Biochemistry Lipids: Phospholipid Metabolism PDF

1A BIOCHEMISTRY LIPIDS: PHOSPHOLIPID METABOLISM DR. JANDOC OUTLINE I. OVERVIEW A. Phospholipids B. Membrane Phospholip...

1A BIOCHEMISTRY LIPIDS: PHOSPHOLIPID METABOLISM DR. JANDOC OUTLINE I. OVERVIEW A. Phospholipids B. Membrane Phospholipids C. Non-Membrane Bound Phospholipids II. STRUCTURE OF PHOSPHOLIPIDS A. Phosphoglycerides (Glycerophospholipids) B. Characteristics of Phosphoglycerides III. SYNTHESIS OF PHOSPHOLIPIDS A. Phosphatidic Acid (PA) B. Phosphotidylethanolamine (PE) and Phosphotadylcholine (PC) C. Phosphatidylserine (PS) D. Phosphatidylinositol (PI) E. Phosphatidylglycerol (PG) F. Cardiolipin (Diphosphatidylglycerol) G. Plasmolagens V. DEGRADATION OF PHOSPHOLIPIDS A. Phospholipid Degradation VI. CLINICAL ASPECTS I. OVERVIEW A. PHOSPHOLIPIDS  Polar ionic compounds  composed of alcohol attached by a phosphodiester bridge to either  DAG  Sphingosine  predominant lipids of cell membranes B. MEMBRANE PHOSPHOLIPIDS  reservoir for intracellular messengers C. NON-MEMBRANE BOUND PHOSPHOLIPIDS  anchor to cell membranes for some proteins  Amphipathic  Hydrophilic Head  have additional roles in the body - phosphate group + whatever alcohol  ex: bile - detergent properties attached (serine, ethanolamine, choline, etc) cholesterol solubilization - polar components of lung surfactant - extends out of the membrane facing the plasma lipoprotein particles intracellular or extracellular aqueous environment II. STRUCTURE OF PHOSPHOLIPIDS  b. Hydrophobic Tail - long  major lipid constituents of cellular membranes - contains fatty acids or fatty acid-derived  In High Concentrations in the Lipids of hydrocarbons  glandular organs - associated with other nonpolar  blood plasma constituents of membranes including glycolipids,  egg yolk protein, and cholesterol  legume seeds  Comprise Trans Finals 3 | ABACCO, ALDERITE, ASISTIN, BALANZA, BAYAS, BIANG 1 of 9 LIPIDS PHOPHOLIPID METABOLISM  40% of lipids in RBC membranes  precursor of the other members  over 95% of the lipid of the inner mitochondrial membrane  20% are cardiolipin (phosphoglycerides)  Contain  phosphorous  backbone  glycerol (phosphoglycerides)  sphingosine (sphingomyelin)  Two Classes of Phospholipids  Those with Glycerol as Backbone 1. PHOSPHOLIPIDS FORMED FROM PHOSPHATIDIC ACID - additional role in the body AND AN ALCOHOL - ex: as essential bile components (detergent propertiescholesterol  phosphate group on phosphatidic acid can be solubilization) esterified to another compound containing an as anchors for some proteins to cell alcohol group membranes (signal transmission across membranes)  ex: as components of lung surfactants  serine + PA phosphatidylserine  Those that Contain Sphingosine  ethanolamine + PA  Both Classes phosphatidylethanolamine (cephalin) - found as membrane components  choline + PA phosphatidylcholine - role in the generation of lipid-signalling (lecithin) molecules  glycerol + PA phosphatidylglycerol  inositol + PA phosphatidylinositol A. PHOSPHOGLYCERIDES (GLYCEROPHOSPHOLIPIDS)  - if fatty acid at carbons 1 or 2 is removed lysophosphoglyceride (lysolecithin)  constitute the major class of phospholipids  all contain phosphatidic acid (DAG with phosphate 2. CARDIOLIPIN (DIPHOSPHATIDYLGLYCEROL) group on the 3rd carbon)  2 molecules of phosphatidic acid esterified through  Triesters of Glycerol 3-Phosphate their phosphate groups to an additional  2 esters formed between the 2 hydroxyl  molecule of glycerol groups and fatty acids side chains (R1 and  the only human phosphoglycerides that is antigenic R2)  recognized by antibodies raised against Treponema  3rd ester formed between the phosphate pallidum group and a hydroxyl-containing compound  important component of (X)  inner 3. PHOSPHATIDYLCHOLINE (LECITHIN)  phosphoacylglycerols containing choline  most abundant phospholipid of the cell membrane  a. Choline  important in - nervous transmission - storage of labile methyl groups  Phosphatidic Acid  simplest phosphoglyceride S1T1 2 of 9 LIPIDS