Chapter 29 Flashcards
_______ and _________ begin with the precursor phosphatidate (diacylglycerol-3-phosphate)
a) TAG; phospholipid synthesis
b) MAG; protein synthesis
c) Amino acid; protein synthesis
d) glucose; pyruvate
a) TAG; phospholipid synthesis
Phosphatidate is made by adding ____ fatty acids to ________________
a) 4; glycerol-6-phosphate
b) 2; glycerol-3-phosphate
c) 3; glycerol-3-phosphate
d) 2; glyceraldehyde-3-phosphate
b) 2; glycerol-3-phosphate
Provide a broad overview to the steps of going from glycerol-3-phosphate to phosphatidate
Glycerol-3-phosphate = acylated by saturated acyl-CoA –> yields lysophosphatidate –> acylated by an unsaturated acyl-CoA –> yield phosphatidate
PATHWAY INTEGRATION: Sources of intermediates in the synthesis of triacylglycerols and phospholipids. List the 4 active pathways
- Glycolysis: glucose –> DHAP –> glycerol-3-phosphate –> phosphatidate
- TAG breakdown
- TAG synthesis
- Phospholipid synthesis
Synthesis of TAG is completed by the ___________ which is located on the ___________
a) Dag synthetase; epithelial cells
b) TAG synthetase complex; lysosome
c) Lysosomal complex; ER membrane
d) TAG synthetase complex; ER membrane
d) TAG synthetase complex; ER membrane
True or False: Phosphatidate is hydrolyzed to give DAG, which is acylated to a TAG
True
The primary site of TAG synthesis is
a) kidney
b) liver
c) muscle
d) small intestine
b) liver
When TAG’s are synthesized from the liver, they are transported to the ________ for use as fuel or to _______ for storage
a) muscles; adipose tissue
b) kidney
c) small intestine
d) adipose tissue; muscle
a) muscles; adipose tissue
Approx. _______% of nonobese person’s energy is stored as TAG, mainly in adipose tissue
a) 75
b) 85
c) 25
d) 90
85%
True or False: Phosphatidate is a precursor for phospholipid synthesis
True
Phospholipid synthesis takes place in the _____
a) Mitochondrial matrix
b) ER
c) TAG synthetase complex
b) ER
To generate phospholipid, DAG (phosphatidate) is combined with an _______
a) alcohol
b) fatty acid
c) acyl group
a) alcohol
True or False: Phospholipids are key constituents of membranes
True
Phospholipid Synthesis: Phosphatidyl Activation
- Pathways begins w/ reaction of phosphatidyl w/ cytidine triphosphate (CTP) to form cytidine diphosphodiacylglycerol (CDP-diacylglycerol)
- Reaction is driven forward by hydrolysis of pyrophosphate
- Activated phosphatidyl than reacts w/ the hydroxyl group of an alcohol
- If alcohol is inositol, products are phosphatidylinositol and cytidine monophosphate (CMPT)
–> Subsequent phosphorylation of phosphatidylinositol catalyzed by specific kinases lead to synthesis of phosphatidylinositol 4,5-bisphosphate ~ a membrane lipid and important molecule in signal transduction
- If alcohol is phosphatidylglycerol, products are diphosphatidylglycerol (cardiolipin)
Phospholipid Synthesis: Alcohol Activation
Alcohol activation occurs via phosphorylation
- Ethanolamine is phosphorylated by ATP to form precursor phosphorlethanolamine ~ A
- Precursor reacts w/ CTP to form activated CDP-alcohol (CDP-ethanolamine) ~ B
- Phosphorlethanolamine unit of CDP-ethanolamine reacts w/ DAG to form the phospholipid (phosphatidylethanolamine) ~ C
Phosphatidylcholine
- Phosphatidylcholine = most common phospholipid in mammals
- Adequate dietary choline ~ phosphatidylcholine is synthesized by CTP-phosphocholine cytidylyltransferase (CCT), which activates choline
- Deficient dietary choline ~phosphatidylcholine is synthesized from phosphatidylethanolamine by methylation w/ S-adenosylmethionine
Sphingolipids have a…
a) glycerol backbone
b) sphingosine backbone
b) sphingosine backbone
Sphingolipids are found in plasma membranes of all ___________ with the concentration being highest in cells of the ______________
a) eukaryotic cells; liver
b) prokaryotic cells; peripheral nervous system
c) eukaryotic cells; central nervous system
