METABOLISM OF ACYLGLYCEROLS AND SPHINGOLIPDS Ben S. Ashok MSc.,FAGE.,PhD., Dept. of Biochemistry
STORAGE AND MEMBRANE LIPIDS
STORAGE LIPIDS Mainly as triacylglycerols (triglycerides) in adipose cells Constitute 84% of stored energy Protein - 15% Carbohydrate (glucose or glycogen) - <1%
MEMBRANE LIPIDS PHOSPHOLIPIDS, GLYCOLIPIDS
CLASSIFICATION OF PHOSPHOLIPIDS Depending on the type of alcohol, PL are classified into two groups Phosphoglycerides Phosphatidate Lysophosphatidate Phosphatidyl choline Phosphatidyl ethanolamine Phosphatidyl serine Phosphatidyl inositol Phosphatidyl glycerol Diphosphatidyl glycerol Sphingophospholipids Sphingomyelins
GLYCEROPHOSPHOLIPIDS Glycerophospholipids are membrane lipids in which 2 fatty acids are attached in ester linkage to the first and second carbons of glycerol. A highly polar alcohol is attached through a phosphodiester linkage to the third carbon.
BIOSYNTHESIS OF MEMBRANE PHOSPHOLIPIDS Synthesis of the backbone molecule (glycerol or sphingosine). Attachment of fatty acids to the backbone in ester or amide linkage. Addition of a hydrophilic head group joined to the backbone through a phosphodiester linkage. In some cases, alteration or exchange of the head group to yield the final phospholipid product.
TRIACYLGLYCEROLS AND GLYCEROPHOSPHOLIPIDS ARE SYNTHESIZED FROM THE SAME PRECURSORS Formation of Glycerol-3-phosphate:
Fatty acyl groups are activated by formation of fatty acyl- CoA. Then they are transferred to ester linkage with glycerol-3-phosphate. PHOSPHATIDIC ACID = DIACYLGLYCEROL 3-PHOSPHATE
OVERVIEW OF ACYLGLYCEROL BIOSYNTHESIS Glycerol 3-Phosphate Dihydroxyacetone phosphate Phosphatidic acid Plasmologens PAF Diacylglycerol Phosphatidylinositol Cardiolipin Phosphatidyl Choline Phosphatidyl ethanolamine Triacylglycerol Phosphatidyl Inositol 4,5 bisphosphate
FUNCTIONS OF PHOSPHOLIPIDS Major components of cell membranes
Distribution of PL in the membranes
FUNCTIONS OF PHOSPHOLIPIDS contd.. Play roles in digestion, absorption, transport of lipids, cellular metabolism Act as biologically active compounds Stores arachidonic acid, which is a precursor for eicosanoids Forms second messengers - role in signal transduction - Phosphatidyl inositol
LIPIDS AS SIGNALS- INTRACELLULAR MESSENGERS PIP 2 is hydrolyzed by phospholipase C in response to hormonal signals. Both of the metabolites produced act as intracellular messengers.
FUNCTIONS OF PHOSPHOLIPIDS contd.. Constituent of lung surfactant Phospholipids are produced by fetal lungs during the last few weeks of intrauterine life. This fluid coats the inner lining of the alveoli thus preventing the alveoli from collapsing with every exhalation. Without surfactant the alveoli collapse between breaths, making each breath extremely difficult. Premature infants lack surfactant production thus predisposing the infants to respiratory distress syndrome.
FUNCTIONS OF PHOSPHOLIPIDS contd.. Cardiolipins (Diphosphatidyl Glycerol) Found mainly in the inner membrane of mitochondria. Used in serodiagnosis of syphilis. Identification of antibodies that react with cardiolipins - diagnosis of antiphospholipid syndrome. ~50% of the heart phospholipids are plasmalogens Platelet-activating factor (PAF) is a potent molecular signal released from leucocytes that stimulates platelet aggregation and serotonin release. It also has a variety of effects on many tissues including roles in inflammation and the allergic response.
DEGRADATION OF PHOSPHOLIPIDS IN LYSOSOMES For each hydrolyzable bond in a glycerophospholipid there is a specific hydrolytic enzyme in the lysosome. Phospholipase A1 hydrolyzes the fatty acid at C1. Phospholipase A2 hydrolyzes the fatty acid at C2. When one fatty acid is removed from either C1 or C2, a lysophospholipase removes the remaining fatty acid. Phospholipases C and D each split one specific phosphodiester bond in the head group.