PHOPHOLIPID METABOLISM  b. Dipalmitoyl Lecithin  major component of lung surfactant 7. LYSOPHOSPHOLIPIDS  intermediate in phosphoglycerol metabolism  contain only 1 acyl radical (lysophosphatidylcholine) important for the metabolism and interconversion of phospholipids 4. PHOSPHATIDYLETHANOLAMINE (CEPHALIN) 5. PHOSPHATIDYLSERINE 8. PLASMALOGENS  constitute about 10% of brain and muscle phospholipids  structurally resemble phosphatidylethanolamine  formed when a fatty acid of a glycerophospholipid is replaced by an unsaturated alkyl group attached by an ether (rather by an ester) linkage at carbon 1 of glycerol - ex:  phosphatidalethanolamine 6. PHOSPHATIDYL INOSITOL - plasmalogen that is similar in structure to  cleaved into - diacylglycerol phosphatidylethanolamine - inositol triphosphate - abundant in nerve tissue act as internal signals or second messengers  phosphatidalcholine - quantitatively significant ether lipid in mammals - abundant in heart muscle 9. 1-ALKENYL-2-ACETYL-PHOSPHATIDALCHOLINE OR PLATELET-ACTIVATING FACTOR (PAF)  unusual ether glycerophospholipid  very powerful chemical mediator  with  saturated alkyl group in an ether link to carbon 1 of glycerol backbone S1T1 3 of 9  LIPIDS PHOPHOLIPID METABOLISM  acetyl residue (rather than a fatty acid) at carbon 2 of glycerol backbone  bind to cell membrane receptor activate transmembrane signal mechanisms (activation of phospholipases) stimulate phospholipid degradation potent physiologic actions  Major Mediator of - hypersensitivity reaction 1. LYSOPHOSPHATIDATE - inflammatory cell activation acute  metabolic precursor of phosphoglycerides inflammatory reaction - anaphylactic reactions and shock 2. PHOSPHOGLYCERIDE SYNTHESIS  Effects  Involves Either - platelet aggregation (thrombotic event) and - donation of phosphatidic acid from CDP-DAG to an degranulation (previously called “platelet-activating alcohol factor or PAF”) - donation of the phosphomonoester of the alcohol - generation of superoxide radicals by from CDP-alcohol to 1,2-DAG - neutrophils  Both Cases - alveolar macrophages - CDP-bound structure is considered as “activated - increase pulmonary and airway edema intermediate” - CMP is released as a side product of B. CHARACTERISTICS OF PHOSPHOGLYRIDES phosphoglyceride synthesis  Amphipathic 3. KEY CONCEPT IN PHOSPHOLIPID SYNTHESIS - possess both - hydrophilic groups  activation of DAG or the alcohol to be added, by - hydrophobic groups can inhabit transition linkage with a nucleoside diphosphate regions between aqueous and nonaqueous phases - phosphoglycerides are the most polar of lipids A. PHOSPHATIDIC ACID (PA)  Amphoteric  formed from the reaction of monoacylated - bearing both lysophosphatidate with a fatty acyl CoA - negatively-charged groups  precursor of many other phosphoglycerides - positively-charged groups  fatty acids esterified to the alcohol group can vary widely heterogeneity of these group of III. PHOSPHOLIPID SYNTHESIS compounds  occurs in the ER transported to the Golgi  dephosphorylation forms -DAG apparatus membranes of organelles  all cells except mature RBCs can synthesize plasma membrane phospholipids secreted from the cell by exocytosis  TAG synthesis occurs essentially only in  essentially all cells except mature RBCs can - liver synthesize phospholipids - adipose tissue - lactating mammary glands S1T1 4 of 9  LIPIDS PHOPHOLIPID METABOLISM - intestinal mucosal cells - decreases the surface tension reduced pressure needed to reinflate alveoli preventing alveolar B. PHOSPHATIDYLETHANOLAMINE (PE) AND collapse PHOSPHATIDYLCHOLINE (PC) iii. Fetal Lung Maturity  most abundant phospholipids in most eukaryotic - gauged by determining the ratio of dipalmitoyl- cells phosphatidylcholine (L) to sphingomyelin (S) in amniotic  utilize choline and ethanolamine obtained from the fluid (L/S ratio) - diet - ratio of > 2 maturity - turnover of phospholipids - reflects the major shift from sphingomyelin to - in the liver, choline can also be synthesized de novo dipalmitoyl-phosphatidylcholine