Lipid metabolism II Flashcards
How can one have excess triacylglycerol stores if the fat intake in diet is low
Major source of carbon for fatty acid synthesis is dietary carbohydrates
A major source of carbon for fatty acid synthesis is
dietary carbohydrates
Fatty acid synthesis occurs primarily in the ____. But also in the ____,_____, _____
liver. But also in the brain, kidneys, and adipose tissue
Fatty acids synthesis takes place in the ______ in contrast to degradation that takes place primarily in the
Cytoplasm, mitochondrial matrix
Components of fatty acid synthesis are located in the cytoplasm. what are they
- enzymes
- Acyl carrier proteins
- Co-factors
- Reducing power
- Energy (ATP)
What ar the major steps in the synthesis of fatty acids
- formation of acetyl CoA
- Conversion of Acetyl CoA to malignly CoA
- Elongation (addition of carbons)
- Desaturation (introduction of double bonds)
The formation of _____ is the committed step in fatty acid synthesis
Malonyl CoA
The synthesis of Malonyl CoA from Acetyl CoA is catalyzed by
Acetyl CoA carboxylase 1 , which contains a biotin prosthetic group
Intermediates in fatty acid synthesis are attached to an ______ carrier protein
acyl carrier protein (ACP)
intermediates in fatty acid synthesis are attached to the _______ of an _______, whereas intermediates in fatty acid breakdown are covalently attached to the _______ group of ______
Sulfhydryl group of an acyl carrier protein (ACP), Sulfhydryl group of Coenzyme A
The enzymes of fatty acid synthesis are jointed in a single polypeptide chain called ______.
fatty acid synthase
Pyruvate dehydrogenase catalyzes
Pyruvate+ SH-CoA + NAD+ ——> Acetyl CoA + NADH + CO2
Pyruvate Carboxylase catalyzes
pyruvate to OAA
Citrate lyase catalyzes
Citrate +ATP ——> OAA + Acetyl CoA + ADP + Pi
Cytosolic malate dehydrogenase catalyzes
OAA + NADH —–> Malate + NAD+
Malic enzyme catalyzes
Malate + NADP+ ——–> NADPH + CO2 + pyruvate
Acetyl CoA carboxylase (ACC) catalyzes
Acetyl CoA + CO2 + ATP + Biotin (prosthetic group) —–> Malonyl CoA + ADP + Pi
Acetyl CoA is converted to malonyl CoA by ______
carboxylation using enzyme Acetyl CoA carboxylase (ACC)
The function of Acetyl CoA carboxylase (ACC) is to add ____ to acetyl CoA
CO2
Malonyl CoA contains ___ carbons while Acetyl CoA contains ___ carbons
3, 2
Acetyl CoA carboxylase (ACC) is allosterically regulated by
- Citrate (+)
- Long chain fatty acids (-)
Acetyl CoA carboxylase (ACC) is positively allosterically regulated by
Citrate
Acetyl CoA carboxylase (ACC) is negatively allosterically regulated by
long chain fatty acids
Phosphorylation has what effect on Acetyl CoA carboxylase (ACC)
negative/ inhibits
Dephosphorylation has what effect on Acetyl CoA carboxylase (ACC)
positive/ induces it
Insulin has what effect on Acetyl CoA carboxylase (ACC)
Induce
Glucagon and epinephrine have what effect on Acetyl CoA Carboxylase (ACC)
inhibit it
Gene expression of Acetyl CoA Carboxylase is up-regulated by
high carbohydrate/low fat diet
Gene expression of Acetyl CoA carboxylase is down-regulated by
high fat/ low carbohydrate diet
The reactions of fatty acid synthesis occur on the
fatty acid synthase complex
____ carbon units form malonyl CoA are sequentially added to the growing fatty acyl chain to form _____ (16:0)
two, Palmitate
Fatty acid synthase (FAS) is a large _______ complex
multi-enzyme
Fatty acid synthase is a _____ is composed of ___ identical sub-units. (____kDa each)
dimer, composed of 2 identical subunits , 260 KDa each
Each monomer of fatty acid synthase has _____ catalytic sites, which is the amount required for activity, as well as an _______. despite this monomers are not active and a dimer is required
