Lipids Flashcards
triglycerides = glycerol + 3 fatty acids = (triester of glycerol) eg 16C palmitic acid
unsaturated bond causes kink in fatty acid
saturated =
no double bonds
even no of C atoms
what do fatty acids do
+ve
1. biological membranes
2. efficient energy store
for aerobic exercise and animals that migrate and hibernate
3. protein tags for interacting w cell membrane receptors i.e. in wnt signalling
-ve
1. obesity
2. type 2 diabetes risk
3 coronary heart disease
cholestrol
4 ring structure
antigens and oestrogens
+ve
1. membrane structure and fluidity
- anabolic precursor
steroid hormones
gives rise to vitamin D - need UV light to break down 7dehydrochlestro
gives rise to bile acids
- tagging onto proteins = hedgehog protein
w 2 lipids:
parmidic acid + cholestrol = aggregate into mice cells where lipids are on inside and proteins on outside = can migrate between cells and iipids interact with lipid membrane + secure hedgehog to the surface of cells
-ve
cholestrol can be deposited in arteries
LDL cholestrol
fatty acid synthesis
- 3 carbon paradox
fatty acids grow in increasing units of 2C each cycle
but the substrate = malonyl-CoA in each cycle has 3Cs
malonyl-CoA comes from acetyl CoA + HCO- + ATP when cell has plenty of ATP = storable form of energy
acetyl-CoA
2 enzymatic sites and 1 carrier protein
substrate channel keeping substrates attached and moving it between active sites makes for a very efficient biochemical process
fatty acid synthase FAS
catalyses reaction where
malonate added to 2C acetate where NADPH gets protonated = 4C acetoacetate + CO2 + H2O
4C acetoacetate substrate for addition of another malonate again = 6C carbon derivative keeps going till = 16C
4 reactions occur in 4 different acttive sites in one protein
reactants and products are covalently attached to the
fatty acid synthase and moved between active cites by the acyl carrier protain which has a long arm of phosphorylated of vitamin B5 pantothenic acid onto which the malonate binds and adds on 2C’s
condensation CO2
reduction NADP+
dehydration h20
reduction NADP
acetyl coA attached by sulfur bond and malonal attaches to acetyl coA now it is in proximity of acetyl group at first active site. condensation reaction - co2 taken off and lost and acetyl froup is transferred nto remaining 2C attached to ACP
keto group reduced to hydroxyl group. ACP group moves substrate through diff enxymatic cells
water is removed double bond formed and moved to other active ste
double bond reduced = saturated acetyl acyl group which is transferred back to the protein itself available for addition of another malony group
why not just add acetyl CoA 2C every time
energy used in breaking carbon carbon bond with the release of Co2 which is driving reaction
use of ATP to generate bond
using energy when bond is broken
acetate comes form coverting citrate back to acetyl coA
NADPH comes from the breakdown of malate into pyruvate as does the break down of glucose into glucose 6 phosphate in the liver
regulating FA synthesis
when citrate is high
citrate lyase activates citrae break down into acetyl co A then is coverted into malonyl co A using acetyl carboxylase
excess of fatty acid causes feedback inhibition on this rate limiting step
palmitoyl-coA production is slowed down
other fatty acids
18C Linoleate cannot be made must be absorbed from the diet
Prostaglandins signalling molecules
inhibited by aspirins to medicate pain, inflammation and fever
they synthesis of cholesterol
conversion of acetate into mevalonate converted into isoprene
6 of which make squalene
which can be modified into cholestrol
start off with 2C acetyl CoA
Thiolase takes 2 acetyl CoA to make 4C acetoacetyl CoA
then HMG coA cynthase takes another acetyl CoA and generates 6C HMG coA
then HMG coA reductase (memebrane protein of the smooth ER catalyses Rate Limitng Step)
converts HMG CoA to mevalonate
regulation of cholesterol levels
Hypotheses:
Post- translational:
1. we might have a sensor that phosphorylates HMG CoA reductase to modify its activity
- sensor acts direct as an allosteric modulator of the activity of HMGCoA reductase
need a cholesterol sensor
and need to influence rate limiting step
transcriptional:
sensor modulates the level of HMGCA reductase
altering transcription of the gene to generate more of the enzme
in endoplasmic reticulum membrane are a series of protein
Insig is involved in secretion,
SCAP - sensor for cholestrol level
and SREBP = transcription factor controlling level of expression of HMG-CoA reductase