SPHINGOLIPIDS They resemble PL, in having polar head group and two nonpolar tails. The core of sphingolipids is a long-chain 18-C amino alcohol, shingosine. SPHINGOSINE
SPHINGOLIPIDS INCLUDE Sphingomyelin Glycosphingolipids» Cerebrosides: galactocerebroside glucocerebroside» Sulfatides» Globosides: upto seven carbohydrate units» Gangliosides:similar to globosides, contain NANA in addition
SPHINGOMYELINS They are the only shingolipids containing phosphate; Hence grouped under PL. Found in the membranes, especially in myelin sheath. The -NH2 group at C2 of sphingosine gives attachment to fatty acid. Metabolites of sphingomyelin are involved in signal transduction. There is loss of sphingomyelin in myelin sheath in multiple sclerosis leading to paralysis
SPHINGOLIPIDS AT CELL SURFACES ARE SITES OF BIOLOGICAL RECOGNITION In humans at least 60 different sphingolipids have been identified. Very prominent in neuronal plasma membranes. Carbohydrate moieties of sphingolipids define the human blood groups. (The human blood groups (O, A, B) are determined in part by the oligosaccharide head groups of these glycosphingolipids) The kinds and amounts of gangliosides vary dramatically during development. These components of the membrane may be protective, insulators, and sites of receptor binding. Among the molecules bound by glycosphingolipids include cell poisons such as cholera and tetanus toxins.
SPHINGOLIPID BREAKDOWN IN LYSOSOMES A genetic defect in any one of these hydrolytic enzymes leads to the accumulation of gangliosides in the cell, with severe medical consequences. A GLOBOSIDE LACTOSYLCERAMIDE GLUCOSYLCEREBROSIDE
LIPID STORAGE DISEASES (Sphingolipidoses / Gangliosidoses) Sphingolipids are normally degraded within lysosomes of phagocytic cells, particularly in the macrophages of RES, located in liver, spleen and bone marrow. A group of disorders where enzymes involved in degradation are absent.
SPHINGOLIPID STORAGE DISEASES OF HUMANS DISORDER DEFECTIVE ENZYME PRINCIPLE STORAGE SIGNS & SYMPTOMS SUBSTANCE Generalized Gangliosidosis Beta-Galactosidase GM1-Gnaglioside Mental retardation, Liver enlargement, Skeletal involvement Tay-Sachs Disease Hexosaminidase A GM2-Gnaglioside MR, Blindness, Cherry red spot on macula, death between 2 nd and 3 rd year Gaucher s Disease Glucocerebrosidase Glucosyl cerebroside Liver and spleen enlargement, Erosion of long bones and pelvis, MR in infantile form only Fabry s disease Alpha-Galactosidase-A Ceramide trihexoside Skin rash, Kidney failure, pain in lower extremities Niemann-Pick Disease Sphingomyelinase Sphingomyelin MR, Liver and spleen enlargement Sandhoff s Disease Hexosaminidase A&B GM2-Gnaglioside, Same as Tay-Sachs Disease. Globoside It has more rapidly progressing course Krabbe s Disease Galactocerebrosidase Galactocerebroside MR, absence of myelin (Globoid Leukodystrophy) Metachromatic Leukodystrophy Arylsulfatase A Sufatide MR, Nerves stain yellow brown with cresyl violet dye (Metachromasi)
COMMON FEATURES OF LIPID STORAGE DISEASES Most of them are autosomal recessive. Enzyme deficiency occurs in all tissues. Usually only a single sphingolipid accumulates in the involved organs. Ceramide portion is shared by various storage lipids. Rate of biosynthesis of the accumulating lipid is normal Catabolic enzyme is missing in each of the disorders
DIAGNOSIS Biopsy of involved organ Assay of the activity of the enzyme. Peripheral leucocytes, cultured skin fibroblasts, chorionic villi can be used. Treatment: only Gaucher s disease is treatable by giving regular infusions of beta-glucosidase. Gene therapy, Liver transplant, bone marrow transplant.
Tay-Sachs Disease Electron Micrograph from a portion of a brain of an infant with Tay- Sachs disease showing abnormal ganglioside deposits in the lysosomes Progressive retardation in development, paralysis, blindness, and death by the age of 3 or 4 years.