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Lipids and Membranes

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					Lipids and Membranes




     Chapter 9
                                   Lipids
Lipids fats oils…. Greasy molecules, mmmmm donuts.

Several levels of complexity:
• Simple lipids - a lipid that cannot be broken down to smaller
   constituents by hydrolysis.
    – Fatty acids, waxes and cholesterol
• Complex lipids - a lipid composed of different molecules held together
   mostly by ester linkages and susceptible to cleavage reactions.
    – acylglycerols - mono, di and triacyl glycerols ( fatty acids and
      glycerol)
    – phospholipids (also known as glycerophospholipids) - lipids which are
      made of fatty acids, glycerol, a phosphoryl group and an alcohol.
      Many also contain nitrogen
    – glycolipids (also known as glycosphingolipids): Lipids which have a
      spingosine and different backbone than the phospholipids
• Phospholipids:
• Two fatty acids covalently
  linked to a glycerol, which is
  linked to a phosphate.

• All attached to a “head
  group”, such as choline, an
  amino acid.

• Head group POLAR – so
  hydrophilic (loves water)

• Tail is non-polar –
  hydrophobic

• The tail varies in length from
  14 to 28 carbons.
Several levels of complexity:
        • Precursor and derived lipids - these include several of the initial
          long chain hydrocarbons and other molecules that make up lipids,
          such as ketone bodies.

Lipids are defined as those molecules soluble in organic solvents and not
   water
Properties of fatty acids
 Typically found as esters , mono,
   di and tri -acylglycerols (good old
   fashioned fat)
 Free fatty acids are found
   associated with carrier proteins
   such as albumin in blood
 These are amphipathic molecules
   with various carbon chain lengths
 Can be up to 30 carbons long but
   generally less than 20

   Most common 12-24 carbons long
Properties of fatty acids
- Saturated fatty acids are
   saturated with hydrogen. No
   double bonds.
- 1/2 of animal fat has one
   desaturation
- Unsaturated fatty acids contain at
   least one double bond separated by
   a methyl group. These are
   typically cis- in nature. Trans
   unsaturated fatty acids have been
   linked to cancer and heart disease.
   (the strength of the proof is not
   clear).
- Most double bonds are separated
   by two carbons
- Polyunsaturated fatty acids - duh
Nomenclature
  - Trivial (greek) system, IUPAC system, omega system
  - Common name most commonly used (trivial system)
  - The systematic name for saturated acids ends in -anoic.
    Unsaturated fatty acids ends in -enoic.
  - The number one carbon is the carboxyl carbon
  – Carbon #1 = alpha carbon
  – Carbon #2 = beta carbon
  – Carbon #3 = gamma carbon
  - Omega vs. delta fatty acids
  – Double bonds counted from the first carbon are delta
    desaturations
  – Double bonds counting from the methyl end are the omega
    desaturations
  – Omega nomenclature helps to identify physiological important
    fats w3 - w6 (can not be intraconverted in body)
Nomenclature
   - Common name most commonly used
   - The systematic name for saturated acids ends in -anoic. Unsaturated fatty
     acids ends in -enoic.
   - The number one carbon is the carboxyl carbon
   – Carbon #1 = alpha carbon
   – Carbon #2 = beta carbon
   – Carbon #3 = gamma carbon
   - Omega vs. delta fatty acids
   – Double bonds counted from the first carbon are delta desaturations
   – Double bonds counting from the methyl end are the omega desaturations


        Trivial       IUPAC              Carboxyl   Omega
        Oleic Acid
Nomenclature
   - Common name most commonly used
   - The systematic name for saturated acids ends in -anoic. Unsaturated fatty
     acids ends in -enoic.
   - The number one carbon is the carboxyl carbon
   – Carbon #1 = alpha carbon
   – Carbon #2 = beta carbon
   – Carbon #3 = gamma carbon
   - Omega vs. delta fatty acids
   – Double bonds counted from the first carbon are delta desaturations
   – Double bonds counting from the methyl end are the omega desaturations


