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318 Cards in this Set
- Front
- Back
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What are lipids?
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General name for, cholesterol, fatty acids, triglycerides, etc
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What is fat?
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Fatty acids, triglycerides (not cholesterol)
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What are fatty acids?
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Carboxylic acids w/ a large hydrocarbon chain
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Which fatty acid 16:0?
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Palmitic acid
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What is the carbon skeleton composition of stearic acid?
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18:0
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What fatty acid has a carbon skeleton of 16:1?
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Palmitoleic acid
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What is the carbon skeleton composition of oleic acid?
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18:1
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What is the carbon skeleon composition of arachidonic acid?
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20:4
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Where are the double bonds located in arachidonic acid?
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Delta 5, 8, 11, 14
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When does melting point of a fatty acid increase?
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If the molecule is saturated, and has a longer chain, it has a higher melting point
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What are the melting points like for unsaturated fatty acids? (ie. w/ introduction of a double bond?)
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Unsaturated fatty acids have a significantly lower melting point
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Why is the melting point so much lower for unsaturated fatty acids?
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Fatty acids with double bonds don't pack as well, and therefore their structure is not as stable
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How are fatty acids amphipathic?
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The OH of the carboxyl give a polarity to that end, while the hydrocarbon chain is very hydrophobic (apolar)
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Where is the double bond located in oleic acid and in palmitoleic acid?
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delta9
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What happens to the MP when comparing a cis double bond to a trans?
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A fatty acid with a trans double bond has a much lower MP than a fatty acid with a cis double bond
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Do mammals make trans fatty acids?
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NO!!!!!!!! We can only synthesize fatty acids with cis double bonds
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Where do you count from to name the double bond, in the delta method of nomenclature?
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From the carboxyl end
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What are three things that fatty acids are good for?
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Energy
Structure/Barrier Leukotrienes, thromboxanes, etc |
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How do fatty acids provide energy?
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By beta oxidation
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How do fatty acids provide a structure to the cell?
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By being part of phospholipids in the membrane of cells
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What is monoacyl glycerol?
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Three carbon backbone, two have an OH, one a ester linkage with a fatty acyl group
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What is diacyl glycerol?
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Signalling molecule in glycogen breakdown
Has two fatty acyl gorups |
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What is triacyl glycerol/triglyceride?
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Has three fatty acyl groups w/ ester linkages on positions SN1, SN2, SN3
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What is the advantage to having three acyl groups on a Triacylglycerol?
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Good for storage: allows packing of fat into small areas
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Which enzyme brings an acyl group onto a glycerol?
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acyl transferase
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Which enzyme REMOVES an acyl group?
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Lipase
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What are phospholipids?
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A component of biological membranes
Looks like DAG except it has a head group with a phosphate at the SN3 position |
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What creates the polarity of the headgroup that is on the SN3 positon of phospholipids?
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The headgroup has a phosphate which gives a negative charge, as well as a head group with a positive charge, resulting in a polar headgroup
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What do you need to degrade phospholipids?
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Phospholipases
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What results when you cleave the phospholipid with phospholipase A2?
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Phospholipase A2 cleaves on the SN2 chain, after the O
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Where does phospholipase C cleave?
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On the SN3 chain, before the P
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Where does phospholipase D cleave?
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On the SN3 chain, after the P
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When cleaving phosphatidyl inositol 3,4 bisphosphate with PLC what results?
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DAG and IP3
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Which organism stores fat? which one uses it? What links these?
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Storage is in adipose tissues, muscle and liver use fat, and the blood is the intermediary
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Why would you make fatty acids?
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To store energy
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When would you make fatty acids?
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When you have EXCESS energy (ex: after a meal)
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When wouldnt you make fatty acids?
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In starvation conditions
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What is ACC?
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Acetyl-Coa Carboxylase
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What does ACC do?
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Adds a carboxyl group to ACETYL-COA to make MALONYL-COA
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How is ACC ACTIVATED?
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Insulin (secreted in high glucose/E conditions) stimulates dephosphorylation (via phosphorylase) of ACC leading to its activation
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How is ACC INactivated?
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Glucagon, adrenalin, activate a cAMP dependent kinase, leads to inactivation of ACC
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Why would we make a 3C compound (malonyl coA) from acetyl coA (2c) if we are adding 2C at a time to the growing chain?
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Energetics and regulation
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How is glucose metabolism and fatty acid synthesis linked?
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By glucagon/insulin regulation of ACC
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What is citrate?
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A Krebs cycle intermediate
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How is citrate formed?
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When acetyl coA feeds into TCA, combines with OAA to form citrate by citrate synthase
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What happens when citrate levels are high?
