Ch. 17: Lipid II Phospholipids, Glycosphingolipids, Cholesterol Flashcards by Samantha Erin De Leon

In what process do phospholipids & glycosphingolipids play an essential role?

What are their 2 other functions?

Synthesis of plasma lipoproteins & eicosanoids

Transduction of messages (cell surface receptors ➡️ 2nd messengers, control cell function)

Surfactants

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Cholesterol: mainly plant or animal origin?

Animal origin

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Cholesterol is an essential part of what structure?

Biomembranes (provides membrane fluidity)

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In plasma, what is cholesterol associated with?

Lipoproteins

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Cholesterol: precursor for what compounds?

Bile acids
Steroid hormones
7-dehydrocholesterol of vit D

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What does esterifying cholesterol do to its properties?

Cholesterol esters: ⬆️ hydrophobic (pushed to center of lipoprotein)

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What are the 2 types of phospholipase A2? Functions?

Cytosolic, soluble: housekeeping, no signals sent (not as powerful)

Membrane bound: receives signal ➡️ releases FAs

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What are glycerolipids?

Types?

Phospholipid w/glycerol backbone

Phosphatidylcholine (lecithin)
Phosphatidylethanolamine (cephalin)
Phosphatidylserine
Phosphatidylinositol
Phosphatidylglycerol

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What is cardiolipin? Importance?

Diphosphatidylglycerol

Only antigenic GPL, important part of inner MT membrane

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What are sphingolipids?

Phospholipids with sphingosine

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What is ceramide?

Sphingosine + LCFA attached to amino group of sphingosine

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What is sphingomyelin? Importance?

Ceramide + phosphorylcholine

Important part of myelin of nerve fibers

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Amino acids needed to synthesize choline?

Gly ➡️ Met ➡️ Choline

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Steps in synthesis of phosphatidylcholine from choline?

Choline ➡️ phosphocholine (+ CTP nucleotide) ➡️ cytidine diphosphate-choline (CDP)

Glycerol ➡️ sn-G3P ➡️ lysophosphatidic acid ➡️ phosphatidic acid ➡️ sn-1,2-diacylglycerol (+ CDP) ➡️ phosphatidylcholine + CMP

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What 2 products can be synthesized from choline?

Acetylcholine

Betaine ➡️ dimethylglycine (via methylation of homocysteine ➡️ met)

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What is the main methyl donor in methylation of homocysteine ➡️ met? Importance?

What is the required cofactor in this reaction?

Methyl THF

Vitamin B12

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What are the products from base exchange reaction between phosphatidylserine & ethanolamine?

What enzyme catalyzes this reaction?

Phosphatidylethanolamine & serine

Phosphatidylethanolamine-serine transferase

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What enzyme directly converts phosphatidylserine ➡️ phosphatidylethanolamine?

Phosphatidylserine decarboxylase (loss of CO2)

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How many SAM molecules are used to synthesize phosphatidylcholine?

What enzymes catalyze this reaction?

3 SAM ➡️ 3 SAH

N-methyltransferases

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Compare phosphatidylethanolamine to platelet-activating factor: what are the differences in structure?

Platelet-activating factor:

1) acyl group on PE replaced with acetyl group via phospholipase A2
2) saturated bond (next to ether link) vs unsaturated bond in PE

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Steps of synthesis of phosphatidylinositol from glycerol?

Glycerol ➡️ ➡️ phosphatidic acid ➡️ CDP-diacylglycerol ➡️ phosphatidylinositol

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Steps of synthesis of cardiolipin (diphosphatidylglycerol) from glycerol?

Glycerol ➡️ ➡️ phosphatidic acid ➡️ CDP-diacylglycerol ➡️ phosphatidylglyceryl phosphate ➡️ phosphatidylglycerol ➡️ cardiolipin

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Steps in the cleavage of phosphatidylinositol 4,5-bis P, with hormone as signal?