        Trivial        IUPAC               Carboxyl   Omega
        Oleic Acid   9-octadecenoic acid
Nomenclature
   - Common name most commonly used
   - The systematic name for saturated acids ends in -anoic. Unsaturated fatty
     acids ends in -enoic.
   - The number one carbon is the carboxyl carbon
   – Carbon #1 = alpha carbon
   – Carbon #2 = beta carbon
   – Carbon #3 = gamma carbon
   - Omega vs. delta fatty acids
   – Double bonds counted from the first carbon are delta desaturations
   – Double bonds counting from the methyl end are the omega desaturations


        Trivial       IUPAC                Carboxyl   Omega
        Oleic Acid - 9-octadecenoic acid   18:1 9
Nomenclature
   - Common name most commonly used
   - The systematic name for saturated acids ends in -anoic. Unsaturated fatty
     acids ends in -enoic.
   - The number one carbon is the carboxyl carbon
   – Carbon #1 = alpha carbon
   – Carbon #2 = beta carbon
   – Carbon #3 = gamma carbon
   - Omega vs. delta fatty acids
   – Double bonds counted from the first carbon are delta desaturations
   – Double bonds counting from the methyl end are the omega desaturations


        Trivial       IUPAC                Carboxyl   Omega
        Oleic Acid - 9-octadecenoic acid   18:1 9 18:1 9
Nomenclature
   - Common name most commonly used
   - The systematic name for saturated acids ends in -anoic. Unsaturated fatty
     acids ends in -enoic.
   - The number one carbon is the carboxyl carbon
   – Carbon #1 = alpha carbon
   – Carbon #2 = beta carbon
   – Carbon #3 = gamma carbon
   - Omega vs. delta fatty acids
   – Double bonds counted from the first carbon are delta desaturations
   – Double bonds counting from the methyl end are the omega desaturations


        Trivial        IUPAC               Carboxyl   Omega
        Oleic Acid - 9-octadecanoic acid   18:1 9 18:1 9

      Linoleic Acid - 9, 12-octadecenoic acid   18:2 9,12 18:2 6
Nomenclature
   - Common name most commonly used
   - The systematic name for saturated acids ends in -anoic. Unsaturated fatty
     acids ends in -enoic.
   - The number one carbon is the carboxyl carbon
   – Carbon #1 = alpha carbon
   – Carbon #2 = beta carbon
   – Carbon #3 = gamma carbon
   - Omega vs. delta fatty acids
   – Double bonds counted from the first carbon are delta desaturations
   – Double bonds counting from the methyl end are the omega desaturations


        Trivial        IUPAC               Carboxyl   Omega
        Oleic Acid - 9-octadecenoic acid   18:1 9 18:1 9

      Linoleic Acid - 9, 12-octadecenoic acid   18:2 9,12 18:2 6

        Essential FA- those that humans can not make but are required to
        Sustain growth - Linolenic 3 and Arachadonic 6
                        Common FA Names

Carbon #       Trivial Name    IUPAC
 12            Lauric acid     Dodecanoate              12:0
 14            Myristic acid   Tetradecanate            14:0
 16            Palmitic acid   Hexadecanoic acid        16:0
 18            Stearic acid    Octadecanoic acid        18:0

 16            Palmitoleic acid 9-Hexadecenoic acid    16:1 9
 18            Oleic acid       9,12 Octadecadienoic acid 18:2 9,12
 20    Arachidonic acid     5,8,11,14 Eicosatetraenoic 20:4 5,8,11,14
Melting points and membrane fluidity. Both length and level of
  unsaturation determine the stability of the hydrophobic
  interactions and thus shift the transition phase - melting point
  of membranes
- Double bonds - usually cis. This results in bends the chain.
- Reductions in hydrophobic effect reduce energy required to
  disrupt the crystalin structure of a membrane or oil. Think of
  animal fat with lower unsaturated fatty acids - butter and plant
  oils that are polyunsaturated, corn oil.
- The longer the fatty acids the higher the melting point.
- Again the more hydrophobic interactions effects the more the
  energy it takes to break the order. Decreases in the packing
  efficiency decreases the mp
- The van der Waals forces then come apart more easily at lower
  temperatures.
- Animal alter the length and unsaturated level of the fatty acids
  in lipids (cholesterol too) to deal with the cold temps
                       Esterification
•   The general name for a chemical reaction in which two reactants
    (typically an alcohol and an acid) form an ester as the reaction
    product. Esters are common in organic chemistry and biological
    materials, and often have a characteristic pleasant, fruity odor.

