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What are the steps of triacylglycerol synthesis from phosphatidate?
phosphatidate, phosphatidic acid phosphatase, DAG, diglyceride acyltransferase, triacylglycerol
What is the initial product of sphingolipid synthesis?
ceramide
What are the steps in the synthesis of ceramide?
palmitoyl CoA + serine, (bunch of rxns), dihydroceramide, ceramide
Which lipids function as second messengers in a variety of signal pathway?
ceramide, sphingosine, sphingosine 1-phosphate
What is the key regulatory enzyme in lipid metabolism?
Phosphatidic Acid Phosphatase
Phosphatidic acid phosphatase catalyzes the conversion of…
phosphatidate to DAG
In lipid metabolism, different lipids are synthesized depending on…
whether phosphatidic acid phosphatase is active or not
Loss of phosphatase activity in mice results in…
loss of body fat and the development of insulin resistance
What is the starting compound of cholesterol synthesis?
acetyl CoA
What are the 3 stages of cholesterol synthesis?
The synthesis of Isopentenyl pyrophosphate from mevalonate (cytoplasm)
Condensing of 6 molecules of isopentyl pyrophosphate to form squalene (ER)
The cyclization of squalene which is then converted into cholesterol (ER)
cytochrome P450 monooxygenases also functions _______ foreign substances
detoxify
Class of membrane-anchored enzymes that use heme as a prosthetic group and catalyze the hydroxylation of cholesterol
cytochrome P450 monooxygenases
What are the fates of the O2 substrate used in cytochrome P450 monooxygenases?
one is used to yield the hydroxylated product and the other is reduced to form H2O
SREBP stands for…
sterol regulatory element binding protein
When cholesterol levels fall SCAP…
escorts SREBP to the Golgi complex where it is proteolytically processed and activated. There, the activated SREBP moves to the nucleus to stimulate reductase mRNA synthesis. (transcription factor)
When cholesterol levels are adequate, SCAP binds to cholesterol, which causes a structural change in SCAP that allows SCAP to bind to…
Insig (insulin induced gene)
What prevents the HMG CoA reductase gene from NOT being transcribed?
The interaction between SCAP and Insig. It traps SCAP and SREBP in the ER mem
Additional regulatory strategies for cholesterol biosynthesis:
Rate of translation of reductase mRNA being inhibited by nonsterol metabolites of mevalonate.
Increase in cholesterol resulting in the proteolytic degradation of the reductase. (leads to the reductase being tagged for degradation by ubiquitin/proteasome)
Phosphorylation of reductase by AMP-activated protein kinase inactivates enzyme (allows cholesterol synthesis to cease when the ATP level is low)
Cholesterol and triacylglycerols are transported in the blood in the form of …
lipoprotein particles
Cholesterol and triacylglycerols serve to _______ lipids and to direct ____________________
solubilize; lipoprotein particles to specific targets
major transporter of cholesterol in the blood to peripheral tissues
Low-density lipoprotein, LDL
carries cholesterol released from dying cells and membranes undergoing turnover and brings it back to the liver for excretion (reverse cholesteroltransport)
High-density lipoprotein, HDL
The 3 steps of receptor-mediated endocytosis:
LDL binds to LDL receptor
LDL-receptor complex is internalizedendocytosis.
LDL is hydrolyzed in lysosomes, and the LDL receptor is returned to the cell surface to bind another LDL particle.
In the process of reverse cholesterol transport, HDL removes…
cholesterol from macrophages and returns it to the liver for use as bile salts or excretion
Competitive Inhibitor of HMG-CoA reductase
Lovastatin
Bile salts are synthesized in the _____ and stored in the _________ until secreted into the ________________
liver; gallbladder; small intestines
Cholesterol is a precursor to…
steroid hormones, vitamin D, and bile salts
detergents that render dietary lipids more accessible (due to having both a polar and nonpolar region) for digestion by lipases and thus facilitate the formation of fatty acid products
bile salts
What are the 5 major classes of steroid hormones?
progesterone, testosterone, estradiol, cortisol, aldosterone
prepares the uterus for implantation and supports pregnancy
progesterone (a progestogen)
promotes development of male sexual behavior and lean muscle mass
testosterone (an androgen)
promotes the development of female sex characteristics
estradiol (an estrogen)
stimulates glucose and glycogen synthesis and inhibits the inflammatory response
cortisol (a glucocorticoid)
regulates salt balance and the volume and pressure of blood
aldosterone (a mineralocorticoid)
a metabolite of testosterone, supports the embryonic development of the male phenotype
dihydrotestosterone
All of the steroid hormones operate in a similar fashion, in that they…
bind to and activate receptor molecules that subsequently regulate gene expression
Vitamin D is formed from cholesterol by the ___________ of UV-light
ring-splitting
In what cellular location does the synthesis of phosphatidate occur?