7, Acyl carrier protein (ACP)
The acyl carrier protein (ACP) on fatty acid synthase has a ________ residue
phosphopantetheine (PP)
Two monomers of FAS arrange in a ______ conformation- with phosphopantetheine (PP) of one aligned with a _____ group of another
Head to tail, cysteinyl sulfhydryl group
ACP has a _____ arm
flexible arm ( Phosphopantetheine (PP))
The elongation phase of fatty acid synthesis starts with
the formation of acetyl ACP and Malonyl ACP
using Acetyl transacylase and malonyl transacyclase respectively
beta-ketoacyl synthase catalyzes
The condensation reaction in fatty acid synthesis
- Acetyl ACP + Malonyl ACP —-> acetoacetyl ACP + ACP + CO2
Why does the initial condensation reaction in fatty acid make s 4-Carbon unit form 3C and 2C molecules and not 2 Acetyl ACP (2-C) molecules
The equilibrium for the synthesis of acetoacetyle ACP form two molecules of acetyl ACP is highly unfavorable . In contrast the equilibrium is favorable if Malonyl ACP is reactant because its decarboxylation contributes a substantial decrease in free energy
Beta-Ketoacylsynthase catalyzes
The first reduction in fatty acid synthesis
Acetoacetyl ACP + NADPH + H+ ——> D-3-Hydroxybutryryl ACP + NADP+
3-Hydroxyacyl dehydratase catalyzes
Dehydration reaction in fatty acid synthesis
D-3-Hydroxybutyryl ACP —-> Crotonyl ACP + H2O
Enoyl Reductase catalyzes
The second reduction in fatty acid synthesis
Crotonyl ACP + NADPH + H+ —–> butyryl ACP + NADP+
Stoichiometry: Palmitate synthesis reaction
8 Acetyl CoA + 7 ATP + 14 NADPH + (6H+) = CH3(CH2)14COO- (palmitate) + (14 NADP +) + 8 CoA + 6H2O + 7 ADP + 7Pi
Fatty Acid Synthase allosteric is increased by what kind of diet
High carbohydrate / low fat
Fatty Acid synthase is inhibited by what type of diet
high fat diet as well as starvation
The major product of fatty acid synthase is _____
palmitate
longer fatty acids are formed by elongation reactions catalyzed by enzymes on the cytoplasmic face of the ______-
Endoplasmic Reticulum (ER)
What has an allosteric effect on regulation of FAS
presence of phosphorylated sugars
Endoplasmic reticulum enzymes responsible for the generation of unsaturated fatty acids
- NADH-cytochrome b5 reductase
- cytochrome b5
- Stearoyl CoA desaturase
NADH-Cytochrom b5 reductase catalyzes
- The first step in the generation of unsaturated fatty acids
- transferes electrons form NADH to FAD.
Explain the sequence of events on the endoplasmic reticulum that leads to the production of unsaturated fatty acids
First, electrons are transferred from NADH to the FAD moiety of NADH-Cytochrom b5 reductase. The heme iron atom of cytochrome b5 is then reduced to the Fe2+ state. The noontime iron atom of the Stearoyl CoA denatures is subsequently converted into the Fe2+ state, which enables it to interact with O2 and the saturated fatty acyl CoA substrate (stearoyl CoA) . A double bond is formed in the fatty acid substrate (making it Oleoyl CoA) and two molecules of H2O are released. Two electrons come from NADH and two from the single bond the fatty acyl substrate
Glycerol phosphate dehydrogenase catalyzes
DHAP + NADH ——> Glycerol 3-P + NAD+
Glycerol kinase catalyzes
Glycerol + ATP —–> ADP + Glycerol 3-P
Glycerol 3-P + 2 Acyl-CoA —–>
Phosphatidic acid + 2 CoA
Diacylglycerol + Acyl-CoA —->
Triacylglycerol (TAG) + CoA
TAG packaged with apoproteins to form ________ and secreted into blood
Very low density lipoproteins (VLDL)
_______ converts Acetyl CoA carboxylase into an inactive form by modifying three ____ residues
AMP- Activated protein kinase(AMPK), serine
Eicosanoids are products generated by the oxidation of _____ carbon fatty acids (_______)