c) eukaryotic cells; central nervous system
Sphingolipid synthesis begins with the condensation with ______________ and _______
a) palmitoyl-CoA; serine
b) acetyl-CoA; serine
c) malonyl-CoA; serine
a) palmitoyl-CoA; serine
The initial product of sphingolipid synthesis is _______
a) Choline
b) acetyl-CoA
c) Ceramide
c) Ceramide
True or False: In sphingolipid synthesis, the terminal hydroxyl group of ceramides are substituted to form other sphingolipids
True
In sphingolipid synthesis, the terminal hydroxyl group of ceramides are substituted to form other sphingolipids
- If terminal hydroxyl group is phosphorylcholine, product is sphingomyelin
- If terminal hydroxyl group is glucose or galactose, product is cerebroside
- If oligosaccharide containing sialic acid is attached to terminal glucose, product is ganglioside
Sphingomyelin
- A component of the myelin sheath surrounding nerve cells (covering nerve fibers)
- Substituent = phosphorylcholine bound to terminal hydroxyl group
Cerebroside
- A component of myelin
- Substituent = glucose or galactose attached to terminal hydroxyl group
Ganglioside
- Derived from cerebroside
- Here, an oligosaccharide containing at-least one sialic acid is linked to the terminal hydroxyl group of ceramides by glucose residue
Gangliosides Serve as Binding Sites for Pathogens
- Ganglioside-binding by cholera toxin = first step in development of cholera, a pathological condition characterized by severe diarrhea
- Enterotoxigenic E. coli = most common cause of diarrhea, including traveler’s diarrhea, produces a toxin that gains access to cell by first binding to gangliosides
- Gangliosides = crucial for binding immune-system cells to sites of injury in inflammatory response
Regulation of Lipid Metabolism
Phosphatidic acid phosphatase (PAP, aka lipin-1 in mammals)
- Plays important role in lipid synthesis regulation
- Helps regulate lipid metabolism
- Catalyzes conversion of phosphatidate to DAG
- Directs which type of lipids are synthesized
–> Loss of PAP function can lead to loss of body fat (lipodystrophy) and development of insulin resistance
–> Excess PAP activity can lead to obesity
Cholesterol Synthesis
Liver = primary site of cholesterol synthesis
- Most tissues synthesize some cholesterol
Cholesterol synthesis occurs in three stages:
- Isopentenyl pyrophosphate is synthesized from mevalonate in cytoplasm
- 6 molecules of isopentenyl pyrophosphate condense to form squalene, takes place in ER
- Squalene cyclizes and is converted into cholesterol in ER
Cholesterol Synthesis: Stage 1
- Starts w/ formation of HMG-CoA (3-hydroxy-3-methylglutaryl CoA)
- HMG-CoA is reduced to mevalonate by HMG-CoA reductase = commitment step ~ B
- Mevalonate (6-C) is converted into isopentyl pyrophosphate (5-C) = activated isoprene ~ C
Cholesterol Synthesis: Stage 2
- Isopentenyl pyrophosphate (5-C) isomerizes to dimethylallyl pyrophosphate (5-C)
- Isopentenyl pyrophosphate (5-C) and dimethylallyl pyrophosphate (5-C) condense to form geranyl pyrophosphate (10-C)
- Another isopentenyl pyrophosphate (5-C) is added to form farnesyl pyrophosphate (15-C)
- Two farnesyl pyrophosphate (15-C) condense to form squalene (30-C)
C5 –> C10 –> C15 –> C30
Cholesterol Synthesis: Stage 3
- Squalene is first activated w/ formation of squalene epoxide (2, 3-oxidosqualene) in a reaction that uses O2 and NADPH
- Cyclization occurs to form lanosterol (C30), which is subsequently metabolized (converted) to cholesterol (C27) in a multistep process in which 3-C units are removed
Regulating Cholesterol Synthesis
HMA-CoA reductase is regulated in multiple ways:
- Synthesis of HMG-CoA reductase mRNA ~ controlled by the sterol regulatory element binding protein (SREBP)
- Translation of the HMG-CoA reductase mRNA to protein (enzyme) ~ controlled by metabolites of mevalonate and dietary cholesterol
- Proteolytic degradation of HMG-CoA reductase ~ activated by increases in cholesterol concentration