ER and outer mitochondrial membrane
Primary site of triacylglycerol synthesis
Liver
Phospholipid synthesis requires the combination of a(n) ________ with an _______. As in most anabolic reactions, one of the components must be activated. Which will depend on the source of the reactants.
CDP-diacylglycerol ; alcohol
The degradation of PHE requires oxygen. Where does the oxygen come from?
molecular oxygen
Amino transferases require PLP for activity. Which of the following is true concerning PLP?
a) The mechanism is very much like a protease breaking a peptide bond.
b) PLP donates high energy electrons to the reaction
c) PLP is covalently attached to the substrate by a Schiff-base linkage
d) PLP is attracted to the substrate by hydrophobic interactions
e) none of the choices
c
The carbon skeletons of ___ directly enter metabloism at the level of pyruvate.
a) TYR and TRP
b) VAL and ILE
c) ALA and SER
d) THR and GLY
e) none of the choices
c
What is the activated diacylglycerol in the synthesis of some phospholipids?
cytidine diphosphodiacylglycerol (CDP-diacylglycerol)
The reaction of phosphatidate with cytidine triphosphate (CTP) to form the activated diacylglycerol (CDP-diacylglycerol) is driven forward by what?
by the hydrolysis of pyrophosphate.
The hydroxyl group on cholesterol and the subsequent hydroxyl groups added in the synthesis of steroid hormones are derived from…
a) water
b) hydroxide
c) carbon dioxide
d) molecular oxygen
e) none of the choices
d
In the synthesis of TAG and phospholipids, fatty acids are first attached to glycerol 3-phosphate . Which molecule is a source of glycerol 3-phosphate?
a) phosphorylation of glycerol
b) pyruvate
c) acetyl CoA
d) malonyl CoA
e) none of the choices
a
The activated phosphatidyl unit (CDP-DAG) reacts with the hydroxyl group of an alcohol to form a phosphodiester linkage. If the alcohol is inositol, the products are __________ and ________
phosphatidylinositol ; cytidine monophosphate (CMP)
phosphatidylinositol 4,5-bisphosphate is the precursor of what two intracellular messengers?
DAG and inositol 1,4,5-trisphosphate
If the alcohol CDP-DAG reacts with is phosphatidylglycerol what are the products?
diphosphatidylglycerol (cardiolipin) ; CMP
In eukaryotes, cardiolipin is synthesized in the __________ and is located exclusively in the ____________.
mitochondria ; inner mitochondrial membranes
Plays an important role in the organization of the protein components of oxidative phosphorylation
cardiolipin
required for the full activity of cytochrome c oxidase
cardiolipin
another word for cardiolipin
diphosphatidylglycerol
Identify the compound
Cardiolipin
Phosphatidylinositol is unusual in that it…….. Stearic acid usually occupies the C-1 position and arachidonic acid the C-2 position.
has a nearly fixed fatty acid composition
most common phospholipid in mammals comprising approximately 50% of the membrane mass
phosphatidylcholine
this compound is the starting point for the formation of sphingomyelin and gangliosides.
ceramide
the most complex sphingolipids
gangliosides
induces apoptosis
ceramide
What are the signal molecules that stimulate phosphatidic acid phosphatase?
CDP-DAG, phosphatidylinositol, and cardiolipin
What are the signal molecules that inhibit phosphatidic acid phosphatase?
sphingosine and dihydrosphingosine
When PAP is ___________it resides in the cytoplasm
phosphorylated
When PAP is ___________it resides in the endoplasmic reticulum
dephosphorylated
modulates the fluidity of animal cell membranes
cholesterol
the committed step in cholesterol formation
the synthesis of mevalonate
The synthesis of cholesterol involves the condensation of C5 units from isopentyl pyrophosphate . Which statement best summarizes the sequence of condensation that produce cholesterol?
a) Three C5 units are condensed to form a C15 unit followed by two C15 units combining to form a C30 unit that is cyclized and has carbons removed to make cholesterol (C27)
b) Nine C5 units combine together and then C3 units are removed until cholesterol (C27) is formed
c)Six C5 units are combined sequentially to make a C30 molecule that has 3C removed before it is cyclized into cholesterol (C27)
d) Two C5 units are combined to make C10. Three of the C10 units combined to make a C30 which is cyclized to form cholesterol
e) none of the above
a
Explain each step in the picture
The SREBP pathway. SREBP resides in the endoplasmic reticulum (ER), where it is bound to SCAP by its regulatory (Reg) domain. When cholesterol levels fall, SCAP and SREBP move to the Golgi complex, where SREBP undergoes successive proteolytic cleavages by a serine protease and a metalloprotease. The released DNA-binding domain moves to the nucleus to alter gene expression.