synthesis that occurs from in pneumocytes at about 32 weeks AOG - phosphatidylserine iv. Lung Maturation - phosphatidylethanolamine - accelerated by giving the mother glucocorticoids shortly before delivery 1. SYNTHESIS OF PE AND PC FROM PREEXISTING CHOLINE AND ETHANOLAMINE 2. DE NOVO SYNTHESIS OF PC FROM PHOSPHATIDYLSERINE  Involves 3 Enzymatic Steps (PS) IN THE LIVER i. Phosphorylation  PS Decarboxylase - of the nitrogen-containing base (choline or - requires pyridoxal phosphate as cofactor ethanolamine) by kinases - PS decarboxylation PE formation ii. Activation of the Phosphocholine or successive transfer of methyl groups from 3 moles of S- Phosphoethanolamine adenosylmethionine (SAM) PC + 3 moles of - by CTP to form CDP-choline (reacts with -DAG S-adenosylhomocysteine (SAH) PC) or CDP ethanolamine iii. Transfer of the Activated Base C. PHOSPHATIDYLSERINE (PS) - transfer of choline phosphate or ethanolamine  Primary Pathway of Synthesis phosphate from the nucleotide to a molecule of DAG - calcium-activated “base-exchange” reaction phospholipid - ethanolamine of PE is exchanged with free serine - CDP-choline reacts with -DAG PC - reversible reaction - -DAG at the hydroxyl carbon reacts with CDP- - used primarily to produce PS for membrane ethanolamine PE synthesis  Significance of Choline Reutilization i. de Novo Choline Synthesis D. PHOSPHATIDYLINOSITOL (PI) - requires the addition of 3 methyl groups derived  synthesized from free myo-inositol and CDP-DAG from methionine (in its activated form, S  phosphatidic acid + CTP CDP-DAG adenosylmethionine)  CDP-DAG + inositol PI ii. Methionine  unusual phospholipid - essential amino acid  contains stearic acid on carbon 1 of glycerol - often deficient in the human diet choline may  arachidonic acid on carbon 2 of glycerol also be an essential dietary nutrient reservoir of arachidonic acid in membranes iia. Adequate Intake PG synthesis - men - 550 mg - women - 420 mg 1. ROLE OF PI IN SIGNAL TRANSMISSION ACROSS  Role of PC in Lung Surfactant MEMBRANES i. Dipalmitoyl-Phosphatidylcholine (Dipalmitoylecithin)  phosphorylation of membrane-bound PI - positions 1 and 2 on the glycerol are occupied by production of phosphatidylinositides (ex: palmitate phosphatidylinositol 4, 5-biphopshate, PIP2) - major lipid content [complex mixture of lipids degradation of PIP2 by phospholipase C occurs (90%) and proteins (10%)] of lung surfactant in response to the binding of a variety of (extracellular fluid layer lining the alveoli) neurotransmitters, hormones, and growth factors to ii. Surfactant receptors on cell membranes formation of inositol 1, 4, 5-triphosphate (IP3) and diacylglycerol (DAG) synergistic action intracellular calcium S1T1 5 of 9 LIPIDS PHOPHOLIPID METABOLISM mobilization and protein kinase C activation evoke specific cellular response 2. ROLE OF PI IN MEMBRANE PROTEIN ANCHORING  cell surface proteins can be covalently attached via a carbohydrate bridge (glycosyl phosphatidylinositol, GPI) rapid lateral mobility on the surface of the plasma membrane  ex:  ALP - digestive enzyme on the surface of the small intestines that attacks organic phosphates  Acetylcholine Esterase - enzymes of the post-synaptic membrane that degrades the neurotransmitter acetylcholine  Lipoprotein Lipase  phospholipase C - cleave the protein releasing DAG (2nd messenger that can activate protein kinase C) - GPI synthesis deficiency in hematopoietic cells hemolytic disease – paroxysmal nocturnal hemoglobinuria E. PHOSPHATIDYLGLYCEROL (PG)  large amounts in the mitochondrial membranes  precursor of cardiolipin  synthesized in a 2-step reaction from  CDP-DAG G. PLASMALOGENS  glycerol 3-phosphate  Three Major Classes  in eukaryotic cells, synthesis occurs primarily in the - phosphatidalcholines mitochondria - phosphatidalethanolamines - phosphatidalserines  Fatty Acids - attached to carbon 1 in an ether linkage (rather than ester linkage)  Myelin - contain large amounts of ethanolamine plasmalogen  Heart Muscle - contain large amounts of choline