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THis indicates that alot of acetyl coA is being fed in to make it, therefore citrate will bind and activate ACC to get rid of this excess acetyl CoA through FA synthesis
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How does palmitoyl coA affect ACC activity?
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Palmitoyl-CoA (product of FA synthesis) exerts feedback inhibition of ACC
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How does malonyl coA regulate fatty acid synthesis?
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Malonyl-CoA inhibits carnitine palmitoyl transferase 1 (CPT1)
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What does CPT1 do?
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Transports acyl-COa into the mitochondria for Beta oxidation
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What does malonyl-Coa inhibition of CPT1 do?
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Prevents a futile cycle: prevents Fa oxidation and synthesis from occuring at the same time
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Do we have the enzymes required to make arachadonic acid?
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No! We do not have all the enzymes needed to insert the double bonds in these positions
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What do we need to digest in the diet in order to synthesize arachadonic acid?
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Linoleic acid. It is then extended by 2C and add 2 double bonds
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What is the rate limiting step of fatty acid biosynthesis?
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ACC (acetyl-Coa-carboxylase)
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Why is the inhibition of palmitoyl coA on ACC only temporary?
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Palmitoyl Coa is acted on by acyl transfereases to make triacylglycerides (therefore removing inhibition)
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Which kinase inhibits ACC?
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AMP kinase, triggered by glucagon, epinephrine
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How is acetyl coA generated from citrate?
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Citrate lyase
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How are carbons added to the growing fatty acyl chain?
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2C at a time
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What types of FA do we synthesize?
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Even number carbon FA only
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What does ACP do?
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Acts as a temporary carrier of the growing acyl chain
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Which molecule is ACP similar to?
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CoA (Coenzyme A)
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Which molecule is added first for FA synthesis and where?
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For the first addition of FA synthesis, ACETYL COA is charged onto the enzyme, onto position KS
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What happens after acetyl coA is charged onto KS?
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Malonyl Coa is ccharged onto ACP
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What happens after malonyl coA is charged onto ACP?
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The carboxyl of the Malonyl coA acts as a very good leaving group. Attacks the carbonyl of acetyl coA.
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What happens after this attack?
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The energy from the carboxyl is transferred to form a bond between carbonyl of acetyl CoA and CH2 of malonyl. Carboxyl of malonyl coA leaves as CO2.
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What is the importance of CO2 leaving?
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1- Energetics
2-Makes the reaction irreversible- allowing regulation and control of FA synthesis |
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What happens after this new bond was formed?
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The new 4C molecule is on the ACP, with the carbons from the acetyl coA at the END of the molecule. The keto group (that was originally from the acetyl CoA) is reduced
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What is used to reduce the keto group?
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The reducing power of NADPH
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What happens after this reduction?
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Perform dehydration of the hydroxyl group, results in the formation of a double bond
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What happens to this double bond?
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Using reducing power of NADPH, is reduced
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What happens to this molecule formed after the reduction of the double bond?
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The new 4C molecule is transferred from the ACP to the KS to allow the addition of a new malonyl coA to the ACP.
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Where did NADPH come from to be used as a reducing power in FA synthesis?
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From the pentose phosphate pathway
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How many cycles of FA synthesis can you have? Which FA do you end up with after this?
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7 cycles TOTAL, end up with 16 C palmitate
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How is the 16 C palmitate released from the FAS?
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By a thioesterase (converts 16C palmitic acid to 16C palmitate)
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What can be done to this 16 C palmitate once it is cleaved from the FAS?
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Can be elongated or add double bonds by desaturases
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Which enzyme is responsible for charging Acetyl COA/Malonyl CoA onto the KS/ACP respectively?
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MAT (malonyl/acetyl cOa-ACP Transacylase)
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Which reaction is the "condensation reaction"?
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When the carboxyl of the malonyl coA attacks the carbonyl of acetyl Coa, resulting in the leaving of Co2 and the merging of the two molecules
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Which enzyme is responsible for the condensation reaction?
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KS (beta ketoacyl-ACP synthase)
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Which enzyme is responsile for the reduction of the keto group?
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KR (beta-ketoacyl-ACP reductase)
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Which enzyme is responsible for the dehydration (removal of water) reaction?
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DH (beta-hydroxyacyl-ACP dehydrase)
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Which enzyme is responsible for the reduction of the double bond?
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ER (enoyl-ACP reductase)
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Which enzyme is responsible for the conversion of palmitoyl coA to palmitate?
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TE (palmitoyl thioesterase)
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What are the differences/similarities between CoA and ACP?
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Mostly identical, but COA has an extra phosphate and adenine group
ACP has a serine/ACP group |
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What is the stoichiometry of palmitate synthesis?