•   This leads to their extensive use in the fragrance and flavour industry.

•    Esterification is a reversible reaction. Hydrolysis- literally "water
    splitting" involves adding water and a catalyst (commonly NaOH) to an
    ester to get the sodium salt of the carboxylic acid and alcohol.

•   As a result of this reversibility, many esterification reactions are
    equilibrium reactions and therefore need to be driven to completion

•    Esterifications are among the simplest and most often performed
    organic transformations.
                              Lipids II
Triacylglycerols (Triglycerides)
- Esterification of glycerol takes place at each of the alcohol
   moieties

- This is the major form of fatty acid storage. Found in adipose
  tissue in specialized cells. These fat cells are filled with TAGs
  and can grow in size.

- Release (hydrolysis) of fatty acids occurs under the control of
  hormone sensitive lipase

- Fatty acids released into the bloodstream are carried via
  albumin.
                          Triglycerides

- The acylated acyl chains are typically different at each position
  of glycerol.

- Each of the three carbons on glycerol are different. The 1 and
  3 carbons are steriochemically different and recognized as such
  by enzymes. The carbons are labeled sn1, sn2, sn3
Triacylglycerols (TAGS)
- TAGs DAG and MAG. The sn3 carbon is typically removed
   first.
- Saponification - hydrolysis by bases (KOH - potash) cleaves the
   fatty acids from glycerol. Using KOH from wood ashes and
   animal fat creates old-fashioned soaps. (divalent cations in
   hard water cause the ppt of soaps)

- There is a large amount of energy available in the storage of
  TAGs. These are highly reduced molecules with low amounts of
  water associated. The result is a molecule that can undergo
  repeated oxidation steps transferring the energy to form ATP.
  The low water content increases the gram per gram energy
  available vs. carbohydrates

- Polar bears can go for up to 8 months without eating. Most of
  energy and water comes from the fats produced by the bear
  and the fat ingested from seals.
Phospholipids
- Phospholipids are the largest constituent of the membrane
- Phospholipids serve two important purposes (different than TAGs)
   structural and signaling. Although DAG is an important signaling
   molecule as well
- You should know the different signaling lipids and there functions
- There are two general classes of phospholipids
- Glycerophospholipids, phospholipids or phosphate esters (same thing)
   and the sphingolipids.
- Glycerophospholipids         - major lipid comonent of biological membranes


-   The sn 1 and sn2 positions on glycerol are esterified (red). The sn2 carbon
    is typically unsaturated. Differences occur between tissues and organism

-The sn3 position is phosphorylated
(blue)


-The phosphoryl group can be
-modified with several different
alcohols.

-Common classes are shown in Table
9.2 pp249 of 3rd ed


-LEARN THEM
- Phosphatidic acid        is the base glycerophospholipid but is not found in
  high concentrations

 -Common head groups (the alcohol
 derivatives) are
 -serine, choline, ethanolamine,
 glycerol and inositol.


 •This divides glycerophospholipids
 into
 •basic
 •neutral
 •acidic lipids.

 -The nomenclature is 1-acyl-2-
 acyl-3-phosphatidyl "head group".

 -Biological use –lung surfactant
                     phospholipases
• These are a set of hydrolytic enzymes which act on both the fatty
  acid chains and the head group

• Phospholipase A2 excises C2 fatty acid group (red) forming a
  Lysophospholipid - recognizes the sn-2 acyl bond
   – Powerful detergent which lyses cells by disrupting membranes
      • Bee and snake venoms rich in this enzyme
      • Inflammatory responses
                       phospholipases
• Phospholipase C cleave phospholipids just before the phosphate group

• plays an important role in eukaryotic cell physiology, particularly
  lipid signaling pathways in a calcium-dependent manner

• proliferation, differentiation, apoptosis, cytoskeleton remodeling,
  vesicular trafficking, ion channel conductance, endocrine function
  and neurotransmission.
                        Phospholipase C
•   Phospholipase C cleave phospholipids just before the phosphate group
    generating inositol triphosphate (IP3) and diacylglycerol (DAG).