20 carbon fatty acids (Arachidonic acid)
Eicosandoid hormones are derived form
polyunsaturated fatty acids
Eicosandoids are ____ lived molecules, that serve as local ___-
short, hormones
What are the 4 families of Eicosanoids
- Prostaglandins
- Prostacyclin
- Thromboxane
- leukotrienes
Eicosanoids are ____ molecules and serve as _____ molecules
signaling molecules and serve as messenger molecules
eicosanoids influence many pathways involved in _____, ______, ______, and ______
growth, inflammation, infection, and immunity
Prostaglandin synthase catalyzes
Arachidonate —–> Prostaglandin H2 (PGH2)
Lipoxygenases catalyze
Arachidonate —–> Leukotrienes
DG lipase catalyzes
Diacylglycerols —-> Arachidonate
PLA2 catalyzes
Phospholipids —–> Arachidonate
Thromboxane synthase catalyzes
Prostaglandin H2 (PGH2) —-> Thromboxanes
Prostacyclin synthase catalyzes
Prostaglandin H2 (PGH2) —–> prostacyclin
ASA inhibits what enzyme
Prostaglandin synthase
Metabolic action (s) of PGD2
Promotion of sleep
Metabolic action (s) of PGE2
smooth muscle contraction
inducing pain, heat, and fever
bronchoconstriction
Metabolic action (s) of PGF2alpha
Uterine contraction
Metabolic action (s) of TXA2
- Stimulation of platelet aggregation
- Vasoconstriction
Metabolic action(s) of PGI2
- Inhibition of platelet aggregation
- Vasodilation
- embryo implantation
Metabolic action (s) of LTB4
Leukocyte chemotaxis
Phosphatidic acid ——> Pi + Diacylglycerol is catalyzed by
Phosphatase
There are how many mechanisms to form phospholipids
2 different mechanisms
In mechanism 1 of phospholipid synthesis phosphatidic acid is cleaved by phosphatase to form _______
Diacylglycerol (DAG)
In mechanism 1 of phospholipid synthesis diacylglycerol (DAG) reacts with various ______ to form different phospholipids
headgroups
In mechanism 1 of phospholipid synthesis the headgroups must be _____ prior to this reaction
activated (this is done with headgroup reacting with CTP) thus making a CDP-headgroup
In mechanism 1 of phospholipid synthesis the activated headgroup (CDP-headgroup) reacts with diaylglycerol (DAG) to form
glycerophospholipid and CMP
What are the two major phospholipids produced by mechanism 1 of phospholipid synthesis
- Phosphatidylcholine (PC)
- Phosphatidylethanolamine (PE)
What are the two major phospholipids produced by mechanism 2 of phospholipid synthesis
- Cardiolipin
- Phosphatidylinositol (PI)
In mechanism 2 of phospholipid synthesis phosphatidic acid reacts with ____ to form ______ and ___
CTP to form CDP-Diacylglycerol (DAG) and PPi
In mechanism 2 of phospholipid synthesis CDP-DAG reacts with ____ to form phosphatidylinositol (PI) and CMP
inositol
In mechanism 2 of phospholipid synthesis CDP-DAG reacts with _______ to form diphosphatidyl glycerol (Cardiolipin), a component of the inner mitochondrial membrane
Phosphatidyl glycerol
In mechanism 2 of phospholipid synthesis CDP-DAG reacts with phosphatidyl glycerol to form ________, a component of the inner mitochondrial membrane
diphosphatidyl glycerol (cardiolipin)
Phosphatidylserine (PS) is formed by exchanging _____ for serine
ethanolamine of Phosphotidylethanolamine (PE)
Phosphatidylserine (PS) can be reconverted to Phosphotidylethanolamine (PE) by _____
decarboxylation
Phosphotidylethanolamine (PE) can me ______ to form Phosphatidylcholine (PC)
Methylated
What is the most abundant sterol
cholesterol (about 0.05% of total body weight)
Cholesterol is a component of membranes and precursor of biological active compounds such as
- bile acids and bile salts
- Vitamin D
- Steroid hormones (progesterone, aldosterone, cortisol, testosterone, estradiol)
