biochem

poorva

PHAR150GBiochemistryDay10.pptx

Home >Chemistry homework help >Organic chemistry homework help >biochem

PHAR150G

Lipids 2

Vicky Mody, PhD

Associate Professor of Pharmaceutical Sciences

Office , Rm 3034

[email protected]

Define the terms lipids, fatty acid and classify biological lipids

Explain structure & nomenclature of naturally occurring fatty acids

Explain structure, nomenclature & functional importance of storage lipids namely triacylglycerols and waxes

Explain structure, nomenclature & functional importance of membrane lipids

Explain function of lipids as biological signal molecules

Explain effects of trans-fatty acids on metabolism

Learning objectives for Lipids 1-2

Disorder	Cause	Explanation
Tay Sachs Disease	Genetic	Deficiency of hexoaminidase leading to the accumulation of ganglioside in nerve cell membranes. This leads to Neurons become swollen w/ lipid filled lysosomes

Diseases discussed in this Class

Lipid derivatives of glycerol

glycerine, glycerin, glycerol

or 1,2,3-trihydroxypropane

Use in food as humectant.

Note use in pharmacy: improve smoothness, give lubrication

A large percentage of fatty acids in humans occur as triacylglycerols, “triglycerides”, TAGs

Glycerol backbone + 3 fatty acid esters

Triglycerides

Structure

Triacylglycerol Structure

glycerol

fatty acids

triacylglycerol

Functional groups:

carboxylic acid

functional groups:

alcohol

functional group:

ester

acyl means the molecule contains a carbonyl group

This is an esterification

Add in note about catalytic NaOH and hydrolysis of TAG vs saponification

Triacylglycerols

Most TAG have different FA in the three positions

FAs in TAG is mainly determined by diet

In humans, most FA in TAG:

saturated or monounsaturated (oleic (18:1) most common)

FA substituents

Triacylglycerol's

a triacylglycerol

Structures generally contain more than 1 type of FA

palmitic acid (C16)

oleic acid (18:1) cis-9

alpha linoleic (18:3)

glycerol

acyl means the molecule contains a carbonyl group

acetyl means acetic

Soaps from fatty acids

Charged, polar

end dissolves in water

Nonpolar, lipophilic end

dissolves in grease

micelle

In a time before soap…

Use of strigil in ancient Rome

Strigil from ~500 BC

Formation of biodiesel by transesterification

Triacylglycerols: Transesterification Reaction

triglyceride

Note excess methanol

Note NaOH is catalytic, not stoichiometric!

Show ester hydrolysis!!!

Use of glycerine byproduct (FYI): Oil for Bombs?

H2O

nitroglycerin

Runaway reaction

Triglycerols

Glycerol phospholipids

(Phospholipids)

Ether glycerolipids

(Phospholipids)

Types of Glycerolipids

Plasmalogens are Membrane Phospholipid

There is one more types of Phospholipids

Glycerolipids can also be classified as Phospholipid

Plasmalogens are Membrane Phospholipid

Types of Glycerolipids and Phospholipids

There is one more types of Phospholipids

Plasmalogens are Membrane Phospholipid

Membrane Lipids

Membrane lipids

3 major kinds

Spingolipids

phospholipids

cholesterol

Note polar and nonpolar groups

Structures of Membrane Lipids

All are Amphipathic.

contain both hydrophilic and hydrophobic moiety

?? membrane lipids are all AMPHIPATHIC or AMPHIPHILIC

http://employees.csbsju.edu/hjakubowski/Jmol/nonhydrated%20DPPC%20membrane/nonhydrated_DPPC_membrane.htm

Membrane Lipids

Membranes form as consequence of amphipathic nature of lipids.

Polar head groups favor contact w/ H2O

hydrocarbon tails interact with one another

in aqueous solution, gobular micelles form

micelles form

?? Polar head group favors contact with water

?? hydrocarbon tails interact; micelles are more stable with FA than phospholipids

Phospholipids/glycolipids

Alternative stable structure to micelles:

lipid bilayer: bimolecular sheet.

composed of 2 leaflets.

makes a hydrophobic interior: acts as permeability barrier.

hydrophilic head groups interact w/ aqueous media on each side.

bilayers form spontaneously by self assembly.