Hormone binds to receptor ➡️ receptor interacts w/Gs protein ➡️ GDP released, bind GTP ➡️ Gq alpha dissociates, ➕ phospholipase C ➡️ phosphatidylinositol 4,5-bisP cleaved to IP3 & diacylglycerol ➡️ IP3 binds to receptor on ER ➡️ Ca2+ released ➡️ Ca2+ & diacylglycerol ➕protein kinase C ➡️ phosphorylation of cellular proteins which mediate cellular response to hormone

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What is sphingosine formed from? What is required for reaction?

Serine & palmitoyl-CoA

NADPH

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What is ceramide formed from?

Sphingosine & 22C FA, oxidation of FAD

What are cerebrosides formed from?

Ceramide & UDP sugars

How are sulfides formed?

Addition of sulfate group to cerebroside

How are gangliosides formed?

Addition of sugars to cerebroside

What is fumonisin B1?

Toxin from fungi disturbs spingolipid metabolism

What is surfactant composed of?

90% lipids (lecithin 70-80%, PG 10%, PI, PE, PS,cholesterol) 5-10% surfactant specific proteins (SP-A, B, C, D)

What are the general ratios of lipids in immature surfactant?

⬆️ PI, PE, PS ⬇️ lecithin

What ratio of PG to PI indicates lung immaturity?

⬇️ PG to PI

What disease is a consequence of prematurity and leading cause of neonatal mortality & morbidity? What disease is associated w/sepsis, pneumonia, & injury to lungs due to trauma or surgery?

Respiratory distress syndrome Acute respiratory distress syndrome

What ratio in amniotic fluid indicates immaturity with ⬆️ likelihood of RDS?

⬇️ lecithin:sphingomyelin ratio (<1.5)

Deficiency in what 2 things are immature infants susceptible to?

Surfactant Antioxidant defense systems (important for when baby is breathing on its own ➡️ ⬆️O2)

Storage disorders of sphingolipids: Tay-Sachs disease Enzyme deficiency? Lipid accumulating? Clinical symptoms?

Hexosaminidase A GM2 ganglioside Mental retardation, blindness, cherry-red macula, muscle weakness, seizures

Storage disorders of sphingolipids: Fabry's disease Enzyme deficiency? Lipid accumulating? Clinical symptoms?

Alpha-galactosidase Globotriaosylceramide (globoside) skin rash, kidney failure, heart failure, (X-linked recessive, full symptoms only in males)

Storage disorders of sphingolipids: GM1 gangliosidosis Enzyme deficiency? Lipid accumulating? Clinical symptoms?

Beta-galactosidase Gangliosides (GM1), keratan sulfate Hepatosplenomegaly, neurological deterioration, cherry-red macula, skeletal deformities

Storage disorders of sphingolipids: Sandhoff's disease Enzyme deficiency? Lipid accumulating? Clinical symptoms?

Hexosaminidase A & B Gangliosides (GM2), globosides Same as Tay-Sachs, but also visceral involvement

Storage disorders of sphingolipids: Metachromatic leukodystrophy Enzyme deficiency? Lipid accumulating? Clinical symptoms?

Arylsulfatase A 3-sulfogalactosylceramide (Sulfatides) Mental retardation & psychologic disturbances (adults), demyelination, nerves stain yellow-brown with cresylviolet

Storage disorders of sphingolipids: Krabbe's disease Enzyme deficiency? Lipid accumulating? Clinical symptoms?

Beta-galactosidase Galactosylceramide (galactocerebrosides) Mental retardation, myelin almost absent, blindness, deafness, globoid bodies in white matter of brain

Storage disorders of sphingolipids: Gaucher's disease Enzyme deficiency? Lipid accumulating? Clinical symptoms?

Beta-glucosidase Glucosylceramide (glucocerebrosides) Hepatosplenomegaly, erosion of long bones, mental retardation (infants), most common lysosomal storage disease

Storage disorders of sphingolipids: Niemann-Pick disease Enzyme deficiency? Lipid accumulating? Clinical symptoms?