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1 acetyl CoA+ 7 malonyl coA + 14 NADPH + 7H+ -> palmitate + 7CO2 + 14 NADP+ + 8CoA + 6H20
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Which molecule requires ATP?
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ACC to synthesize the 7 malonyl coA
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How does FAS work?
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As a dimer
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How does the FAS function in the dimer?
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Fatty acid grows on domain 1, passes it on to domains 2 and 3 of the SECOND enzyme
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What type of enzyme is FAS?
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It is a multifunctional enzyme where the enzyme activities are spaced, into different domains
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Where is malonyl added in relation to acetyl Coa?
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On the "inside" of the chain
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At which FA are we stuck? Ie. do not have the desaturases to move further?
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Oleate
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What is linoleate?
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18: 2 (delta 9, 12)
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What is linoleate degraded to?
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Gamma-lineolenate
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How is arachadonic synthesized from gamma lineolate?
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Elongated and desaturated
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Which desaturases do humans have?
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Delta 5,6, 9
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What type of reaction is the desaturase reaction?
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It is an oxidative reaction, that needs a reducing equivalent NADH, that passes electrons down from elements of the ETC to desaturate
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What is different about the first reductive step of mitochondrial elongation, and fatty acid synthase elongation?
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NADH in Mito
NADPH in FAS |
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What is different about the enzyme structures in ME and in FAS?
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ME enzymes are all separate
FAS enzyme is 1 enzyme that is multifunctional |
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What is the difference in the carbon donors between ME and FAS?
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ME- always acetyl coA
FAS- malonyl Coa + release of Co2 in condensation step (except 1st is acetyl coA) |
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What is the difference between the hydoxy-acyl group intermediate formed after the reduction of the keto in ME and FAS?
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ME is is L-hydroxy intermediate
FAS is a D-hydroxy intermediate |
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Where is acetyl coA generated? why is this a problem for FAS?
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Acetyl coA is generated in the mitochondria
However, FAS occurs in the cytosol, so we need to get acetyl coA into the cytosol from the mito somehow! |
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How is acetyl coA generated?
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from pyruvate or aa
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How is acetyl coA transporteed across the membrane?
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as citrate by the citrate shuttle
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How does this transport of citrate work?
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Acetyl coA is converted to citrate w/ Oaa (no energy)
Transported as citrate In cytsol, using 1 ATP, is broken down to OAA and acetyl cOA |
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How is OAA recycled and brought back to the mitochondria?
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OAA is converted to malate or pyruvate
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What is the reaction like when you use malate to regenerate OAA?
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OAA is converted to malate using an NADH molecule
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How does OAA recycling work with pyruvate?
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Pyruvate is generated from OAA using NADP+ generating NADPH and CO2
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What are the two mechanisms of NADPH generation?
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Pentose phosphate pathway, and citrate shuttle w/pyruvate
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What would the components be of a fatty molecule if it were solid?
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More unsaturated, saturated long chain
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What would the components be of a fatty molecule if it were soft?
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More short chains, less longer chains
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What would the components be of a fatty molecule if it were liquid?
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Mostly unsaturated
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What happens when you alter the proportions of saturated/unsaturated/short/long FA?
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You change the properies of triglycerides
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What would happen to the membrane of E.coli if it were grown at 20 degrees?
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It would become more rigid
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What would happen to the membrane of E.coli if it were grown at 40 degrees?
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It would get more fluid
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What would you have to alter in the E.coli membrane to counteract the rigidity induced by growing at 20 degrees?
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Increase unsaturated, or decrease length (these have lower MP and therefore will be fluid at lower temps)
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What would you have to alter in the E.coli membrane to counteract the fluidity induced by growing at 40 degrees?
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Increase the length/saturation of the FA (these have higher MP, and therefore wont be as fluid at this temp!)
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What are the differences between the plasma membrane, inner mitochondrial membrane, and lysosome membrane?
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PM- tough, prevents anything from entering cell
IMM- specialized, allows certain things in and out Lysozome- do not want membrane to rupture, many important processes occur inside |
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How are fatty acids stored?
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In the form of triglycerides
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What is a triglyceride?
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A glycerol with three FA attached to it
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What is phosphatidic acid?
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Similar to DAG except w/ a phosphate at the SN3 instead of an OH
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How are specific phospholipids made from phosphatidic acid?
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Different headgroups are attached
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What are the two steps to synthesize TAG from phosphatidic acid?
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The phosphate is cleaved off PA to form DAG by PAphosphatase.
An acyl transferase puts a third fatty acid at the SN3 position |
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Which enzyme performs the acyl transferase to convert DAG to TAG?
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DGAT- is important, regulated, controls TAG synthesis
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What does the "lyso" prefix mean when added to the name of a phospholipid?
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Indicates that the molecule is missing an acyl group
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What does MGAT do?
