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Peroxisomal Inborn Errors of Metabolism


Major function is for lipid metabolism; Example: B-oxidation of VLCFA (very long ... my ... – PowerPoint PPT presentation

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Title: Peroxisomal Inborn Errors of Metabolism

Peroxisomal Inborn Errors of Metabolism
  • Mylai Le
  • Li Cao
  • Mai Le
  • Benson Kua
  • March 18, 2009

What are peroxisomes?
  • Single-membraned organelles in eukaryotic cells
  • Lots in liver and kidney (for detoxification)
  • Contain various enzymes (catalase and various
  • Enzymes are transported into peroxisomes from the

Rat liver peroxisome internal dark areas are
urate oxidase crystals
Enzyme Uptake in Peroxisomes
  • Enzymes have a Ser-Lys-Leu (SKL) sequence on
    carboxyl terminus which signals for peroxisome
  • SKL on enzyme is recognized by a cytosolic
    carrier protein
  • Enzyme-carrier protein complex can then bind to a
    membrane receptor for internalization

Uptake of Catalase into Peroxisome
What do peroxisomes do?
  • Peroxisomal enzymes carry out oxidative reactions
  • Oxidases catalyze the reaction
  • RH2 O2 --gt R H2O2
  • Catalase can use H2O2 for further oxidation
  • H2O2 RH2 --gt R 2H2O
  • Catalase also detoxifies excess H2O2 generated
    from oxidase reactions
  • Some oxidase substrates are phenols, formic acid,
    formaldehyde, and alcohol
  • Also involved in other pathways like biosynthesis
    of phospholipids and cholesterol

Major Role of Peroxisomes
  • Involved in lipid metabolism
  • Example ß-oxidation of fatty acid molecules
  • Usually handles VLCFA (very long chain fatty
  • Alkyl chain of fatty acid shortened sequentially
    by 2 carbons at a time (stops at octanyl)
  • Cleaved carbons transformed to acetyl-CoA
  • Can also have a-oxidation (shortening by 1

What can go wrong?
  • Peroxisomal Biogenesis Disorder - peroxisomes are
    not made
  • Deficiency/defect in one enzyme
  • Deficiency/defect in multiple enzymes

Zellweger Syndrome
(aka Cerebrohepatorenal Syndrome)
  • Inherited human disease
  • Usually fatal within first year of life
  • Severe peroxisomal deficiency due to defect in
    importing proteins into peroxisomes
  • Leads to empty peroxisomes (no enzymes to get rid
    of toxic substances)
  • Individuals have severe abnormalities in the
    brain, liver, kidneys
  • Common features enlarged liver, high levels of
    iron and copper in bloodstream, and vision
  • Symptoms at birth lack of muscle tone, inability
    to move, and glaucoma
  • Other symptoms unusual facial characteristics,
    mental retardation, seizures, and inability to

Zellweger Syndrome
  • Transport of many or all proteins into
    peroxisomal matrix is impaired
  • Newly synthesized peroxisomal enzymes remain in
    the cytosol and are eventually degraded
  • Remarkable feature is that cells contain empty
    peroxisomes that have normal complement of
    peroxisomal membrane proteins
  • Thus Zellweger mutations cause defects in a
    peroxisomal receptor or transport protein for
    peroxisomal matrix proteins but not for membrane
  • Enzymes/proteins used for lipid oxidation cannot
    be imported into the peroxisome so lipid
    peroxidation cannot occur

Classic Refsums Disease Biochemistry
  • Rare, autosomal recessive disorder on chromosome
  • Caused by impaired a-oxidation of phytanic acid
    (a fatty acid found in food products such as
    dairy products, certain meats, and fish)
  • The defective enzyme is phytanoyl-coenzyme A
    hydroxylase, a peroxisomal enzyme responsible for
    catalyzing the second step of the metabolism of
    phytanic to pristanic acid. This results in an
    accumulation of phytanic acid in the brain,
    tissues and blood
  • Mechanism of phytanic acid toxicity is unclear
    but it may get incorporated into tissue lipids
    and impair myelin formation or it may affect the
    metabolism of fat-soluble vitamins

Classic Refsums Disease
  • Impaired metabolism of phytanic acid
  • Refsums Disease--gt defective phytanoyl CoA

Classic Refsums Disease Clinical Presentation
  • Infants generally appear normal at birth
  • Onset of symptoms is usually late childhood or
  • Progressive with periods of remission
  • Initial presentation is ataxia and/or failing
  • Clinical manifestations peripheral neuropathy,
    impaired vision from retinitis pigmentosa,
    hearing deficit, anosmia, cardiomyopathy and
    conduction defects, and ichythyosis

Classic Refsums Disease Prognosis
  • Phytanic acid restricted diet (lt 10 mg/day)
    delays progression of disease
  • However, vision and hearing problems may persist
    and sense of smell may not return
  • If left untreated, premature death usually occurs
    due to heartbeat abnormalities

Characteristic shortening of fourth toe in
Refsums disease
Treatments and Therapies
  • No standard course of therapy, mainly supportive
    (emotional, physical and psychological therapies)
    to alleviate symptoms and complications
  • Dietary supplementation with
  • - Antioxidant vitamins
  • - Limitation of intake of fatty acids,
  • VLCFAs (very long chain fatty acids)
  • - Pure DHA (an essential omega 3 fatty
    acid),early in
  • life, in conjunction with a
    well-balanced diet
  • Dietary changes should be monitored closely

Hepatocyte Transplantation
  • Re-population with normal hepatocytes containing
    fully functional peroxisomal enzymes
  • Experiments done in mice?
  • Host cells are ablated to provide growth
    advantage to donor cells

Gene Therapy
  • Amplification of the cDNA of the peroxisomal gene
    of interest, followed by liposomal transfection
    techniques to selectively deliver into cultured
    human hepatocytes ?
  • In vitro, high efficiency of transfection and
    appropriate intracellular localization to

  • Peroxisomes are organelles that contain a lot of
    enzymes used for detoxification (mainly oxidases)
  • Enzymes are transported from the cytosol into the
    peroxisomal matrix using carrier/transport
    proteins and membrane proteins
  • Major function is for lipid metabolism Example
    B-oxidation of VLCFA (very long chain fatty
    acids) cuts fatty acid sequentially by 2 carbons
    at a time a-oxidation can also occur (cuts fatty
    acids by 1 carbon at a time)
  • Peroxisomal errors peroxisomal biogenesis
    disorder, defect/deficiency in one or multiple
  • Zellwegers Syndrome --gt transport of enzymes
    into peroxisome is impaired so peroxisome does
    not have normal detoxification function
    (deficient in peroxisomal matrix enzyme)
  • Classic Refsums Disease --gt an enzyme for
    a-oxidation of phytanic acid is impaired (defect
    in peroxisomal enzyme)
  • No standard treatment, mainly supportive and
    dietary restrictions to alleviate symptoms and

  • Alberts et al. Molecular Biology of the Cell.
    Garland Publishing, 1994.
  • Stryer et al. Biochemistry 5th Ed. W.H. Freeman
    Company, 2002.
  • Lodish et al. Molecular Cell Biology. W.H.
    Freeman Company, 2000.
  • Wills et al. Refsums Disease. Q J Med, 94,
    403-406, 2001.
  • National Institute of Neurological Disorders and
    Stroke, Accessed on March 10, 2009
  • Wanders et al. The inborn errors of peroxisomal
    B-oxidation A review. J Inh Met Disease, 13,
    4-36, 1990.
  • Accessed on March 17, 2009 - http//www.cartage.o