when cholesterol levels are high it will bind to SCAP kept tagged within ER
when cholesterol levels go down
insig is detached from the SCAP strip and is targeted for degradation
insig and SCAP help SREBP to move from ER to golgi because in golgi there are 2 proteases and what they do is they cut the regulatory domain SREBP can move to nucleus where it acts a s a transcription factor and activates the transcription of enzymes including HMG
CoA reductase
in high cholestrol levels - complex retained in the endoplasmic reticulm
in low cholestrol SCAP dissociates from insig and ScaP and SrEBP move to the golgi
get acted on by proteases which releases a part of SREBP protein moves to nucleus binds to promoter of genes like HMG CoA reductase activating transcription increasing amount of enzyme to make more cholesterol
statins
inhibit the production of cholesterol by inhibiting the HMG CoA reductase
sonic hedghog signalling -
shh produced by the notochord induces the formation of the neural tube floor plate = divides the left and right sides of the neural tube by defining the midline = designs the structure of the vertebrate neural tube
cholesterol is attached to activated sonic hedgehog affecting the way shh can diffues as can the cholestrol within the membrane
interacts on the cell surface with a receptor called patched
in absence of sonic hh patch inhbits smoothened allows some of the repressive gle factors to inhibit gene exp in nucleus
when shh binds to patched it no longer interacts with smoothened
smoothened then can activate the active gle factors = gene expession
sHH has 2 domains
1. for signalling
Active
2. protease to process it self auto cleavage and adds a molecules of cholesterol onto new carboxy terminus of cholesterol
can plug sonic hedghog to the outside of the cell with the cholesterol sitting in the membrane and the protein on outside
allows a high concentration of sonic hedgehog to accumulate on the outside of a notochord cell
to signal to make the floor plate
in order for it to move any distance the cholesterol couples together to make a hydrophobic core = can diffuse away - biologically active part of sonic hedgehog
patched and smoothened were important for sonic hedgehog
signalling
in absence of shh
patched suppressed the activity of smoothened by depleting cholesterol in the membrane around smoothened molecules
in absence of shh
patched exports cholesterol out of the membrane the depleted membrane does not allow smoothened to signal
when sonic hedgehog binds causes a dimer of patched to form
but now its ability to export cholesterol is stopped
when shh is bound the levels of cholesterol can build up in the membrane = changes in the structure of smoothened = allows it to signal
jervene inhibits cholesterol synthesis - disrupts shh signalling = midline defects in neural tube floor plate doesn’t form no division of left side and right side
mobilisation of fatty acids to generate ATP
fatty acids are stored in adipocytes - fat but energy needed in the muscles
glucagon bind to ecptors on the cell surface which activate some protein kinases =
1. phosphorylates perrylipin protein which surrounds the fatty acid droplet inside the adipose cell
once phosphorylated then it no longer interacts with a protein called CGI58 = activation of the adipose tri glcerol lipase an enzyme which takes off one fatty acid from the triglyceride leaving a diglyceride
in cytoplasm the kinase pka phosphoryase activtates an enzymes clalled hormone sensitive lipase by phosphorylating it = can associate with the lipid droplets and convert the di-glycerol into the mono glycerol. plus another free fatty acid
monoglycerol can be converted by monoglycerol lipase into glycerol and the third fatty acid
diffused out of cell and bind with serum albumin in the bloodstream and transported to muscle cells
taken up by fatty acid transporter into the cell
oxidised in muscle cell to generate ATP
triglycerides as an energy source
3 fatty acids that can undergo beta oxidation but also glycerol that can be adapted to enter glycolysis
how do the the fatty acids get into the mitochondria to be oxidised
degredation occurs in mitochondria unlike snthesis in cytoplasm
has to get through 2 mitochondria membranes
small fatty acids ess than 12C can diffuse in
palmitic acid needs to be transported in comination with acyl carnitine/ carnitine transpor system