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Adds an acyl to the lysophosphatidic acid (MAG)
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How can intermediates of glycolysis feed into phospholipid synthesis?
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Products (DHAP, G3P) can be modified by MGATS, DGATs to eventually get TAGS or phospholipids
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Where do we store fat?
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Adipocytes, or under the skin
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Why do we store fat?
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Insulation from cold
Energy during starvation |
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Which enzyme indicates that we are starving?
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Glucagon or adrenaline
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What does glucagon/adrenaline eventual activation of PKA result in?
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PKA phosphorylates HORMONE SENSITIVE LIPASE and PERILIPIN
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What is hormone sensitive lipase?
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The main lipase in cleaving fatty acyl groups
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What is perilipin?
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Coat protein of lipid droplets containg TAG
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What happens when perilipin is phosphorylated?
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It changes conformation, allowing a small patch of TAG to be revealed
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Now that a small patch of TAG is exposed, what happens?
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Hormone sensitive lipase cleaves off FA from TAG. FA are liberated.
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What happens to the FA once they are liberated from TAG by hormone sensitive lipase?
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They are transported into the blood by ALBUMIN
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Where does albumin bring FA?
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To whichever cells need energy, undergo Beta oxidation, and energy is increased
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What type of acyl chain is normally at the SN1 position in phospholipids?
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Saturated fatty acids (like palmitic)
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What type of acyl chain is normally at the Sn2 position of phospholipids?
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Generally unsaturated, often arachadonic
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What is the substiuent group of phosphatidic acid?
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H
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What is the net charge of PA?
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-1 (because of phosphate)
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What is the substituent group of phosphatidylethanolamine (PE)?
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Ethanolamine
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What is the net charge of PE?
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0 (+ charge on amino counteracts - charge of phosphate)
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What is the net charge of phosphatidylcholine and how is PC similar to PE?
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0 (similar to PE except there are methyl groups instead of hydrogens on N+ group)
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What is the net charge of phosphatidyl serine?
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-1 (even though N+ group, there is a carboxyl with a - charge)
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What is the net charge of phosphatidyl glycerol?
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-1 (no + charge to counteract - charge of phosphate, just addition of OH groups with no charge!)
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What is the net charge of PI (phosphatidylinositol-4,5-bisphosphate)?
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-4 (extra phosphates)
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Which phospholipids are synthesized by the Kennedy pathway?
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PE, PC
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Which phospholipids are synthesized by the Alternate Pathway?
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PG, PI
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Which phospholipids are synthesized in the Exchange pathway?
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PS
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Which phospholipids are synthesized in the Decarboxylation pathway?
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PE
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Which phospholipids are synthesized in the Methylation pathway?
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PC
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Which is the most common phospholipid? (in practically every membrane)
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PC
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How does the Kennedy pathway work? (for ex: choline)
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CDP-choline + DAG-> PC +CMP
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What does the Kennedy pathway use for energy?
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From CTP
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How is CDP-choline made?
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Choline is phosphorylated using an ATP molecule, making phosphocholine. CT adds CDP to phosphocholine using CTP, and PPi is lost.
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How does CDP-choline get converted to PC?
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CMP falls off and DAG comes on, using a transferase
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What is the key difference between the Alternate and Kennedy pathways?
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The CDP is on the DAG, not the substrate for the phospholipid (glycerol or ionositol)
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How is CDP-DAg formed?
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A CTP molecule is added to PA to form CDP-DAG, release of PPi
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What happens to CDP DAG to form PG?
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It is combined with GAP and through the action of CT forms PG phosphate, which is then dephosphorylated to form PG
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What happens to CDP-DAG to form PI?
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It is combined with inositol to form PI through the action of CT
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What happens in the exchange reaction?
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The head group of PE is exchanged with a serine to form PS by a phosphatidylethanolamine:serine transferase
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What type of reaction is the exchange reaction?
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Reversible
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What happens in the decarboxylation reaction?
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PS is decarboxylated to PE
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What is the difference between PS and PE?
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Carboxyl in PS, none in PE
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What is the enzyme that performs the decarboxylation reaction?
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Phosphatidyl serine decarboxylase
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What is the methylation reaction?
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SAM adds three methyl groups to PE to form a tertiary methyl amino group, PC
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What is SAM?
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S-adenosil-methionine-
Extra group on end of methionine, acts as a methyl donor |
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Where is cardiolipin located?
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It is specific to heart cells
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What is the structure of cardiolipin like?
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Two phospholipids sharing a GLYCEROL headgroup
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What properies of phospholipids make them excellent membrane components?
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They are amphipathic: create a barrier to water
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What allows us to create domains to specify which phospholipid will go to which membrane?