?? hydrophobic acts as permeability barrier

FA form

micelles

Phospholipids

more readily form

bilayers

Hydrophobic interactions

are the driving force

Lipid bilayers

Nonpolar tails are attracted to each other

Polar head groups are attracted

Van der Waals attraction in tails favors close packing (induced dipole)

Electrostatic and H-bond interaction between polar head groups and water (dipole-dipole)

Formation from

aqueous solution

?? Van der walls (induced dipole) favors packing;

VDW = dipole-dipole (Keesom force),

dipole-induced dipole

induced dipole-induced dipole

H- bond = 5=30,

?? electrostatic and hydrogen bonding interaction for polar head groups

Phospholipids

Phospholipids:

abundant in all biological membranes

4 components

a backbone for attachment of groups

one or more fatty acids

phosphate

an alcohol esterified to phosphate

Phospholipids

4 components

a backbone for attachment of groups

one or more fatty acids

phosphate

alcohol esterified to phosphate

have 4 parts

phosphatidylcholine

e.g. phosphatidylethanolamine

Phosphoglycerides Vary in FAs & in Polar Head Group

Alcohol Groups in Phosphoglycerides

Esterification of phosphate at glycerol C3 by hydroxy group on various alcohols

Backbone

ethanolamine = 2nd most common head group in phospholipids

choline = precursor for acetylcholine (muscle control, memory)

Common Membrane Phosphoglycerides

“lecithins”

http://telstar.ote.cmu.edu/biology/MembranePage/index2.html

Used in the formation of Mitochondrial Membrane

PS usually kept in inner leaflet, -> cell surface in apoptosis: C grade for memory from Nat’l Std.

PC is such maj. component of lecithins, word used as synonym.

PEA found in all cells but particularly in nervous tissue

makes more viscous membrane vs. PC

PI = minor component of cell membrane, but vital in signaling (PIP2, etc)

cardiolipin = major component of inner mitochondrial membrane (& most bacteria)

Phospholipids

(Phosphatidylserine)

Phosphatidylserine: Function in Apoptosis

Normal location: inner leaflet of membrane

Moved to outer during apoptosis

Signals phagocytes to consume cell remnants after apoptosis complete

Moved to outer during apoptosis

Phosphatidylserine

FYI: Dietary Supplements

“Aid Mental Focus & Improve Memory Hurry Buy 1 Get 2 Free!”

$19.29

2003 FDA: “Not significant agreement of association of PS with reduced dementia, but:

"Consumption of phosphatidylserine may reduce the risk of dementia in the elderly" and "Consumption of phosphatidylserine may reduce the risk of cognitive dysfunction in the elderly".

PS gets C grade from Nat’l Std for cognitive disorders & lipid lowering

Phospholipids

(Phosphatidylethanolamine)

Phosphatidylethanolamine (PE) is an important phospholipid that makes up cell membranes and organelle membranes.

It is also called cephalin. Because it is abundant in the brain, spinal cord, and other nervous tissues and is believed to play an important role in cognition and memory.

Phosphatidylethanolamine

Phospholipids

(Phosphatidylinositol)

Phosphatidylinositol

In a 2nd messenger cascade:

Conversion of extracellular signal into intracellular

“Very important at GPCRs

PI = minor component of cell membrane, but vital in signaling (PIP2, etc)

Cleavage of phosphatidylinositol 4,5-bisphosphonate in cell membranes by PLC

This section on needs clarification

GPCR = G protein coupled receptor

e.g. many hormones (angiotensin II receptor: binds peptide hormone/controls BP)

Phosphatidylinositol Precursor to Phosphatidylinositol Bisphosphonate (PIP2)

PIP2 is very important for

second messenger systems

(later)

Phosphorylation by specific kinases:

membrane-bound PIP2

two 2nd messengers formed:

DAG: stays in membrane

IP3: diffuses away

PIP2 Signaling Mechanism

JCS March 1, 2008 vol. 121 no. 5 551-559

Phospholipids

(Phosphatidylcholine)

