Sphingo/Phospho/TG

Question 1

What is the common precursor between TG and PL synthesis?

Answer 1

Phosphatidic Acid

Question 2

How is glycerol-3-P transformed into PA?

Answer 2

The successive addition of 2 acyl-coA by transferase to the OH moieties forming ester linkages.

Question 3

Where does PL and TG synthesis occur?

Answer 3

Mainly on interface of ER and some on outer mitochondrial membrane.

Question 4

Where does the pathway of synthesis of TG predominate?

Answer 4

In the adipose tissues

Question 5

What step follows PS formation if we want to get neutral lipids in adipose tissue?

Answer 5

Removing the P residue by a phosphatase yields diacyl glycerol. Then the addition of an acyl group by a transferase gives a TG.

Question 6

Describe the intestinal triglyceride pathway starting exogenous TG and their transport. What is the function of chylomicrons in the body?

Answer 6

Pancreatic lipase acts to hydrolyze exogenous dietary TG yielding 2 Free FA and 1 monoacyl glyceride which will be esterified with 2 FA once absorbed. They will be packaged by chylomicrons forming the core along with other lipid soluble vitamins and cholesterol. Chylomicron are carried through circulation, then TG will be released in adipocytes and muscles by the action of lipoprotein lipase that is triggered by the apo-c apoprotein. Muscles use them for energy and adipocytes for storage. The remnant chylomicron (having small TG amount and all dietary cholesterol) is carried to the liver taken by the high affinity receptor to apoE. CM is the largest lipoproteins that is responsible for dietary transport of lipids and cholesterol.

Question 7

What are lipoproteins?

Answer 7

Lipid-protein complexes made up of a phospholipid monolayer with a lipid core not like the cytoplasm hydrophilic core.

Question 8

What is the difference between CM and LDL?

Answer 8

CM has 4 apoproteins: C,E,A, and B48.

LDL has one B100 apoprotein that carries mainly cholesterol.

Question 9

What causes hypercholesterolemia?

Answer 9

One cause is the deficiency in the ApoB100 receptors on plasma membrane which lead to lower cholesterol uptake by the cell.

Question 10

For the synthesis of type 2 glycerolipids: Phospholipids, what is needed as a precursor?

Answer 10

Phosphatidic acid is activated by the CTP (pyrimidine nucleotide cytidine triphosphate) via cytidyl transferase that forms CDP-DAG.

Question 11

CDP is similar to — in glycogen.

Answer 11

UDP

Question 12

CDP-DAG is transformed into?

Answer 12

Phosphatidyl inositol, P ethanol amine, P serine, P-choline.

Question 13

Only the — will distribute exogenous + endogenous cholesterol to the various tissues via —.

Answer 13

liver, VLDL

Question 14

Phosphatidyl serine can give rise to — when CO2 is removed. Enzyme — is needed with a cofactor —.

Answer 14

Phosphatidyl ethanolamine

mitochondrial decarboxylase, vitamin B6

Question 15

Mechanism of nascent CM and remnant CM.

Answer 15

The core of nascent CM (has apo B48 and apo-A only) gains from HDL the following: apo C the activator of LPL and Apo E . activated LPL release free FA into extrahepatic. If these FAs are to be stored, TG are formed. We then get a smaller size CM called remnant chylomicron rich in cholesterol. The remnant CM loses Apo-A and Apo-C, so it is taken by the liver as recognized by 2 receptors: ApoB48 and ApoE.

Question 16

How is Pserine formed from CDP-DAG?

Answer 16

The CDP-DAG transesterifies with the hydroxyl of serine releasing CMP and forming Phosphatidyl serine. Pserine is called acidic PL and has a net charge of -1.

Question 17

What are PEA and PS called?

Answer 17

Cephalins

Question 18

Phosphatidyl Serine to Phosphatidyl Choline (lecithin)?

Answer 18

3 methylations via SAM (PC is the major component of cell membranes and food industries)

Question 19

What causes respiratory distress syndrome?

Answer 19

PC is a very effective lung surfactant which prevents adherence of inner surface of lungs( by lowering surface tension). Dipalmityol PC deficiency in lung surface causes RESPIRATORY DISTRESS SYNDROME . baby will have bluish skin, cyanosis shallow breathing .

Question 20

What is an assessment for fetal lung maturity?

Answer 20

Assessing the level of pC/sphingomyelin in amniotic fluid is used as good index of fetal lung maturity.

Question 21

How is PI formed from CDP-DAG? Where is this reaction active?

Answer 21

Inositol is transferred to CDP-DAG releasing CMP to form PI. Active in CNS and brain.

Question 22

Further phosphorylation of PI yields —. What does it generate?

Answer 22

PIP2
two second messengers IP3 and DAG
DAG activates PKC
IP3 causes release of Ca2+ from ER and further activation of PKC
Cleavage of PIP2 is initiated by Phospholipase C activ

Question 23

What are Phorbol esters?

Answer 23

Artificial compounds/Analogs of DAG that were seen to cause skin cancer.

Question 24

Why is PC mostly using the salvage pathway?

Answer 24

Because it is a phospholipid that requires 3 methylations involving the costly SAM molecule. SAM requires 3 ATP and essential aa methionine for its synthesis. So in situation where intake of methionine is limited, the cells makes all efforts to salvage choline, so that no SAM is synthesized.

Question 25

Where does the salvage pathway occur?

Answer 25

LIVER ONLY

Question 26

Do all phospholipids have salvage pathways?

Answer 26

No, PS doesn't. It has an exchange reaction instead.

Question 27

Steps of a salvage pathway.