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The fact that the movement of phospholipids is dificult
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What is a "flip movement"?
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Movement from being in the outer leaflet to in, opposite is "flop"
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What type of reaction is the flip movement of phospholipids?
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It is energetically UNFAVORABLE, because you have a hydrophillic headgroup trying to pass though the hydrophobic interior of the bilayer. Therefore the uncatalyzed reaction is VERY slow. You need enzymes to catalyze this reactin
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Which enzyme catalyzes the flip/ transverse diffusion?
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Flippases
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Why is it necessary to have this control, with PS?
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PS is exposed on the outer leaflet (cell surface) of all cells undergoing APOPTOSIS. Therefore for a normal healthy cell you do not want to have PS exposed, but you want to be able to flop it out when necessary. Therefore only when flippases act, will PS be on the outside and then the cell will undergo apoptosis
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What type of reaction is the lateral diffusion (movement within the membrane) of phospholipids?
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Energetically favourable, very fast
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Do the outer and inner leaflets of a membrane have to be the same?
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NO. Different membranes have different leaflets, or even within the same membrane, the outer and inner leaflet can be different
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When cleaving PC w/ Phospholipase A 2, what would you get?
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FA+ Lysophosphotidyl choline
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When cleaving PE w/ PLC what would you get?
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DAG + phosphoethanolamine
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When cleaving PC w/ PLD what would you get?
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PA + choline
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What happens when you cleave phospholipids and get arachadonic acid?
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Arachadonic acid can be oxidized to form prostaglandins, thromboxanes, and leukotrienes
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What does aspirin (NSAIDS) inhibit?
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The formation of prostaglandin and thromboxane from arachadonic acid
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What are the differences between sphingolipids and phospholipids?
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-No phosphate at Sn3, therefore looks like DAG
-At Sn2, there is an amide bond instead of an ester -C=C bond instead of ester in Sn1 |
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What is sphingosine?
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Looks like MAG, sphingolipid w/ no acyl at SN2 or X at SN3
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What is ceramide?
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-A sphingolipid with an H as the substituent on the SN3
-An analog of DAG, also stimulates PKC |
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What is sphingomyelin?
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-A sphingolipid with a phosphocholine substituent group
-Important lipid that coats nerves to help electropotential travel the length of the nerve |
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What is glucosylcerebroside?
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A sphingolipid with a glucose subsituent
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What is a globoside?
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A sphingolipid that has multiple (2,3,4) sugar groups as the subsituent
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What is a ganglioside?
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A sphingo lipid that has branched sugar groups as the substituent
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What does the solubility of ceramide depend on?
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Lengths of FA chains
Ex: if a DAG has short chains, is less hydrophobic and has a greater chance of penetrating the membrane |
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What are sphingolipids derived from?
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Palmitoyl-CoA and Serine
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What does a serine provide to the sphingolipid structure?
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The glycerol backbone
The NH2 for the amide link in the SN2 position |
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What type of reactions are in the conversion of palmitoyl coA +serine to sphingolipids?
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A number of reductive steps, acyl transfer...
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What would radiolabelled palmitoyl coA feed to a cell?
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You would see it in sphingolipids, TAG, fatty acids, phospholipids (basically anything with a fatty acyl group!!!)
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Where would radiolabelled serine be detected in a cell?
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Proteins (serine is an amino acid) and in sphingolipids
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How is sphingomyelin generated?
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An exchange reaction where a phosphocholine group is transfered from phosphatidyl choline onto a ceramide, DAG is released
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What would happen if gangliosides were ingested in the diet?
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We would want to degrade them, because if they were not degraded, would accumulate and cause problems for the nerves
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What are some diseases where there are mutations in enzymes required to break down sphingolipids?
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Tay-Sachs, Fabry's, Sandhoff's, Gaucher's
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Why are many of these diseases only in children?
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They have a short life span due to the nerve degeneration caused by accumulation of complex sphingolipids
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What is abnormal about plasmalogen and platelet-activating factor?
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Plasmalogen have an ether-linked alkene at the SN1 position, while platelet activating factor has an ether linked alkane!
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What are some other features of plasmalogen and platelet activating factor?
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They have a choline headgroup
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What is platelet-activating factor involved in?
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Blood clotting
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What are some properties of cholesterol?
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There is a four ring structure, with a hydroxyl at the 3' position, which renders that part hydrophillic, and a hydrophobic hydrocarbon chain at the opposite end. Therefore cholesterol is amphipathic
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How does cholesterol orient itself in the membrane?
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Cholesterol would turn on its side and slide in by its flat rings. The OH would be pointing outwards are react with water.
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What do we make cholesterol from?
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Acetate (acetyl coa)
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What would we see when adding radiolabelled acetyl coA to the cell?