- inside cytosol combines with coenzyme A in a process drivin by ATP and acyl-coA synthase = fatty acidCoA interacts with Carnitine-acyl transferase 1 in the outer mitochondrial memrbane. coenzme is removed and the energy derived from that allows a fatty acid group to be attached to carnitine - this allows the fatty acid transport through porins and into matrix through the acyl-carnitne/carnitine transporter
in the matrix fatty acid coenzyme is reconsitituted = generating free carnitine the fatty acid group is transferred from carntine to Coenzyme a
carnitine interacts with carnitine ccyl transferase 2 which transfers carnitine back to outer mitochondrial memrbane so it can interact with another fatty acid
cycle continues
fatty acid oxidation - integrated metabolic pathways
acyl CoA dehydrogenase efficiently works with 16C and 14C chain
medium chain acyl CoA
short chain 8 and below
- beta oxidation
16C palmiate is converted to 8 molecules of 2C acetyl coA generating 28 electrons into the electron transfer chain:
Dehydrogenase introduces a double bond between the second and third carbons from the coenzyme A = generates electrons to enter ETC
water is added to this compound forming hydroxyl group on third carbon
second dehydrogenase step - converts hydroxide group on third carbon along to a ketone double bond oxygen = electrons to ETC = ATP
transferase splits acetyl CoA away from 16C coenzyme A = acetyl CA and 14C to which another coenzyme A is added = undergoes same process to generate 12C carbon coenzyme derivative and so on
different acyl CoA dehydrogenase work with different length fatty acids so very long acyl CoA dehydrogenase efficiently works with 16C and 14C chain
medium chain acyl CoA
and
short chain with 8C and below making process more efficient
- TCA cycle
feeds acetyl CoA into TCA converted into 16 Co2 and 64 electrons which enter ETC = ATP
once a fatty acid chain is greater than 12C
second and third active - hydratase and second dehydrogenase within the same protein forms alpha subunit of larger tri-functional protein
substrate is passed to the fourth enzyme thiolase which forms the product
= efficient channelling of substrate through this system
once fatty acid derivative is less than 12C, soluble enzymes used instead of collection of enzymes embedded in inner mitochondrial membrane
how much energy do we get from FA oxidation?
generate metabolic water harvest mice and camels 23h20 molecules produced
7 cycles which generated electrons from FADH each produces 1 and a half molecules of ATP and NADH = more efficient electron transporter 2.5 per cycle
8 acetyl coA = 80 ATP from TCA cycle and ETC chain
= 108 molecules made
some used in initial addition of CoA to fatty acid
=106 ATPs made form1 16C parmitic acid
compared to glucose via glycolysis and TCA = 38 ATP
regulating fatty acid degradation
1fatty acyl CoA has 2 fates
- fatty acyl CoA converted to triacylglcerols to be stored in adipocytes
or made into membranes by making phospholipids - transported to mitochondria to generated ATP via undergoing beta oxidation
transfer into the mitochondria catalysed by cartinine acyl transferases
are regulated by interaction with malonyl CoA
when glucose is high it is the prefered energy source producing alot of acetyl coA to enter TCA cycle
but alot to spare can be used by aceyl COA carboxylase to generate malaonly CoA carboxyase to generate malonyl CoA
PPARs co ordinate fatty acid metabolism over long periods of time
3 genes producing 3 proteins PPAR alpha - fatty acid oxidation
gamma - synthesis of FA + responsive to insulin
and delta
long term physiological aspects of FA
fetal heart uses alot of glucose but once born heart uses more fatty acids
this switch is co-ordinated by PPAR alpha turning on required genes
skeletal muscles will use glucose and is slow to use fatty acids as energy sources
long term aerobic exercise athletes will have high PPAR alpha = increased expression of the enzymes involved in fatty acid oxidation = quickly use fatty acids as a source of energy
ketone bodies a reserve fuel
entry of acetyl-CoA into citric cycle require oxaloacetate
oxaloacetate + Acetyl-CoA = Citrate + CoA
depleted Oxaoacetate (when used in gluconeogenesis and as acceptor of acetyl-CoA for entry in the TCA cycle to generate citrate) = acetyl-CA is converted into ketone bodies freeing coEnzyme A for continued beta oxidation
3 forms of ketone bodies:
acetone
acetoacetate
and beta-hydroxybutyrate
formation of ketonebodies
reverse of thiolase reaction = 2 acetate units join up
third acetyl CoA is incorporated in the second step and 2 CoA are freed
post modification acetone
acetoacetate
and beta-hydroxybutyrate are made post CoA removal by HMG-CoA liase into tissues
