Neurobiochem Exam 3

What kind of fatty acid is DHA?

Omega-3, non-essential in adults

What happens to fatty acids as the number of carbons increases?

melting temperature increases

• more carbons increases the rigidity, making it harder to break down and needs a higher temperature

What happens to fatty acids as the number of double bonds increases?

Melting temperature decreases

• double bond adds more fluidity in the molecule allowing it to be broken down at a lower temperature

What are the two essential fatty acids?

• Linoleate (LA): Omega 6

• Linolenate (ALA): Omega-3

What fatty acids are the most abundant in the brain overall?

Palmitate and Stearate

True or false: fatty acids an be made in astrocytes

True! fatty acids can be made in the liver and the astrocyte

Describe the fatty acid synthase pathway, also known as the malonyl CoA pathway.

• citrate comes out of TCA in mitochondria

• converted into acetylcoA in cytosol

• AcetylcoA turned into fatty acids such as palmitate

What enzymes are found in the endoplasmic reticulum and are useful in the creation of fatty acids?

• Elongase: adds 2 carbons—- which is why fatty acid chains will always be even-numbered!

• Desaturase: adds double bonds

What are some sources of linolenate/ALA? an Omega-3

• flaxseeds

• fish

• soybean oil

• nuts

What are some sources of linoleate, an omega-6?

• eggs

• meat from grain-fed animals

• vegetable oils

• nuts, grains, seeds

Describe the process for fatty acid naming with the cis-delta system.

1. Begin at the carboxyl end

2. Count the carbons, and see at which carbon you encounter the first double bond at.

Describe the process for fatty acid naming with the omega system.

1. Begin at the methyl end

2. Count carbons, and see at which number carbon you encounter the first double bond at.

What is an allylic carbon?

In a PUFA, this is a carbon beside a C-C double bond

this is important because these kinds of carbons are weak points.

Where are the most free radicals in the body produced?

Mitochondria

What is a common source of free radicals? Give the name of the radical too.

Mitochondria electron transport chain: oxygen terminal electron acceptor only accepts 1 electron instead of 2

Superoxide

What prevents superoxide from leaving the mitochondria?

Superoxide dismutase

• turns it into hydrogen peroxide and oxygen

Catalase or Glutathione peroxidase

• turns peroxide into oxygen and water

What happens when iron reacts with hydrogen peroxide?

A hydroxyl radical is created when iron reacts with peroxide.

it has one free electron and is attracted to hydrogen from allylic carbons within a fatty acid. this causes the fatty acid to become a radical as well

What steps happen within fatty acids that encounter iron?

1. Fatty acid is turned into a radical

2. electrons delocalize over double bond because of resonance. However, exposure to oxygen makes it a radical again

3. Oxygenation causes further oxidation

4. Peroxyl fatty acid is created, which is very unstable (unpaired electron)

5. Peroxyl fatty acid steals proton from a neighboring fatty acid to create a peroxidized fatty acid

6. second fatty acid becomes a radical, and cycle repeats all over again

What antioxidants can be found in the membrane?

Fat soluble and can be found in the membrane!

• Vitamin E (tocopherol: toc-OH)

• Vitamin C

• Ubiquinol

• Lutein (eye health)

• Beta-carotene (vit A)

What are the antioxidant properties of vitamin E (steps)?

• Vitamin E/ tocopherol/ toc-Oh

• toc-oh donates an electron, becoming unpaired

• toc-o (with one electron) and becomes a stable radical

• Vitamin C (ascorbate) regenerates Vitamin E thru electron donation

• VitC+ another VitC regenerates itself

What are most common forms in which you’ll find the fatty acid in the brain?

• R1 almost always palmitate or stearate

• R2 almost always DHA or AA

1. Phosphatidylethanolamine (0)

   1. Most common in neuron:

   2. cone-shape curvature during membrane fusion

2. Phosphatidylserine (-1)

3. Phosphatidylcholine (0)

4. Phosphatidylinositol (-1)

   1. important for signaling pathways

5. Sphingomyelin

   1. has sphingosphene backbone

What is the most abundant fatty acid in the brain?

DHA

What kinds of carbons are the most susceptible to oxidation?

Allylic carbons, specifically bis-allylic (sandwiched between 2 c-c double bonds)

What transporter allows for crossing of DHA into the BBB?

MFSD2A transporter

True or false: cholesterol crosses the BBB.

FALSE. the brain makes its own cholesterol through astrocytes so there is no need for transport from other parts of the body.

Describe the structure of cholesterol.

Amphipathic

• hydrocarbon tain at one end (non-polar)

• OH group at the other end (polar)

How does cholesterol interact with phospholipids?

• orients itself to be parallel with phospholipid fatty acid chains

• OH (polar) group interacts with phospholipid head (also polar)

What are some uses of acetyl-coA?

• fatty acid synthesis

• neuronal TCA cycle

• making ACh

• Acyl group used for histone acetylation

True or false: cholesterol is used to make steroid hormones.