Explain what is occuring in the picture
In the presence of sterols, a subclass of Insig associated with ubiquitinating enzymes binds HMG-CoA reductase. This interaction results in the ubiquitination of the enzyme. This modification and the presence of geranylgeraniol results in extraction of the enzyme from the membrane and degradation by the proteasome.
Triacylglycerols, cholesterol, and other lipids obtained from the diet are carried away from the intestine in the form of large …
chylomicrons
Identify the structure and the color-coded regions
low-density lipoprotein (LDL)
the polar derivatives of cholesterol
bile salts
major sites of synthesis for progestogens
corpus luteum
major sites of synthesis for androgens
testes
major sites of synthesis for estrogens
ovaries
major sites of synthesis for glucocorticoids and mineralocorticoids
adrenal cortex
Give examples of the wide variety of compounds formed from the C5 isopentenyl pyrophosphate
terpenes, natural rubber, carotenoids, and the side chains of": CoQ, chlorophyll, and Vit K
an isoprenoid
farnesene
All glycerol-containing phospholipids are derived from:
a) Ceramide
b) Ganglioside
c) Mevalonate
d) Phosphatidate
d
Sphingolipids are synthesized from:
a) Ceramide
b) Phosphatidylserine
c) Diacylglycerol
d) Isoprene
a
The synthesis of phosphatidylcholine from phosphatidylethanolamine requires:
a) Tetrahydrofolate
b) Glycine
c) Choline
d) S-Adenosylmethionine
c
Cholesterol is synthesized entirely from:
a) Oxaloacetate
b) Glycerol 3-phosphate
c) Acetyl CoA
d) Serine
c
Bile salts are synthesized from:
a) Cholesterol
b) Prostaglandin
c) Triacylglycerol
d) Ceramide
a
Describe the roles of glycerol 3-phosphate, phosphatidate, and diacylglycerol in triacylglycerol and phospholipid synthesis.
G3P is the foundation for both TAG and phospholipid synthesis. G3P is acylated twice to form phosphatidate. In TAG synthesis, the phosphoryl group is removed from G3P to form DAG, which is then acylated to form TAG. In phospholipid synthesis, phosphatidate commonly reacts with CTP to form CDP-DAG, which then reacts with an alcohol to form a phospholipid. Alternatively, DAG may react with a CDP-alcohol to form a phospholipid
How is the glycerol 3-phosphate required for phosphatidate synthesis generated?
G3P is formed primarily by the reduction of DHAP and to a lesser extent by the phosphorylation of glycerol.
Differentiate among sphingomyelin, a cerebroside, and a ganglioside.
All are synthesized from ceramide.
In sphingomyelin, the terminal hydroxyl group of ceramide is modified with phosphorylcholine.
In a cerebroside, the hydroxyl group has a glucose or galactose attached.
In a ganglioside, oligosacc. chains are attached to the hydroxyl group.
There are only 3 ways to make glycerol-based phosholipid. Describe the 3 pathways....
Activate the diacylglycerol as CDP-DAG.
Activate the alcohol as CDP-alcohol.
Use the base-exchange reaction.
What is the activated reactant in the biosynthesis of phosphatidylinositol from inositol?
CDP-DAG
What is the activated reactant in the biosynthesis of phosphatidylethanolamine from ethanolamine?
CDP-ethanolamine
What is the activated reactant in the biosynthesis of sphingomyelin from ceramide?
phosphatidylcholine
What is the activated reactant in the biosynthesis of ceramide from sphingosine?
acyl CoA
What is the activated reactant in the biosynthesis of cerebroside from ceramide?
UDP-glucose/galactose
What is the activated reactant in the biosynthesis of Ganglioside GM1 from ganglioside GM2?
UDP-galactose
What is the activated reactant in the biosynthesis of farnesyl pyrophosphate from geranyl pyrophosphate?
geranyl pyrophoshate
What would be the effect of a mutation that decreased the activity of phosphatidic acid phosphatase?
The amount of adipose tissue would decrease severely because DAG is acylated to form TAG. If there were deficient phosphatidic acid phosphatase activity, no TAGs would form.
Would the development of a "super statin" that inhibited all HMG CoA reductase activity be a useful drug? Explain.
No. Cholesterol is essential for membrane function and as a precursor for bile salts and steroid hormones. The complete lack of cholesterol would be lethal.
Glycerol-based membrane lipid
phospholipid
Product of the committed step in cholesterol synthesis
mevalonate
Ceramide with either glucose or galactose attached
sphingolipid
Note
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