Sphingomyelinase Sphingomyelin Hepatosplenomegaly, mental retardation, fatal in early life

Storage disorders of sphingolipids: Farber's disease Enzyme deficiency? Lipid accumulating? Clinical symptoms?

Ceramidase Ceramide Hoarseness, dermatitis, skeletal deformation, joint deformity, mental retardation, fatal in early life

All tissues in body synthesize cholesterol ➡️ which tissues make the most?

Liver Intestine Adrenal cortex Reproductive tissues

Where do the carbons in cholesterol come from? What provides the needed reducing equivalents?

Acetate NADPH (from PPP)

What are the 3 major sources of liver cholesterol?

Dietary cholesterol ➡️ chylomicron remnants Cholesterol synthesized in extrahepatic tissues ➡️ HDL De novo synthesis in liver

What are the 3 main ways cholesterol leaves the liver? Which is the major of the 3?

Secretion of VLDL Conversion to bile acids/salts Free cholesterol secreted in bile (major)

Steps in biosynthesis of mevalonate? Enzymes for each step?

2 acetyl CoA ➡️ acetoacetyl CoA (via thiolase) Acetoacetyl CoA ➡️ HMG-CoA (via HMG-CoA synthase) HMG-CoA ➡️ mevalonate (via HMG-CoA reductase)

What drugs inhibit HMG CoA reductase? What are the ➖ allosteric modulators of HMG-CoA?

Statins ➖: bile acid, cholesterol, mevalonate

How does the liver use HMG-CoA in the MT? In the cytosol?

MT: ketogenesis Cytosol: cholesterol synthesis

Mevalonate ➡️ squalene ➡️ cholesterol How many carbons for each?

Mevalonate: 6C Squalene: 30C Cholesterol: 27C

What is the major control point for cholesterol biosynthesis? (Rate limiting step)

Reaction catalyzed by HMG-CoA reductase

What are the 4 methods of regulation of cholesterol synthesis through HMG-CoA reductase?

1) sterol-dependent regulation of gene expression of HMG-CoA 2) sterol-independent phosphorylation/deP (inactive when phosphorylated) 3) hormonal regulation 4) inhibition by drugs: statins

Which are the naturally occurring statins? Synthetic statins?

Natural: lovastatin, simvastatin, pravastatin Synthetic: fluvastatin, atorvastatin, cerivastatin

Bile acids in human bile: 45% is ? 31% is ? 24% is ?

45% chenodeoxycholyl-CoA (CDCA) 31% cholyl-CoA (CA) 24% deoxycholyl-CoA (DCA, secondary bile acid)

2/3 of bile acid is derived from what?

HDL cholesterol delivered to liver

What is rate-limiting step of bile acid synthesis? What is required for this reaction?

Formation of 7alpha-hydroxy cholesterol via 7alpha-hydroxylase NADPH, O2, cyt P-450

What two amino acids are conjugated to bile acids?

Taurine | Glycine

Microbial enzymes convert primary bile acids ➡️ secondary bile acids: CA ➡️ ? CDCA ➡️ ? Which is reabsorbed/not reabsorbed?

CA ➡️ deoxycholic acid (reabsorbed) CDCA ➡️ lithocholic acid (not reabsorbed, toxic)

Where is majority of bile reabsorbed?

Ileum (90-95%) 5-10% excreted in feces

Serum bile acid levels are a sensitive indicator for what?

Liver disease

What occurs in hyperbile acidemia?

Pruritus Steatorrhea Hemolytic anemia Further liver injury

What is cholelithiasis?

Presence/formation of gallstones due to precipitation of cholesterol in bile

What causes pigment stones to form?

⬆️ biliary (bile pigments/bilirubin glucuronides)

If mole ratio of bile salts & PLs to cholesterol is < 10:1, what occurs?

Lithogenic (stone forming)