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All lipids and CHOLESTEROL would be labelled!!!
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What is the first step in cholesterol synthesis?
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Combining two acetyl coa molecules to form a 4C intermediate, acetoacetyl-CoA
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What happens to acetoacetyl-CoA to continue in cholesterol synthesis?
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A third acetyl coA is added by HMG-CoA synthase
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What happens to HMG-CoA?
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It is reduced to MEVALONATE by HMG-CoA reductase, using NADPH
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What is NADPH used to make?
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Fatty acids and CHOLESTEROL!
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Why is the conversion of HMG-CoA to mevalonate so important?
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It is a rate-limiting step that is tightly regulated
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What is the rate-limiting enzyme of cholesterol biosynthesis?
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HMG-CoA reductase
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What are statins?
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Cholesterol reducing drugs that target HMG CoA reductase!
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What happens to mevalonate?
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Through a series of phosphorylation steps, it is converted to 5 C activated isoprene units
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What is lost at the final step of the conversion of mevalonate to isoprene?
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CO2
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What do two isoprenes make?
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Geranyl pyrophosphate (10C)
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What do three isoprenes make?
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Farnesyl pyrophosphate (15 C)
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What do two geranyls make?
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Gernanyl gernayl (20 C)
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What do two farnesyl (2x15C) or a 3 geranyls make? (3x10C)
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Squalene (30C)
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How is squalene (30C) converted to cholesterol (27C)?
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Through a number of steps: 3 decarboxylation, 1 reduction that require NADPH, cholesterol is generated
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Where else are farnesyl and geranyl geranyl used besides cholesterol synthesis?
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To tag a molecule, making it hydrophobic so it will want to go to the membrane
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What are examples of other tags that are used to target molecules to the membrane?
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GPI anchor, fatty acyl groups (palmitoyl or myristoyl)
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What is an example of a molecule that is geranyl/ geranylated?
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Ras
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What would be a benefit of targeting squalene synthase with a drug rather than HMG COa reductase for reduction of cholesterol?
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If you block cholesterol at this step, you dont inhibit the synthesis of geranyl geranyl, and therefore you wouldnt inhibit the Ras pathway. As a result of inhibition of Ras pathway using statins that target HMG Coa Reductase, there is some muscle weakness as a side effect
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What are some derivatives that come from the cholesterol biosynthesis pathway?
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Vitamin K, E, A, Rubber, Isoprene, etc..
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Besides acting as an important component of biological membranes, what are some other functions of cholesterol?
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Used in bile acids, Vitamin D, steroid hormones
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What are some steroid hormones that are formed? Where does this occur?
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Steroid hormones are synthesized in the mitochondria: some examples are cortisol, progesterone, testosterone, estradiol, aldosterone, corticosterone
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What is different about the structure of steroid hormones with that of cholesterol?
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A hydroxyl replaces the hydrophobic tail in cholesterol
The hydroxyl at the 3' postion (in cholesterol) is replaced with a keto group |
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What is the structure like of statins?
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They resemble mevalonate, and therefore act as a competitive inhibitor of HMG CoA reductase
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How is phosphatidyl choline converted to cholesterol ester?
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By ACAT/LCAT
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Where is ACAT located?
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In the cell
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Where is LCAT located?
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In the plasma
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What do LCAT/ACAT do to convert phosphatidyl choline to cholesterol?
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Transfers fatty acyl group from SN2 of PC to cholesterol, and as a result make it more HYDROPHOBIC
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What is the advantage to making cholesterol more hydrophobic by esterifying it?
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STORAGE- Normally, cholesterol is in the membrane, now it is no longer amphipathic so it will move to where triacyl glycerides are stored, in lipid droplets.
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How can cholesterol be secreted?
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Through bile acids, this is the ONLY way to get rid of cholesterol, we cannot degrade cholesterol
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How does cholesterol act as its own regulator?
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It can feedback inhibit HMG CoA reductase
It activates ACAT, stimulating its storage within the cell |
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What effect does cholesterol storage have on its feedback inhibition?
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It relieves the inhibition by removing cholesterol into the lipid droplets
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What is a second way to get cholesterol?
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Through endocytosis of lipoprotein cholesterol carriers
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What are the sources for the pool of cholesterol in the cell?
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-new cholesterol from acetyl CoA
-Store cholesterol in the form of cholesterol ester via ACAT -brought in by extracellular LDL-cholesterol |
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What are lipoproteins?
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Complexes of phospholipids, proteins, cholesterol, and sometimes triglycerides.
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What is LDL?
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low density lipoprotein
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What are some components of LDL?
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Has APoB100
Cholesterol is in ester form |
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How is LDL recruited to the PM?