Answer 27

During membrane turnover of the PLs, choline released from PC will be used again (re-salvaged). A choline kinase phosphorylates Choline into choline phosphate that gets further activated by cytidyl transferase forming CDP- choline that couples with DAG forming PC and releasing CMP. A similar pathway exist for ethanolamine forming PEA: P-ethanolamine => CDP-ethanolamine couples with DAG, releasing CMP.

Question 28

What is the exchange reaction that allows the formation of serine?

Answer 28

* Serine in the presence of phosphatidyl ethanolamine can exchange to form phosphatidyl serine (like the trans-esterification reaction). This occurs through base exchange enzyme (found in the ER) * Phosphatidyl serine by decarboxylation can form the phosphatidyl ethanolamine through the Phosphatidylserine decarboxylase (occur in the mitochondria) * However there is NO CDP-serine like molecule like that found with ethanolamine and choline molecule.

Question 29

What happens if there is a defect in the salvage pathway?

Answer 29

A defect in the kinase or cytidyl transferase will fail to activate the choline and hence impair as well the coupling with DAG causing accumulation of the latter. The only fate for the DAG is to be converted into TG leading to fatty liver (excessive deposition of TG in the Liver) since salvage pathway occurs in the Liver.

Question 30

What are the causes of Fatty Liver?

Answer 30

Causes of Fatty liver is defect of the salvage pathway, chloroform/CCl4 intoxication, defects in VLDL (TGs cannot be distributed to other tissues), abnormal beta oxidation (FAs accumulate), and alcohol intoxication, and ETC disorders (no recycled NADH => no beta oxidation).

Question 31

Does the catabolism of Phospholipids generate ATP?

Answer 31

NO

Question 32

What is the role of phospholipases?

Answer 32

1- Remodeling of acyl groups in membrane to make the environment suitable for enzymes and receptors. 2- Generate 2nd messengers 3- Regulatory role by activating different kinases for diff pathways

Question 33

Describe the action of the 4 phospholipases.

Answer 33

PLA1 hydrolyzes the first ester linkage , PLA2 hydrolyzes fatty acyl ester linkage at position 2 usually it is poly unsaturated arachidonic acid that is acted upon by cyclooxygenase or lipoxygenase systems.; PLC cleaves before the phosphate group; it generates the phosphorylated polar head of the PLs. ex: If the PL is PI, then PLC generates IP3 and DAG, and PLD (cleaves after the phosphate group), releasing the polar head group + PA (phosphatidic acid).

Question 34

Functions of Sphingolipids

Answer 34

1- Mediate Cancer (angiogenesis) 2- Mediate Aging (cell senescence and apoptosis) --> opposite to 1 3- Act as 2nd messengers 4- Antigens (A,B,O grps) 5- Tumor Markers 6- Cell-to-cell interaction 7- Receptors for ligands and toxins like cholera toxin

Question 35

Differences btw phospholipids and sphingolipids.

Answer 35

Alcohol : sphingosine ……. Glycerol FA : 1 …….. 2 FA type : VLong, saturated …… S/M/L, poly un- mono unsat, OH saturated Pi content : SM only …….. All Basic unit : Ceramide ……… Phosphatidate Bond : amide, Glycosidic …….. Ester

Question 36

When is sphingosine synthesis active, where, and how is it fomed?

Answer 36

Synthesis of SPL is quite active during the 1st years of CNS and brain development, and first years of childhood. Can occur in all tissues/organs however they are specially found in CNS. The biosynthesis occurs in ER membrane with all steps and substrates being membrane bound. It involves initially synthesis of sphingosine alcohol in its biologically inactive reduced form, followed by the formation of dihydro-cermaide (inactive) that gets desaturated to ceramide the basic unit of all SPL.

Question 37

When is sphingosine synthesis active, where, and how is it formed?

Answer 37

Synthesis of SPL is quite active during the 1st years of CNS and brain development, and first years of childhood. Can occur in all tissues/organs however they are specially found in CNS. The biosynthesis occurs in ER membrane with all steps and substrates being membrane bound. It involves initially synthesis of sphingosine alcohol in its biologically inactive reduced form, followed by the formation of dihydro-cermaide (inactive) that gets desaturated to ceramide the basic unit of all SPL.

Question 38

What is the biological role of sphingolipids?

Answer 38

1- Ceramide (Cer) levels increase, accompanying or preceding cell cycle arrest, apoptosis, or differentiation 2- Cer level increases following treatment with chemotherapeutic agents leading to cell death (irradiation and cytokines as well were noted to increase Cer level) 3- Exogenous Cer exhibit similar effects. This however does not mean that cer is toxic to the cell, but it must be well controlled and regulated. Moreover, the source and location where cer level is increased dictates whether cell death will occur. Increase in Cer inside mitochondria triggers apoptotic events that leads to cytochrome c release from IMM. 4- Ceramide targets inside the cell include kinases, phosphatases, or proteases.

Question 39

What are the acidic SPL and how are they formed?

Answer 39

characterized by presence of sialic acid derivative NANA ( N-acetyl neuramininc acid). NANA is a 9-C acid formed from the condensation of PEP (phosphorenol pyruvate) and N-Acetyl mannose-amine. Gangliosides are synthesized by the step by step transfer of CBHY /CBHY derivatives /NANA onto Cer. The immediate donors are UDP gal, UDPG, UDP galactosamine, UDP Glucosamine, UDP N-acyl galactosamine, UDP N-acyl galucoseamine, etc. whereas NANA is transferred as CMP-NANA. Gangliosides abbreviated as GM, GD, GT…etc depending on mono, di or tri NANA residues.