- Phosphorylation of HMG-CoA reductase inactivates enzyme ~ by AMP-dependent kinase
Regulating Cholesterol Synthesis: HMG-CoA Reductase
SREBP = sterol regulatory element binding protein
Resides on ER membrane
Is associated w/ SCAP (SREBP cleavage activating protein)
Low cholesterol:
- SCAP escorts SREBP to the Golgi complex
- SREBP is proteolytically activated by a serine protease and a metalloprotease
- Activated SREBP moves to nucleus, which stimulates reductase synthesis
Lipoproteins Transport Cholesterol & TAGs
Lipoproteins transport cholesterol and TAGs in blood as lipoprotein particles
Lipoproteins consist of proteins(s) and lipids
Proteins help to solubilize the lipids and help direct the particles to specific targets
Lipoprotein classified by density
- Great protein content = more dense
- Greater lipid content = less dense
Low-density lipoprotein (LDL) = major carrier of cholesterol in blood
High-density lipoprotein (HGL) = carriers cholesterol back to liver
Lipoprotein Metabolism
- The TAGS in VLDL are hydrolyzed by lipases on capillary surfaces, and the freed fatty acids are taken into the cells
- When TAGs and cholesterol that are synthesized in the liver are in excess of the livers needs, they are exported into the blood in the form of very low lipoproteins (VLDL)
Delivery of Cholesterol by LDL
The TAGS in VLDL are hydrolyzed by lipases on capillary surfaces, and the freed fatty acids are taken into the cells
When TAGs and cholesterol that are synthesized in the liver are in excess of the livers needs, they are exported into the blood in the form of very low lipoproteins (VLDL)
At the tissues, cholesterol enters the cell by receptor-mediated endocytosis
- LDL binds to the LDL-receptor in cell surface
receptors for LDL are localized in specific regions called coated pits, surrounded by a specialized protein called clathrin
- The receptor-LDL complex is internalized (endocytosis)
plasma membrane vicinity of complex invaginates (folds itself)
membrane than fuses itself to form an endosome, enclosing the receptor-LDL complex
- The LDL is hydrolyzed in lysosomes
LDL receptor recycled
vesicles containing the LDL fuse w/ lysosomes
acidic environment induces the receptor to relinquish its cargo
protein component of LDL is hydrolyzed to free amino acids
cholesteryl esters in LDL are hydrolyzed by a lysosomal acid lipase
LDL receptor usually returns unscathed to plasma membrane. The round-trip time for a receptor is about 10 minutes; in its lifetime of about a day, it brings many LDL particles into cell
Biochemical Synthesis: Bile Salts
Bile salts are detergents that render dietary lipids more accessible for digestion by lipases
Bile salts are synthesized in liver and stored in gallbladder until secreted into small intestine
Cholesterol = present in bile
- Excess cholesterol in bile may precipitate to form gallbladder stones
- The stones lead to inflammation of the gallbladder, condition called cholelithiasis
Biochemical Synthesis: Steroid Hormones
Progesterone (progestogen)
prepares the uterus for implantation and supports pregnancy
Biochemical Synthesis: Steroid Hormones
Testosterone (androgen)
promotes the development of male sexual behavior and lean muscle mass
Biochemical Synthesis: Steroid Hormones
Estradiol (estrogen)
promotes the development of female secondary sex characteristics
Biochemical Synthesis: Steroid Hormones
Cortisol (glucocorticoid)
stimulates glucose and glycogen synthesis and inhibits the inflammatory response
Biochemical Synthesis: Steroid Hormones
Aldosterone (mineralocorticoid)
regulates bile sale balance and the volume and pressure of blood
Biochemical Synthesis: Vitamin D
Vitamin D plays key role in regulation of calcium and phosphate metabolism
Calcitriol = active form of vitamin D
- Formed from cholesterol
- Requires UV light-induced cleavage
- Functions in a manner similar to steroid hormones