Phosphatidylcholine

“lecithins”

Neutral zwitterion at physiological pH

Dipalmitoyl-lecithin is part of pulmonary surfactant

Palmitate at R1 & R2 is major (80%) phospholipid in the extracellular lipid layer lining pulmonary alveoli

Neutral zwitterions (German: “hybrid”)

PC = Most common phospholipid

“Lecithin” generic term = mixture of fatty substances (FAs, PLs, TGAs, etc); egg, soy

PAM

Phosphatidylcholine plays an important role in the maintenance of cell-membrane integrity and fluidizing effect on cellular membranes.

Decreased cell-membrane fluidization and breakdown of cell membrane integrity, are associated with liver disease, neurological diseases, cancers and cell apoptosis.

Phosphatidylcholine

FYI: Dietary Supplements

“Brain enhancing product Mind Power Rx”

$13.99

2003 FDA: “Not significant agreement of association of PS with reduced dementia, but:

"Consumption of phosphatidylserine may reduce the risk of dementia in the elderly" and "Consumption of phosphatidylserine may reduce the risk of cognitive dysfunction in the elderly".

PS gets C grade from Nat’l Std for cognitive disorders & lipid lowering

Phosphatidylcholine – Clinical Correlation

reduction in the surface tension within the air spaces (alveoli) of the lung, preventing their collapse.

Alters molecular structure of phospholipid film secreted by pneumocytes

Stabilizes film, maintains its flexibility

Surfactant in alveoli: hydrophilic portion in water & tails in air

Phosphatidylcholine – Clinical Correlation

Respiratory distress syndrome (RDS) in neonates

The respiratory distress syndrome (RDS) of a premature infant is, in part, related to a deficiency in the synthesis of a substance known as lung surfactant.

The premature infant has not yet begun to produce adequate amounts of lung surfactant.

Phosphatidylcholine – Clinical Correlation

RDS only in premature (occurs in ~1% of newborn; leading cause of death in pre-term)

Maturity of lungs assessed by lecithin/sphingomyelin (L/S) ratio in amniotic fluid

Phosphatidylcholine Clinical correlation: RDS & L/S

Prior to 28 wks, fetal lung synthesizes primarily sphingomyelin

After this: synthesis of dipalmitoyllecithin (Phosphatidylcholine)

Surfactant begins to appear in lung/amniotic fluid

L/S ratio useful for timing elective births, determining if mother should receive glucocorticoid to accelerate maturation of fetal lung

Clinical Correlation: RDS

Treatment: pulmonary surfactant

e.g. calfactant (Infasurf):

Dipalmitoylphosphatidylcholine

Phosphatidylcholine (lecithin) is not required in the diet because it can be synthesized in the body.

The components of phosphatidylcholine (including choline) all can be produced.

A pathway for de novo choline synthesis from glucose exists, but the rate of synthesis is inadequate to provide for the necessary amounts of choline.

Thus, choline has been classified as an essential nutrient, with an adequate intake (AI) of 425 mg/day in women and 550 mg/day in men.

Phosphatidylcholine in Diet

Because choline is widely distributed in the food supply, primarily in phosphatidylcholine (lecithin), deficiencies have not been observed in humans on a normal diet.

Deficiencies may occur, however, in patients on total parenteral nutrition (TPN), that is, supported solely by intravenous feeding.

The fatty livers that have been observed in these patients probably result from a decreased ability to synthesize phospholipids for VLDL formation.

Phosphatidylcholine in Diet

Phospholipids

There are two more types of Phospholipids

Phospholipids can also be Glycerolipids

There are two more types of Phospholipids

Phospholipases

Mellitin: potent stimulator of PLA2; primary component of bee venom

other PLA2s: pancreatic digestion of dietary fats

PLA1: venoms, normal metabolism

PLC and PLD are phosphodiesterases, but distinct from cyclic nucleotide PDEs involved in e.g. viagra & cilostazol

Example question:

Which of the following phospholipases starts the arachidonic acid cascade?

