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Sphingolipid Diseases

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					Sphingolipid Biochemistry
                  Sphingolipid definitions


Sphingosine: an 18-carbon amino alcohol with a trans double bond; the
starting point for ceramides.




Ceramide: a sphingosine molecule connected to a fatty acid by an amide bond.
Ceramides are the starting point for sphingomyelin, cerebrosides and gangliosides.




Sphingomyelin: a ceramide that has a phosphorylcholine head group group in
place of its hydroxyl. Present in myelin sheaths around nerves.
Palmitoyl CoA + Serine = Sphingosine

          Palmitoyl-CoA             Serine

                          1. Serine donates 2 carbons and
                             an amino group
                          2. Reduction of the carbonyl to a
                             hydroxyl
                          3. Then, oxidation to add a
                             double bond
                              – Look familiar?
                                 • Resembles both b-oxidation
                                   and D4 desaturation



  Sphingosine
                   Sphingosine-1-phosphate




•   Sphingosine can be phosphorylated by     •   Outside the cell, S1P exerts many of its
    sphingosine kinase, a ubiquitous enzyme      effects through interaction with five specific
    in the cytosol and ER to make                G protein-coupled receptors on cell surfaces.
    sphingosine-1-phosphate (S1P).               Different cells have different receptor
•   Sphingosine-1-phosphate, a                   profiles.
    lysophospholipid, acts as a potent       •   S1P is vital to the function of several
    messenger molecule that operates both        immune cells. It is a major regulator of T
    intra- and inter-cellularly.                 cell development, B and T cell recirculation,
•   Within the cell, it promotes mitosis and     tissue homing patterns, and chemotactic
    inhibits apoptosis. It also regulates        responses to chemokines.
    calcium mobilization and cell growth in
    response to a variety of extracellular
    stimuli.
Sphingosine + Fatty Acid = Ceramide




                      Simple acyl transfer,
                        but to an amide
                        bond instead of the
                        typical ester
Ceramide + Choline = Sphingomyelin
                     Phosphocholine head group gives
                     sphingomyelin a hydrophilic end

                      Choline carries a positive charge
                      the whole molecule becomes
                         more amphoteric



                     CDP-choline is the activated
                     choline donor- same as for PC

                           Choline
Comparison of Sphingomyelin and PC
Comparison of S-1-P and LPA
                    More Definitions
                              Glycosidic
  Galactose (polar head)      bond

                               Cerebrosides: a ceramide
                               that has a sugar added to the
                               head group. Most commonly,
                               the sugar is glucose (Glu) or
Ceramide (non-polar tail)      galactose (Gal).
Sialic acid

                                Gangliosides: a ceramide
                                that has multiple sugars
                                including at least 1 sialic
                                acid residue added to the
                                head group. Increased
                                variety and complexity.
Ceramide + Sugar = Cerebroside
         Ceramide




                              Sugar is activated by
                                UDP

                              Addition of sugar
                                occurs at the C1
                                OH group of
                                ceramide



Cerebroside
(Example:glucosyl-ceramide)
  Ceramide + (Many Sugars) = Gangliosides
                                       GM1
                                                                                           Sugars are
                                                  GM2                                      activated by
                                                               GM3
                                                                                           UDP
                                                                                           Each sugar is
                                                                                           added
                                                                                           individually

                                                                                           Gangliosides can
                                                                                           have varied,
                                                                                           complex structures
                                                                                           They often
                                                                                           function as
                                                                                           antigens and
                     Stearic acid (C18) N-acyl chain                                       surface markers
Trivia: Do you know your blood type? Is it A+? B-? O? The letters refer to the
specific multi-sugar structures are attached to gangliosides and proteins on the surface
of your red blood cells.
           Degradation of Sphingolipids

• Sphingolipids do not break down easily
   – which is why they make good membrane components
• Degradation is an issue
   – LOTS of degradation enzymes exist
        • it’s a long, complicated bunch of pathways
• Genetic defects in these enzymes cause a long list of diseases
   –   all involve unhealthy accumulation of some sphingolipid
   –   most are rare, but more common in specific ethnicities
   –   key diseases: Gaucher’s, Tay-Sachs’, Fabry’s and Niemann-Pick
   –   Resources: (Online Mendelian Inheritance in Man)
        • OMIM Web site: www.ncbi.nih.gov/OMIM/searchomim.html
                                                                    Degradation of Sphingolipids

                      GM1                                                                                     Sulfatide
                                                Globoside


GM1 b-galactosidase
                                               Hexosaminidase A/B                                          Arylsulfatase A
GM1 Gangliosidosis
                            Gal                Sandhoff’s disease                             Metachromatic leukodystrophy
                                                                       GalNAc                                                       SO42-




                      GM2
                                          Trihexosylceramide                                          Galactocerebroside


 Hexosaminidase A                            a-galactosidase A                                        Galactocerebrosidase
 Tay-Sachs disease          GalNAc              Fabry’s disease                                          Krabbe’s disease
                                                                     Gal                                                            Gal