plasmalogen V. DEGRADATION OF LIPIDS F. CARDIOLIPIN (DIPHOSPHATIDYLGLYCEROL)  synthesized from phosphatidic acid  Phospholipases  phosphatidic acid + CTP CDP-DAG - found in  CDP-DAG + glycerol 3-phosphate - all tissues phosphatidylglycerol - pancreatic juice  phosphatidylglycerol + CDP-DAG cardiolipin - degrade phosphoglycerides  Toxins and Venoms - have phospholipase activity  Some Bacteria S1T1 6 of 9  LIPIDS PHOPHOLIPID METABOLISM - produce phospholipases dissolve cell membranes spread of infection  Sphingomyelinase - lysosomal enzyme - degrade sphingomyelin A. PHOSPHOGLYCERIDE DEGRADATION 1. PHOSPHOLIPASES  hydrolyze the esters of the phosphodiester bonds of phosphoglycerides  each enzyme cleaves the phospholipid at a specific site  fatty acid removal from carbon 1 or 2 of phosphoglyceride lysophosphoglyceride (substrate of lysophospholipases)  release molecules that can serve as - messengers - DAG - IP3 - substrates for the synthesis of messengers (arachidonic acid)  degradation and remodelling of phospholipids - ex: phospholipase A1 and A2 - remove specific fatty acids from membrane-bound phospholipids can be replaced with alternative fatty acids using fatty acylCoA transferase - used to create the unique dipalmitoylphosphatidylcholine - insure that carbon 2 of PI is bound to arachidonic acid 2. REACYLATION  Direct Acylation - with appropriate fatty acyl CoA  Exchange-Type Reactions - ex: arachidonic acid-specific acyl CoA acyltransferase (lecithin : lecithin acyltransferase) which shows preference for unsaturated acyl CoA derivative Acyl CoA + 1-acylglycero-3-phosphocholine (lysolecithin) CoA + 1, 2-DAG-3-phosphocholine (lecithin) VI. CLINICAL ASPECTS S1T1 7 of 9  LIPIDS PHOPHOLIPID METABOLISM A. LUNG SURFACTANT IN RDS - steroid sulfatase  Lung Surfactant - secretion with marked surface-active properties - prevent pulmonary alveolar collapse - activity resides on dipalmitoyl phosphatidylcholine (synthesized shortly before parturition in full-terms) 1. RESPIRATORY DISTRESS SYNDROME (HYALINE MEMBRANE DISEASE) - in preterm infants - insufficient surfactant production - 15% of all neonatal deaths in western countries - prevention and treatment - administration of natural or synthetic surfactant by intratracheal instillation 2. ADULT RESPIRATORY DISTRESS SYNDROME - due to destruction of surfactant-producing pneumocytes (adverse effect of immunosuppressive or chemotherapeutic medications) insufficient surfactant production B. MULTIPLE SCLEROSIS - demyelinating disease - loss of phospholipids (ethanolamine, plasmalogen) and sphingolipids from the white matter - white matter lipid component resemble that of the gray matter - CSF shows increased phospholipid levels C. LIPID STORAGE DISEASES  Constant Features - ceramide - common structural portion of accumulated complex lipids in various tissues - rate of synthesis of stored lipid is comparable to that in normal - enzymatic defect - a deficiency secondary to specific lysosomal hydrolytic enzyme gene mutation important for lipid breakdown or enzyme activation - extent of reduction of affected enzyme activity is similar in all tissues of affected individuals D. MULTIPLE SULFATASE DEFICIENCY  Accumulation of - sulfogalactosyl ceramide - steroid sulfate - proteoglycans  Combined Deficiency of - arylsulfatase A - arylsulfatase B - arylsulfatase C S1T1 8 of 9 LIPIDS PHOPHOLIPID METABOLISM  Niemann-Pick Disease  Autosomal recessive – inability to degrade sphingomyelin  Type A - severe infantile form (less than 1% of normal enzymatic activity) - liver and spleen – primary sites of lipid deposits (hepatosplenomegaly) - rapid and progressive neurodegeneration as a result of sphingomyelin deposition in CNS -occurs with greater frequency in the Ashkenazi Jewish population  Type B - less severe variant (5% or more of normal enzyme activity) - later age of onset, longer survival time - affects lungs, spleen, liver and bone marrow – chronic form of disease REFERENCES th 1. Lippincott’s Illustrated Reviews: Biochemistry, 6 edition S1T1 9 of 9