•   IP3 is soluble, and diffuses through the cytoplasm and interacts with IP3
    receptors on the endoplasmic reticulum, causing the release of calcium and
    raising the level of intracellular calcium.

•   DAG remains tethered to the inner leaflet of the plasma membrane due to
    its hydrophobic character, where it recruits protein kinase C (PKC), which
    becomes activated in conjunction with binding calcium ions
                      phospholipases
• Phospholipase D cleave phospholipids just after the phosphate group,
  form phosphatidic acid (PA), releasing the soluble choline headgroup
  into the cytosol

• Phosphatidic is extremely short lived and is rapidly hydrolised by the
  enzyme PA phosphohydrolase to form diacylglycerol (DAG).
  •   Phospholipids preferentially hydrolyze substrates that are located in
      bilayer membreases. They carry our interfacial catalysis at the
      boundry of water and a lipid phase

  Plasmalogens
        Different than the other
        phosphoglycerides -

  Has an ether lipid where the first
  position of glycerol (sn1)binds a vinyl
  residue (from a vinyl alcohol) with
  the double bond next to the ether
  bond.
  The second carbon has a typical
  ester-linked fatty acid, and the third
  carbon usually has a phospholipid
  head group like choline

These are typically involved in platelet aggregation & vasiodialation.
Protect the heart
Sphingolipids
-   Another class of phospholipids
-   Do not contain glycerol as a backbone instead an amino alcohol called
    sphingosine.
-   Add one fatty acid and it is ceramide
     - regulates differentiation, proliferation, programmed cell death

-   Add an head group (choline or ethanolamine) and it is a sphingophospholipid
-   These are very different in location and concentration than the
    glycerolipids
                     Eicosanoids

- These are a diverse group of hormonelike molecules produced in
  nearly all mammalian cells


- Can be formed from the action of   Phospholipase A2

- Stem from the greek word eikosi meaning twenty

- Because they act on the same organ they are produced in they are
  autocrines, vs a paracrine which act distal to the site of origin

- Most are derived from arachidonic acid 20:4   D5,8,11,14
-   Leukotrienes are hydroxylated fatty acid derivatives of arachidonate
     - Initially found in leukocytes - white blood cells
     - Often congugated
     - Secreted by damaged cells during anaphylaxis
     - Promotes bronchioconstriction and vasioconstriction
     - Acts as a chemotractant to bring white blood cells to fight
       infection
-   Aspirin inhibits    Prostoglandins have a
    the formation of    cyclopentane ring and is
    cyclic ecosanoids   hydroxylated at various
                        carbons.
                        There are several versions
-   The Serine in       each with a different effect.
    the active site
    of the enyme        Different types and
    cyclooxygenase      concentrations of
    is acetlyated by    prostaglandins are found in
    aspirin             different tissues.
                        •Induce inflammation and cause
                        fever and pain
                        •Ovulation and uterine
                        contraction during conception
                        and labor
                        •Antiplatelet aggregation
                        •Vasiodialation
                        •Smooth muscle contraction
                            -   Thromboxanes produced by
-   Thromboxanes (TxB)          platelets Alterations in double
    produced by                 bonds in arachidonate still leads
    platelets to cause          to TxB formation but they are
    aggregation at sites        less able to aggregate platelets
    of cardiovascular
    injury.                 -   These fatty acids are found in
-   Leads to clot               some cold fish oils omega 3 fatty
    formation and foam          acids
    cell formation
    (platelets
    differentiate into
    cells that cause
    plauques in arteries)
Prostacyclin produced
  by blood vessels and
  inhibit platelet
  aggregation
- These are
  antagonistic to
  thromboxanes
- The omega 3 fatty
  acids leads to a more
  potent antiaggregant
  activity
Steroids
- Cholesterol plays an important role in membrane fluidity and the
   starting material for steroids and vitamin D
- Six rings three cyclohexane and one cyclopentane