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A clathrin coated pit is formed, causing an invagination in the membrane. This recruits LDL-R and subsequently LDL
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How does LDL enter the cell?
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LDL/LDL-R are endocytosed
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What happens to this LDL/Receptor complex once it enters the cell?
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-LDL and LDL-R are separated, the receptors can be recycled back to the cell surface
-The LDL is degraded in the lysozome: Proteins->amino acids Phospholipids by phospholipases Triglycerides by lipases Cholesterol ester to cholesterol |
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What happens to the cholesterol that is now in the cell from the LDL digestion in the lysozome?
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Cholesterol is transported to the ER membrane
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What happens at the cell surface of the ER w/ cholesterol?
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Normally, ER does not have alot of cholesterol in the membrane. Therefore proteins in the ER can detect free cholesterol and respond.
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What is the response of the ER to cholesterol?
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There is a protein SCAP that binds free cholesterol, and when it does so, also bings SREBP
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What happens to SCAP when cholesterol is not detected by the ER?
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Cholesterol does not bind SCAP, and therefore SREBP is free to move and through a series of proteolytic cleavages, SREBP becomes a soluble protein that can go into the nucleus activates transcription of LDL-R and HMG CoA reductase
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What are some components of micelles?
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Interior is hydrophobic
Monolayer of phospholipids Individual units are wedge-shaped |
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What is an example of a micelle?
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LDL!
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What are some characteristics of bilayers?
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Formed by cyllindrical phospholipids, allows tighter packing
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What are liposomes?
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Similar to a bilayer except a spherical partical with an aqueous cavity in the center.
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What does formation of a liposome or bilayer or depend on?
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[ ] of cyllindrical phospholipids
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What are the proportions of proteins/ phospholipids/ and sterol like in membranes of different organisms?
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Membranes of different organisms have different proportions of proteins, phospholipids, and sterol
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What does cholesterol form a high affinity bond with?
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Sphingolipids!!!
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What does cholesterol binding with sphingolipid result in?
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Aggregation/raft formation,
-can target other proteins to this aggregation |
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What is the most dense lipoprotein?
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Chylomicrons
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What is the 2nd most dense lipoprotein?
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VLDL
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What is the 3rd most dense lipoprotein?
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LDL
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What is the least dense lipoprotein?
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HDL
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How does size of a lipoprotein relate to its weight?
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The bigger a lipoprotein, the lighter it is (inverse relationship)
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Where is cholesterol absorbed in the body from the diet?
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The intestine
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Which lipoprotein is synthesized in the brush border cells of the intestine and is the first carrier of cholesterol?
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chylomicrons
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What does chylomicron have on its surface?
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ApoB48
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What type of protein is ApoB48?
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Integral membrane protein
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What happens as chylomicron moves in the blood?
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It is acted on by lipases
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What is leftover after lipases act on the chylomicron?
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A remnant particle
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What is different about this remnant particle from chylomicron?
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In addition to ApoB48, has ApoE
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What type of protein is ApoE?
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Exchangeable
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What does ApoE do?
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Binds to remnant receptor of hepatocytes, and endocytosis occurs
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What does the liver do to remnant chylomicrons?
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Makes VLDLs (very low density lipoproteins)
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What is different about VLDL?
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Only has ApoB100
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What is the difference between ApoB48 and ApoB100?
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ApoB48 only has 48% of the length of ApoB100, and in the 52% that ApoB48 does NOT have, is the receptor binding domain for cell receptors
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Which organ regulates whole body cholesterol metabolism?
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The liver!
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What happens to VLDLs?
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In the blood, is degraded by lipases. A remnant LDL is formed, that still contains ApoB100
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What happens to the remnant VLDL?
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Is taken into cells, and cholesterol is regulated by free cholesterol binding to SCAP at the ER..etc...
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What happens when we eat alot of cholesterol?
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LDL-R on normal cells is downregulated, so LDL has nowhere to go and is floating around the blood. It accumulates and becomes a target for oxidation
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What happens once the LDL particle is oxidized?
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It becomes a target for macrophages which recognize it as "non-self"
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How will the macrophage take up the oxidized LDL?
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By a scavenger receptor, oxidized LDL will accumulate in the macrophage
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What does the accumulation of the oxidized LDL in the macrophage result in?
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Macrophage death, which releases inflammatory cytokines, recruits more macrophages,etc and eventually a plaque will be formed on the arterial cell wall
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What happens if the plaques on the arterial cell walls rupture?
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Heart attack!!!
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What is the "good" cholesterol or "hero"?
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HDL
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How is HDL formed?
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APOA1 will interact with ABCA1 transporter to aquire cholesterol from the cell and will form an HDL particle
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What type of particle is HDL initially?
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A discoidal
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What happens to this discoidal HDL particle?