acetone is removed as a gas and exhaled but acetoacetate and beta hydroxybutyrate can traffic to the brain for use in energy production
ketone bodies formed in some tissue by the condensing of acetyl CoA can be broken down into acetyl CoA for TCA cycle + ETC = ATP energy
ketone bodies needed during starvation
when not enough glucose to fuel brain body tries to make some via gluconeogenesis as fatty acids cannot be used
depleting amount of OAA available to accept acetyl CoA and so acetyl CoA builds up + noow no free coenzyme for fatty acid breakdown to provide more energy for other tissues so instead it is converted to ketone bodies - acetate acetone hydroxybutyrate - coenzyme A free for oxidation of fatty acids
acetate + hydroxybutyrate can be exported and used by cells such as a heart, skeletal muscle, kidney + brain
-ve role in type 1 diabetes
low insulin therefore low uptake of glucose
levels of malonyl CoA decrease and transport of fatty acid-CoA to the mitochondria increases and is oxidised to acetyl CoA = elevated Acetyl CoA
at the same time cells are trying to make more glucose by gluconeogenesis taking out OAA from TCA cycle to export glucose for fuelling the brain
Acetyl CoA doesnt enter TCA cycle and builds up but it is needed to break down fatty acid so acetyl-CoA are converted into ketone bodies == acetates and beta hydroxy butyrate are exported as energy
BUT high ketone body count from liver circulating than can be taken up by the brain and extrahepatic tissue to be used as fuel =
lowered blood pH
= causes acidosis inducing a coma
how lipids are transported around the body
hydrophobic but need to be transported in aqueous blood stream as lipoproteins when bound to apoliopoproteins
logistics in the liver
cholestrol and fatty acids enter body via intestines then taken up into lymphatic system by chylomicrons go into blood stream and free fatty acids are taken up by muscles and stored in adipose tissue
whats left over are taken to liver where it is organised and monitors if there is enough.
some is broken down and mixed with bile salts and secreted back into intestines.
if not they are sent back into body combine with apolipoproteins to form the very low density lipoproteins which circulate around blood stream contribute free fatty acids and cholesterol to a range of tissues.
and goes along endougeous pathway and back to the liver through the LDL receptor, where the levels of cholesterol if oo much is excreted. if too much LDL cholestrol will be deposited in macrophages that lined the blood vessels = foam cells initial phase of blockage of arteries by cholesterol. high density lipoproteins collects excess cholesterol and recycles it back to liver for excretion = good cholestrol
liver is logistics site for fuel adipose tissue is the main store for fuel and both interact w and mucle where its used
white WAT (storage of lipids - produces hormones) an BAT adipocytes express uncoupling protein 1 - important in using energy from ETC to generate heat
muscle contraction energy
light activity uses fatty acids ketone bodies and glucose
phosphocreatin cycles ADP to ATP rapidly for sprinting - very limited time (6seconds)could be used before phosphocreatine used up and resort to glycogen stores which can produce lactate which lowers pH causing muscle cramp (2 minutes)
lactate produced is recycled by liver by the Cori cycle to glycogen
what happens during feeding and soon after
elevated blood glucose = insulin production by pancreas
causes glycogen production to store lglucose in liver
and cause pyruvate production = CcCoA = Free fatty acids = triose glycerols
insulin can act on muscle increase glucose uptake
= glycogen stores in muscles improved and conversion of pyruvate to AcCoA to free fatty acids and triacylglycerol in adipose tissue
TAG in liver transported to adipose tissue get an expansion of the white adipose tissue
how does the pancreas detect blood glucos levels in order to release insulin
glucose enters beta cells via Glut 2 transporter and undergo glycolysis and TCA and oxidative phosphorylation generating elevated levels of ATP
beta cell has a polarised membrane maintained by ATP gated potassium channels and at high levels these channels are blocked causing a depolarisation of the membrane. this leads to voltage gated calcium channels to open up allowing calcium into the cell. this calcium can act on the secretion of insulin from secreted granules to release insulin into the circulation
elevated Levels of ATP in response to glucose act as a sensor for glucose in the blood stream
