Complex Lipid Metabolism

Question 1

Phospholipid

Answer 1

Alcohol+FA (2)+P group

Question 2

Phospholipid synthesis/degradation

Answer 2

Synthesized from phosphatidic acid 1-2 diacyclglycerol (DAG).
Activated intermediates-above and CDP-bound molecule
Site-Smooth ER and and Golgi
ETHER PL-in peroxisomes.
Degradation-phospholipases at C1 and C2–>produce Arachidonic acid (hormone synthesis) and DAG/IP3.
CC NOTE-Venoms and toxin are rich in phospholipases.

Question 3

Degradation of Glycerolphospholipid

Answer 3

Phospholipase A1-cleaves first ester bond
Phospholipase A2-cleaves 2nd-most important. Act on PiP2 (phosphatidylinositol 4,5-bisphosphate)to release AA. Proenzyme of pancreatic enyzme activated by trypsin and needs bile salts. Inhibited by glucorticoids
Phospholipase C- present in liver lysosomes, α-toxin of clostridia. Activated by PiP2 (Gq system) to produce IP3 and DAG

Question 4

Sphingomyelin degradation

Phos phorylcholine-Cerbramide (alternative name)

Answer 4

Sphingomyelin is degraded by sphingomyelinase, a lysosomal enzyme that hydrolytically removes phosphorylcholine, leaving a ceramide.The ceramide is, in turn, cleaved by ceramidase into sphingosine and a free fatty acid.
Sphingomyelin abundant in brain and nerve tissue.

Niemanns Pick Disease A + B- Accumulation of sphingomyelin, Type A-severe infantile form with extensive neurologic involvement. Type B no central nervous system involvement. Foaminess to the cytoplasm, Zebra bodies in inclusions (descriptive term for a lysosome containing broad transversely-stacked myelinoid membranes, an ultrastructural finding typical of certain lysosomal storage diseases

Diagnosis: Biochemical assays for Sphingomyelinase activity in liver or Bone marrow biopsy, DNA analysis

Treatment: Enzyme replacement, bone marrow transplantation gene therapy are all in the experimental or clinical trial phases.

Question 5

Phosphatidyl Choline (GPL)

Answer 5

Most abundant (in cell membranes). Called LECITHIN as well. DPPC(form of lecithin)-dipalmitoylphosphatidycholine is 90% lung surfactant.
CC Note-RDS absent DPPC or PC (same thing)

Question 6

Phosphatidyl ethanolamine (cephalin) (GPL)

Answer 6

kinase degrades to make CDP-ethanolamine

Question 7

Phosphatidyl Inositol (GPL)

Answer 7

Attachment of certain proteins to membrane surface by linking through a carbohydrate residue and these proteins are termed as GPI-anchored proteins. Acytl choline esterase and Alkaline phosphatase (serum marker for MI or jaundice)

Question 8

Phosphatidylinositol 4,5-bisphosphate (GPL)

Answer 8

Membrane bound PiP2–>after activation of GQ receptor–> activation of Phospholipase C, which acts on 3rd ester bond–>Products are IP3 and DAP. Relation with increase in cytosolic calcium, which activates protein kinase C.

Question 9

Cardiolipin (GPL)

Answer 9

Also called Diphosphatidyl glycerol. Present in mitochondrial membranes (most inner) and mainly in cardiac muscle. Has antigenic properties. Highest # of FA’s.

Question 10

Plasmalogens (ether linked)

Answer 10

SN-1 Carbon has Unsaturated FA. Ether bond rather than ester bond. Big role in brain PL (compose 10%).

CC Note-Loss of plasmaloens in white matter of brain leads to multiple sclerosis.

Question 11

Platelet Activating Factor (PAF)-Ether linked (GPL)

Answer 11

mediator of hypersensitivity, acute inflammatory reactions and anaphylactic shock. Causes platelets to aggregate, neutrophils and alveolar macrophages to generate O2.

Question 12

Glycosphingolipid synthesis/degradation

Answer 12

Site-Golgi, enzymes for synthesis glycosyltransferase. UDP sugars donate their sugar to make glycosyl monomers. PAPS (3’-phosphoadenosine-5’-phosphosulfate) is the donor of sulfate group by sulfotransferase.
Degraded by sphingolipases. Defieincey of any sphingolipases leads to sphingolipodoses (all autosomal except for X-LINKED FABRY Disease)

Question 13

GM1-NANA

Answer 13

B-Galactosidase cleaves galactose of GM1–deficiency of B-Galactosidase–>accumulation of GM1 and keratin sulfate.
GANGLIOSIDOSIS- Neurologic deterioration. Hepatosplenomegaly. Skeletal deformities. Cherry-red macula (part of eye) in infantile form

Question 14

GM2-NANA

Answer 14

B-Hexosaminodase A cleaves galnac of GM2–deficiency of B-Hexosaminodase A–>accumlation of GM2.

Tay Sachs-.Rapid, progressive and fatal neurodegeneration. Blindness, Cherry-red macula, Muscular weakness, seizures. Deficiency of activator
protein (GM2 activator) in some cases

Question 15

GM3

Answer 15

Neuroaminodase will cleave nana. No known issues.

Question 16

Gal-Glu-Cer (lactosyl cerbramide)

Answer 16

Lactsyl cerbramide-cleaved by B-Galactosidase. No known issues.

Question 17

Glucocerebrosides

Answer 17

Glucocerbrosidase cleaves glucose. Deficiency of B glucosidase (glucocerbrosidase)–accumulation of glucocerebrosides.

Gauchers disease- Most common lysosomal storage disease, Hepatosplenomegaly, Osteoporosis of long bones, CNS involvement in rare infantile and juvenile forms. Enzyme replacement therapy (treatement) or bone marrow transplants for treatement

Question 18

Ceramide

Answer 18

Cermindase cleaves cearmide to make sphingosine. Deficiency of cermidase–>accumulation of ceramide.

Farbers Disease- Painful and progressive joint deformity, Subcutaneous nodules of lipid-laden cells, Hoarse cry, tissues show granulomas

Question 19

Globoside-GM2

Answer 19

B-Hexosaminidase A and B cleave gal-nac of globoside-GM2. Deficiency of B-Hexosaminidase A and B–>accumulation of GM2 and globosides.

Sandhoff disease- Same neurologic symptoms as Tay-Sachs (including red macula) but visceral involvement as well.

Question 20

Globoside

Answer 20

A-galactosidase cleaves GM2 galactose of globoside (to make lactosyl cerboside). Deficiency of A-galactosidase–>accumulation of Globotriaocyl ceramide

Fabry syndrome- X linked, Red-purple skin rash, Kidney and heart failure, Burning pain in lower extremities, Enzyme replacement therapy may slow progress of disease.

Question 21

Sulfatide

Answer 21

Cleaved by Arylsulfatase A. Deficiency of Arylsulfatase A–>accumulation of sulfatide

Metachromatic leukodystrophy- Cognitive deterioration, difficulty in speech, Demyelination, progressive paralysis, dementia. Nerves stain yellow brownish.

Question 22

Galactocerebroside

Answer 22

B-Galactosidase (galactocerbrosidase) cleaves galactose from galactocerbroside. Deficiency of B-Galactosidase–>accumulation of galactocerbrosides.

Krabbe disease- Mental and motor deterioration, Blindness and deafness, Near-total loss of myelin. Globoid bodies (glycolipid-laden macrophages ) in white matter of brain. Limited clinical trials show umbilical stem-cell transplants help.