What is the daily intake of cholesterol and about what percent is absorbed in the gut
about 250 mg per day, about 30-60% is absorbed in the gut
What is the daily production of cholesterol and where is it produced
about 1 gram, mostly in the liver
Biosynthesis of cholesterol is regulated by
dietary intake
What is the daily excretion percentage of cholesterol
about 5%
What is the daily re-absorption percentage of cholesterol
about 95%
Cholesterol is a ______ compound made of ____ (#) fused rings
allicyclic compound, 4 fused rings
What is the molecular weight of cholesterol
386 kDa
Cholesterol has ____ carbons, ___ rings, ___ double bonds between _______, ___ 2 CH3 at C__ and C___, ___ member hydrocarbon chain attached to _____
Cholesterol has 27 carbons, 4 rings, 1 double bond between C5 and C6, 2 CH3 at C18 and C19, 1 OH at C3, 8 member hydrocarbon chain attached to C17
3-hyroxy-3 methylglutaryl CoA reductase (HMG CoA Reductase) catalyzes
First step in the synthesis of cholesterol (rate limiting step)
Acetyl CoA + NADPH —-> Mevalonate + NADP+
What is the target for statins
HMG CoA reductase
what is a major carrier of cholesterol in the blood
Low density lipoprotein
Cholesterol is synthesized form ____ in how many stages
Acetyl CoA in 3 stages
What are the 3 stages of cholesterol synthesis
- ) synthesis of isopentenyl pyrophosphate, an activated isoprene unit that is the key building block of cholesterol
- ) Stage two is the condensation of six molecules of isopentenyl pyrophosphate to form squalene
- ) in stage three, squalene cyclizes and the tetracyclic product is subsequently converted into cholesterol
Note that the first stage takes place in the cytoplasm and the next tow in the endoplasmic reticulum
The synthesis of _____ is the committed step in cholesterol formation
mevalonate
The the cytoplasm HMG-CoA is converted into ______. In the mitochondria it is converted into ____ and ____
Mevalonate, Acetyl CoA and Acetoacetate
Mevalonate is converted into 3-isopentenyl pyrophosphate in 3 consecutive reactions each requiring _____. In the last step, the release of ____ yields isopentenyl pyrophosphate
ATP, CO2
The conversion of mevalonate to 3-isopentenyl is induced by
ATP
The conversion of mevalonate to 3-isopentenyl is inhibited by
CO2
Squalene (C30) is synthesized from ___ molecules of isopentenyl pyrophosphate (C5)
6
Stage II of the biosynthesis of cholesterol starts with the
isomerization of isopentenyl pyrophosphate to dimethylallyl pyrophosphate
The last step in the in the synthesis of squalene is a
reductive tail-to-tail condensation of two molecules of frankly pyrophosphate catalyzed by the ER enzyme squalene synthase
Stage III of cholesterol biosynthesis
Starts with cyclization of squalene. Squalene is first activated by conversion into squalene epoxide (2,3-oxidosqualene) in a reaction that uses O2 and NADPH. Squalene epoxide is then cyclized to lanosterol by oxidosqualene cyclase.
Oxidosqualene cyclase holds
squalene epoxide in an appropriate conformation and initiates the reaction by pronating the epoxide oxygen
The role of LDL is to
transport cholesterol to peripheral tissues and regulate de novo cholesterol synthesis at these sites
LDL is composed of
- unesterified cholesterol
- phospholipid
- cholesteryl ester
- apolipoprotein B-100
what are the three bad cholesterol particles
VLDL
IDL
LDL
what is good cholesterol particle
HDL
HDL properties
- smallest
- most dense
- high protein and phospholipid content
HDL has what three Apoproteins
ApoA-I
ApoC-II
Apo-E
VLDL has what three Apoproteins
ApoB-100
ApoC-II
Apo-E
IDL has what two apoproteins
ApoB-100
ApoE
LDL has what one apoproteins
ApoB-100