 -Modified with
 hydrophobic
 functional groups on
 carbons 10,13 and
 17
 -Inflexible
 hydrophobic bulky
 molecule
 --OH on the 3rd
 carbon - makes the
 molecules ampipathic
 -Found in all tissues
 in the membranes
 often acylated at
 the OH
Function in membranes
- Cholesterol broadens the phase change from solid to fluid or oil like state.
- The stiff ring decreases coiling and movement of the fatty acid tails in the
   phospholipids. This can have two effects on fluidity

  -Below the melting
  point - cholesterol
  is too bulky to fit
  into the rigid
  crystal state. This
  increases the
  melting point
  -Above the melting
  point the cholesterol
  still restricts the
  movement of the
  fatty acid tails.
  Thus the melting
  point is decreased
• Atherosclerosis - heart disease where plaque form blockages in
  blood flow. Specialized cells macrophages are converted to
  foam cells where they are filled primarily with cholesterol and
  cholesterol esters. Eventually these cells can calcify and
  harden ultimately blocking the flow of blood to the heart.

• Precursor for the steroids
Steroid hormones - do not act by binding receptors like other
  hormones. These are lipid soluble hormones that are
  transported through the plasma and interstitial fluids bound to
  steroid carrier proteins (SCP). Once to the cells, the steroid
  crosses the membrane and binds specifically to a cytosolic
  steroid receptor. The complex often travels to the nucleus and
  acts at the level of altering DNA-> RNA ->Protein production.
  (transcription)
Steroid hormones
•   Glucocorticoids -
    involved in
    reducing
    inflammation, pain
    and carbohydrate
    metabolism.

-   Can bind to
    proteins which act
    then bind to DNA
    and alter gene
    expression and
    protein production
•   Mineralcorticoids -
    required for normal
    kidney function in the
    regulation of K+ and
    Na+ ion filtration
•   Glucocorticoids,
    mineralcorticoids
    and some
    androgens are
    produced in
    adrenal cortex -
    small organ just
    above the kidney.
    Over 50 varieties
    found in this
    tissue
Regulation of blood pressure and volume
 When sodium ions levels are high- so a
 high blood volume a glucocorticord
 (cortisol) makes the heart release atrial
 natriuretic hormone (ANH)

 Kidneys excrete sodium ions and water
 follows. Volume and pressure return to
 normal.



When sodium ions levels are low- a low
blood volume makes kidneys secrete
renin (ENZYME)

Adrenal cortex secretes a
mineralocorticoid (Aldosterone), which
makes the kidneys reabsorb sodium ions
and thus water. Volume and pressure
return to normal.
Sex steroids;
  Androgens and
  estrogens.
  Structures are
  related and
  formed from the
  other. Effect of
  these are
  hormonal. Source
  is generally from
  the gonadal
  tissues.
Membrane dynamics -
   - Formation of lipid bilayers - these structures form due to the
     insolubility in water.
-  When enough lipids are present, micelles form.     Eventually these can
   fill out enough to form a bilayer where the polar heads face the
   aqueous phase and the hydrophobic tails are buried in the nonpolar
   phase
- Lipids easily diffuse
lateraly but rarely "flip"
due to the changes in
entropy changes that
must accompany such
a switch.
                    New - Lipid rafts and caveolae
•   Lipid rafts - Lipid rafts are specialized membrane domains enriched in
    certain lipids cholesterol and proteins.
     – three types of lipid rafts; caveolae, glycosphingolipid enriched
        membranes (GEM), and polyphospho inositol rich rafts.
     – The main role of rafts is in signal transduction where the rafts act
        as an anchor for signaling protiens to assemble into “scafolds” and
        the raft also acts as a binding site for actin related proteins.

•   Caveolae - Caveolae are flask shaped invaginations on the cell surface
    that are a type of membrane raft, these are cave shaped and associated
    with proteins called caveolin. Involved in receptor internalization and cell
    signaling


                                       The fatty-acid chains of lipids within the rafts tend to
                                       be extended and so more tightly packed, creating
                                       domains with higher order. It is therefore thought that
                                       rafts exist in a separate ordered phase that floats in a
                                       sea of poorly ordered lipids. Glycosphingolipids, and
                                       other lipids with long, straight acyl chains are
                                       preferentially incorporated into the rafts.

				
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posted:11/11/2011
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