Lesson 6 Lysosome and Peroxisome

7/25/2019 Lesson 6 Lysosome and Peroxisome

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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 >>
http://www.simdnama.org/Day_4/4_5_Perox%20Biogen_Didactic_slide06.swfhttp://www.simdnama.org/Day_4/4_5_Perox%20Biogen_Didactic_slide06.swf


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Role of peroxins in matrix protein

import

Gould, Raymond, Valle.In: Metab & Molec Basis of Inh Dis. Ch129 p. 3190.
http://www.simdnama.org/Day_4/4_5_Perox%20Biogen_Didactic_slide07.swfhttp://www.simdnama.org/Day_4/4_5_Perox%20Biogen_Didactic_slide07.swfhttp://www.simdnama.org/Day_4/4_5_Perox%20Biogen_Didactic_slide07.swf


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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
http://www.simdnama.org/Day_4/4_5_Perox%20Biogen_Didactic_slide14.swfhttp://www.simdnama.org/Day_4/4_5_Perox%20Biogen_Didactic_slide14.swf


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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 >>
http://www.simdnama.org/Day_4/4_5_Perox%20Biogen_Didactic_slide16.swfhttp://www.simdnama.org/Day_4/4_5_Perox%20Biogen_Didactic_slide16.swfhttp://www.simdnama.org/Day_4/4_5_Perox%20Biogen_Didactic_slide16.swfhttp://www.simdnama.org/Day_4/4_5_Perox%20Biogen_Didactic_slide16.swf


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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

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Lesson 6 Lysosome and Peroxisome