               GM3                         Lactosylceramide                       Glucocerebroside                      Ceramide


                                     Ganglioside neuraminidase                   b-galactosidase                Glucocerebrosidase


                                                          NANA                              Gal                 Gaucher’s disease         Glc
 Sphingomyelin
                                                                      Sphingomyelinase

                                                                           Niemann-Pick disease
                                                 Phosphocholine

                                                                                                                             Ceramidase
                                             Fatty acid      +      Sphingosine
                                                                                                                             Farber’s disease
                                                 Tay-Sachs’ Disease
                                                                      • Incidence: Like Gaucher’s but rarer
                                                                          – ~1:30 Ashkenazi Jews are carriers
                                                                          – ~1:500 carriers in general population
                                                                      • Symptoms:Neurodegenerative
                                                                          – mental retardation and seizures
                                                                          – listlessness, fixed gaze, hypotonia
                                                                          – cherry-red spot on retina (see picture)
                                                                      • Mechanism: Genetic
                                                                          – Lack of GM2 hexosaminidase A
                                                                               • Auto recessive, OMIM #272800
                                                                          – Ganglioside GM2
                                                                               • Builds up in CNS
Cherry-red spot on a patient’s retina, a common
                                                                      • Treatments: No good therapy yet
  finding in patients with Tay-Sachs’ disease.
                                                                          – Supportive and symptomatic
                                                                          – Patients die by age 5
Trivia: Injections of recombinant hexosaminidase A do not help Tay-
Sachs’ patients because it cannot cross the blood-brain barrier.          – Gene therapy target (future)
                                   Gaucher’s Disease
                                             • Incidence: Uncommon in most groups
                                                – ~1:13 Ashkenazi Jews are carriers
                                             • Symptoms:
                                                –   enlarged liver and spleen (see picture)
                                                –   easy bruising and bone fractures
                                                –   hyperpigmentation of skin
                                                –   sometimes: anemia
                                             • Mechanism: Genetic
                                                – Lack of working b-glucosidase
                                                     • Auto recessive, OMIM #230800
                                                – Glucosyl acylsphingosine
                                                     • Builds up in liver, spleen & bone
                                             • Treatments:
                                                – Recombinant acid b-glucosidase
  Magic marker outlines of the enlarged
liver and spleen in a school-aged boy with      – Symptomatic support
     Gaucher’s disease. Note also the           – Gene therapy target (future)
           hyperpigmented skin.
                     Niemann-Pick Disease Type A
                                    • Incidence: Type A is the most severe of the 5
                                      subtypes of Niemann-Pick Disease
                                        – ~1:90 Ashkenazi Jews are carriers
                                    • Symptoms: Neurodegenerative
                                        – Large abdomen within 3 to 6 months and
                                          jaundice
                                        – Progressive loss of early motor skills,
                                          progressive spasticity, developmental delay
                                        – Cherry red spot in the eye
                                        – (Generally) a very rapid decline leading to
                                          death by two to three years of age.
                                    • Mechanism: Genetic
                                        – Lack of Sphingomyelinase
                                            • Auto recessive, OMIM #257200
Patient with Niemann Pick Disease
                                        – Sphingomyelin
                                            • builds up in CNS, liver and lungs
                                    • Treatments:
                                        – Supportive and symptomatic
                                        – Patients die by age 3
                                        – No effective therapy to date
       Summary of Today’s Sphingolipids

Molecule(s)      Synthesis Scheme             Significance                   .
Sphingosine      Palmitoyl CoA + Serine       Brings in the amine group
                                              Important signaling molecule
Ceramides        Sphingosine + Fatty Acid     Amide bond, hydrophobicity
                                              Important signaling molecule
Sphingomyelins   Ceramide + Choline           Amphoteric & charged, diseases
                                              Membrane component
Cerebrosides     Ceramide + Monosaccharides   Amphoteric & neutral, diseases
                                              Rich in brain
Gangliosides     Ceramide + Polysaccharides   Complexity, diseases
                                              Rich in brain
           Review of Lipid Metabolism
    LIPIDS           CARBOHYDRATES                        PROTEINS

   fatty acids            glucose                         amino acids


                        Acetyl CoA


  malonyl CoA              citrate                      acetoacetyl CoA

    fatty acid                                            HMG-CoA

  neutral lipids        CO2 + ATP              ketone bodies   cholesterol
 phospholipids           (energy)
  sphingolipids
cholesterol esters
                      Oversimplified picture
           Organ Localization

                     BLOOD TRANSPORT
                     • TG on lipoproteins
 Brain               • FA on albumin          Adipose
                     • Glucose dissolved
                     • Ketone Bodies dissolved
                                      TG
         Glucose                                  FA
         (Ketones)

                            Liver

                Glucose, FA
                                           Bile
                (Ketones)
Muscles                                                Intestine

                      Oversimplified picture
        Intracellular Localization




   FA

Acetyl CoA

				
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