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LCAT binds APOA1, converts free cholesterol to cholesterol ester, and cholesterol ester will migrate to the membranes, creating a SPHERICAL HDL particle
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What happens to the spherical HDL particle?
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Takes cholesterol back to the liver, therby removing it from peripheral tissues and macrophages
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What is forward cholesterol transport?
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Cholesterol moving from the diet to peripheral tissues
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What is reverse cholesterol transport?
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APOA1 mediating HDL transport to the Liver
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What is beta oxidation?
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Breaking down FA for energy
Essentially the reverse of Fatty acid synthesis |
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What is the first step of beta oxidation?
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Insert double bond between alpha and beta carbon of palmitoyl coA
Using FAD |
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What is the second step of beta oxidation?
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Convert double bond to hydroxyl group by adding water
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What is the third step of beta oxidation?
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Convert hydroxyl to keto using NAD+
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What happens when we convert the hydroxyl to a keto grouP?
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Bond becomes labile and we can cleave off acetyl coA
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How many acetyl coA can we produce from palmitoyl coA?
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8! (2x8=16 C of palmitoyl coA)
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What can happen to the acetyl coA once it has been cleaved off?
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-Fed to TCA by combining with OAA to form citrate
-ALl the C that are fed into TCA by acetyl coA will be cleaved off as CO2 -electrons generated can be fed to ETC to generate ATP |
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What are the differences in location of B oxidation and FAS?
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FAS- cytoplasm
beta oxidation- mitochondria |
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Why is it important to have these in different compartments?
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Prevents establishment of a futile cycle (happening at the same time)- this would be a waste of energy!!!
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What are two problems that could occur in beta oxidation?
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Odd number fatty acid chain
Double bond in wrong location (not alpha-beta needed for step 2 of beta oxidation) |
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Do humans make odd chain fatty acids?
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No, we only obtain these by digestion
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What are all odd chain fatty acids degraded to by normal beta oxidation?
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Propionyl-CoA (A 3C molecule) Can perform Beta oxidation only up until this point
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What is done to the propionyl coA?
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It is carboxylated by propionyl-coA carboxylase!
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What is a cofactor of this carboxylase (and all carboxylases)?
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Biotin
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What is consumed in the process of adding this extra carbon to propionyl-CoA?
|
ATP, Bicarbonate
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What is the four C intermediate eventually converted to?
|
By a series of moving the coA group, and we generate SUCCINYL COA, which can be degraded or fed to the TCA
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What are two cases where the double bond could be in the wrong place for beta oxidation?
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1- Double bond is in beta-gamma position
2-After 1st oxidation of 2nd cyle of beta oxidation, there is a double bond at the gamma position, in addition to the alpha-beta double bond |
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How is the first case regulated?
|
An ISOMERASE will change the location of the bond from beta-gamma to alpha-beta, and then the molecule is fed to beta oxidation
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How is the second case regulated?
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The two double bonds are condensed by a REDUCTASE, using NADPH, but this reduction results in a beta-gamma double bond. Therefore we need to regulate this in the same way as case 1, by treating with an ISOMERASE
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What is Carnitine acyl transferase 1?
|
Protein that transfers acyl groups from cytoplasm to IMM, brings fatty acids to mitochondria for beta oxidation
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What inhibits carnitine acyl transferase 1?
|
Malonyl CoA
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What happens when you have alot of energy?
|
ACC is activated, generate malonyl CoA which inhibts CAT1 so that we can store FA and not degrade it!
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What is different about peroxisomal beta oxidation?
|
Less efficient than mitochondrial
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Where does the glucose pathway/FA pathway connect?
|
-Intermediates of glycolysis are shunted off to the pentose phosphate pathway which generates NADPH used for fatty acid synthesis
-Acetyl CoA is produced by glucose oxidation to pyruvate, used also for FAS -Can feed acetyl coA from beta oxidation to TCA |
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What is the primary ATP source?
|
Glucose, but it is used up quickly, conserved for the brain
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Why do we need alternate energy sources besides glucose?
|
Glucose needs H2O, doesnt allow glucose to pack tightly. Fat packs more tightly!
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When do we have ketone body production?
|
In diabetes/starvation
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How are ketone bodies generated?
|
A acetyl coAs combine to form acetoacetyl CoA.
HMG synthase converts it to HMG COa. Lyase converts it to acetoacetate which can be converted to Acetone, or beta-hydroxybutyrate |
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Which ketone body can the brain use as an energy source?
|
Acetoacetate
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Why are ketone bodies produced in diabetes?
|
Body thinks its starving, generates ketone bodies
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What is the different between the steps of ketone body formation/ first steps of cholesterol synthesis?
|
There is no HMG coA reductase in ketone body formation
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