Phospholipases located in cell membranes or in lysosomes degrade glycerophospholipids. Phospholipase A1 removes the fatty acyl group on carbon 1 of the glycerol moiety.

Phospholipase A2 removes the fatty acid on carbon 2. For e.g. the C2 fatty acid in cell membrane phospholipids is usually an unsaturated fatty acid, which is frequently arachidonic acid. It is removed in response to signals for the synthesis of eicosanoids.

The bond joining carbon 3 of the glycerol moiety to phosphate is cleaved by phospholipase C. Hormonal stimuli activate phospholipase C, which hydrolyzes PIP2 to produce the second messengers DAG and IP3.

Phospholipases

Phospholipases e.g. snake venom

Some venoms hemolytic due to phospolipase activity

venom contains phospholipase A2

hydrolyzes a FA from phosphoglyceride

breakdown product (lysolechithin) acts as detergent, dissolves membranes of RBC

Some snake venoms hemolytic due to phospolipase activity

e.g. rattlesnake

Example question:

Which of the following phospholipases is involved in rattlesnake venom?

Which of the following phospholipases is involved in producing the second messengers PIP2 and DAG?

Ether lipids (Phospholipids or Glycerolipids)

Ether Lipids

vs. usual ester linkage of other lipids

Include:

Plasmalogens

platelet activating factor (PAF)

Plasmalogens are Membrane Phospholipid

Plasmalogens in many tissues, but especially nervous, immune, cardio

Heart: 30-40% of choline phospholipids are plasmalogens

70% myelin sheath ethanolamine lipids

Functions unclear, but protect vs. ROS, change membrane dynamics, signaling molecules

Example question: Which of the following (names) are ether lipids?

Ether Lipids: Platelet Activating Factor (PAF)

Platelet aggregation, blood vessel dilation

Mediates broncho-constriction

Platelet aggregation, degranulation, BV dilation: Important in hemostasis

Toxins, e.g. bacteria fragments can induce PAF  drop BP, reduced blood vol. pumped: shock

Phospholipids

There is one more types of Phospholipids

Phospholipids can also be Glycerolipids

There is one more types of Phospholipids

Sphingolipids

Sphingolipids- Sphingosine backbone

Amino group of sphingosine is linked by amide to a FA

Phosphocholine esterifies the OH group

Sphingomyelins:

important in nervous

tissue

Sphingolipids in all cells, but highest in white matter of CNS

Discovered in brain tissue; named after Sphinx due to mysterious nature

There is one more types of Phospholipids

Sphingolipids

Sphingolipids can also be Phospholipids

There is one more types of Sphingolipids

Glycolipids

Glycolipids- Are sugar-containing lipids

Can have glycerol or sphingosine backbone

e.g. cerebroside

amino group acylated by a FA

primary hydroxyl group is linked to a sugar

Glycolipids

Found in bilayer facing outward, act as recognition sites

Gangliosides :

contain branched chain carbohydrates

characteristic of nervous tissues

oriented w/ carbohydrate extracellularly

carbohydrate important for cellular recognition

e.g. binding of cholera toxin

Glycolipids- More Complex Example

Glycolipids- Clinical Correlation Tay Sachs Disease

Inherited autosomal recessive disease

Deficiency of hexoaminidase (metabolizes gangliosides)

Accumulation of ganglioside in nerve cell membranes

Neurons become swollen w/ lipid filled lysosomes

symptoms begin at 6 mo., often fatal by 4 yrs

Example question: What is the pathology of Tay-Sachs?

Sphingolipids can also be Phospholipids

Different Types of TG and Membrane Lipids

Lipids, fatty acid and different types of biological lipids

Structure & nomenclature of naturally occurring fatty acids

Structure, nomenclature & functional importance of storage lipids namely triacylglycerols and waxes

Structure, nomenclature & functional importance of membrane lipids

Function of lipids as biological signal molecules

Effects of trans-fatty acids on metabolism

Summary

-3H

NaOH

triglyceride(esteroffattyacid

withglycerine)

Glycerine(byproduct)

OR'

OR''

R=longfattyacid

(catalyst)

methylesteroffattyacid

Glycerin

O-NO

HNO

(CH

)