True! Cholesterol can be used to make estrogen and testosterone, among other hormones. Cholesterol has rigid steroid rings that help create the steroid hormones.

What is the net charge of phosphatidylserine? Where is it found?

-1

inside the membrane

What is the net charge of phosphatidylethanolamine? Where is it found?

net charge of 0

• most densely concentrated at synaptic membranes

What is the net charge of phosphatidylcholine?

net charge 0

What is the most abundant phospholipid in the body?

Phosphatidylcholine

Which phospholipid is made from glucose? What is it’s net charge?

Phosphatidylinositol

net charge of -1

Wat is the base of sphingomyelin? How many fatty acids does it have?

Based on palmitate and stearate

ONLY ONE FA: palmitate or stearate

What is something unique about the structure of phosphatidylethanolamine? Why is it useful?

Unlike the other cylindrical phospholipids, phosphatidylethanolamine is cone-shaped

This structure promotes negative membrane curvature which is helpful in membrane fusion and budding

In aqueous solutions, what are lipid bilayers stabilized by?

1. van der Waals interactions: nonpolar tails

2. Electrostatic + H-bonding between polar head groups

How are peripheral membrane proteins attached to the membrane?

Non-covalent (ionic + hydrogen) bonds with integral proteins or lipid head groups

What are some functions of DHA?

1. anti-inflammation activation of nuclear receptors

2. activating/regulating transcription factors that are essential to neuronal health

3. membrane fluidity due to double bonds

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Why are there many PUFAs specifically in the brain?

Increase membrane fluidity

What two fatty acids are considered essential as they cannot be made by the body?

1. ALA: omega-3

2. LA: omega-6

What is DHA synthesis in the body limited by?

Limited amount/nature of enzymes, low efficiency of conversion

True or false: the enzymes used to make AA from LA are the same ones used to make DHA

True. Consuming a high amount of omega-6 shifts the enzymes to make more AA and inflammatory markers versus making more of the DHA which is anti-inflammatory

What fatty acid is most commonly found in sphingomyelin?

Palmitate or Stearate

Describe the structure of sphingomyelin.

SATURATED Fatty acid + sphingospine= ceramide

sfa allow for tight packing of molecule

What fatty acids are found on phosphatidylethanolamine?

Position 1: Palmitate (C16:O) or Stearate (C18:O)

Position 2: DHA or AA

What enzyme cleaves AA from the membrane?

cPLA2

What enzyme cleaves DHA from the membrane?

iPLA2

What are the three areas within the RXR receptor?

1. Ligand binding domain/activation domain

2. Dimerization domain

3. Ligand binding domain

What are the two fates for a DHA molecule?

1. Activation of RXR thru binding of DHA

2. Conversion to docosanoid such as Neuroprotectin D1 or Resolvin D1

How is DHA converted into molecules that activate PPARgamma?

Thru lipooxygenases and cyclooxygenases, DHA is converted into either neuroprotectin D1 or resolvin D1

What are the hydrophilic interactions that occur between DHA and RXR?

RXR has Arginine, Lysine, Histidine, and Serine

RXR amino acids ionic and hydrogen bond with carboxyl of DHA

What are the hydrophobic interactions that occur between DHA and RXR?

RXR has Met, Phe, Val, ile, gly, ala, leu that have hydrophobic and Van Der Waals interactions with the hydrocarbons of DHA

True or false: Dimerization of RXR and PPARgamma happens after ligand binding.

False. Dimerization occurs independently of ligand binding.

What about RXR and PPARgamma helps stabilize it?

these proteins have cysteine resides that bind to a zinc molecule. this makes these proteins zinc-finger proteins

What happens at the PPAR response element?

1. RXR and PPARgamma each bind at a GG section of the response element.

2. The Arginine guanidium group from RXR and PPARgamma bind to the guanines in the response element— symmetrical H bonding

What happens when a ligand is bound to RXR and PPARgamma bound to the PPRE?

when a ligand is bound (DHA to RXR) and (NpD1 and RvD1 for PPARgamma) , these proteins recruit histone acetyltransferases

this causes the upregulation of gene expression of neurotrophins (BDNF, interleukin-10, SOD, etc)

what happens when a ligand is NOT bound to RXR/PPARgamma/PPRE complex?

histone deacetylases are recruited

Describe the pathway that arachadonic acid takes to cause inflammation.

1. Glutamate binds to metabotropic glutamate receptor, releasing a GalphaQ subunit that increases intracellular Ca2+

2. Increased intracellular calcium activates cPLA2, which cleaves arachadonic acid from the phosopholipid bilayer of the ER

3. arachadonic acid diffuses to Prostaglandin GH2 Synthase I, which has cyclooxygenase activity. there are two binding sections

   1. Hydrophobic binding pocket: Leu, ile, val, phe, met

   2. Ser, Lys, and Arginine also can bind

   3. Ser-OH specifically binds to AA in the cox enzyme

4. binding of arachadonic acid causes PGE2 synthesis, which then diffuses out of the cell

5. PGE2 can cause vasodilation in smooth muscle cells of veins/arteries

6. PGE2 can activate