (PBD)
Zellweger spectrum disorder (ZSD) (~1/60,000)
Rhizomelic chondrodysplasia punctata spectrum(RCDP)(~1/100,000)
Single enzyme deficiencies
X-linked adrenoleukodystrophy (X-ALD) (~1/20,000)
3-methyl-CoA racemase deficiency Adult Refsum disease
Hyperoxaluria Type I
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Some single enzyme deficiencies can
mimic PBDs
VLCFA oxidation Zellweger spectrum disorder
Acyl-CoA oxidase
D-Bifunctional protein (hydratase/dehydrogenase)
Plasmalogen biosynthesis RCDP spectrum
DHAPAT (RCDP2)
ADHAPS (RCDP3)
Some PBDs mimic SEDs Adult Refsum disease causes PEX7 deficiency
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Zellweger Syndrome Infantile Refsum Disease
Zellweger spectrum disorder (ZSD), a
clinical continuum
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Craniofacial dysmorphism (ZS)
Widely patent fontanels and sutures Prominent high forehead
Shallow orbital ridges
Low broad nasal bridge
Anteverted nares Hypertelorism
Epicanthal folds
High arched palate Micrognathia
Redundant skin folds of neck
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Neonatal adrenoleukodystrophy
15 mo old with FTT
Weight: 50th% for 6-mo old
Height: 10th%
Frontal bossing
Wide anterior fontanel
Depressed nasal bridge
Epicanthal folds
Diffuse hypotonia
White matter changes on MRI
Developmental delays andseizure disorder
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Infantile Refsum disease?
42-yr old woman
Hearing loss at 2-3 yrs
Progressive retinal disease Legally blind at 11 yrs
Intermittent
behavioral/psychiatricproblems
Lives in a group home
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Disease course
About 1/2 of PBD patients have NALD-IRDphenotypes
Patients show progressive deterioration over
time and become blind, deaf and loosecognitive abilities
Deterioration may coincide with onset or
progression of leukodystrophy If effective treatment was available, it might
halt the disease progression
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Infantile Refsum disease
Diagnosed ~18 months
Retinitis Pigmentosa
(RP) and hearing loss
Walked at ~30 months
Developed seizures at 4
yrs
Deterioration in vision
Moderate to severe MR
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Rhizomelic Chondrodysplasia Punctata
(RCDP)
Dysmorphic facies: frontal bossing, short saddle
nose with anteverted nares, congenital cataracts
profound impairment of growth and mental retardation,
variable survival