Exam #3: (24-31b) Flashcards
(268 cards)
0
Q
What is the term for a non-enzymatic addition of sugars to a protein, i.e. no transferase used, e.g. glucose added to Val to produce HbA1c?
A
Glycation.
1
Q
List six biological functions of glycoconjugates and give examples of each
A
- ) Cell-cell adhesion: Glycan-binding proteins (GBP)
- ) Cell signalling: Many receptors and growth factors are glycoproteins, e.g. GPCR, RTK.
- ) Receptors for viruses and bacteria: Specific GBP on cell surface, e.g. CD4 on T-cells.
- ) Gene regulation: Transcription factors are O-glycosylated, e.g. CREB.
- ) Immune response: Many antigens are glycans, e.g. blood group antigens.
- ) Protein sorting: Lysosomal targeting by glycan tagging, e.g. Mannose 6-P.
2
Q
Compare and contrast the formation of O-linked vs. N-linked glycosylation, i.e. when and where are they formed, and using what?
A
- ) N-linked: N-glycans are added CO-TRANSLATIONALLY to proteins IN THE ER using pre-assembled lipid-linked oligosaccharide donors, i.e. they are added BEFORE the protein synthesis is complete.
- ) O-linked: In general, they are added POST-TRANSLATIONALLY to proteins IN THE GOLGI apparatus by single step additions of sugars; NO OTHER PRECURSORS ARE INVOLVED.
3
Q
What are the two types N-Glycans and where are they synthesized?
A
- ) Complex-type: Synthesized in the Golgi apparatus.
2. ) High mannose-type: Synthesized in the ER.
4
Q
List the major steps in N-Glycosylation (5).
A
- STEPS 1 and 2 MOST IMPORTANT*
1. ) Precursors built in the cytoplasm, e.g. Man-6-P from Glc-6-P.
- ) Build lipid-linked oligosaccharide on and in the ER membrane/LUMEN(??? –> 33:53 lecture 24). The result is a unique 14-sugar precursor to N-glycosylation (generally known as a DOLICHOL PYROPHOSPHATE).
- ) Transfer of 14-sugar precursor to the NASCENT POLYPEPTIDE in the ER by oligosaccharide transferase (OST).
- ) Trimming reactions in ER to generate Man8GlcNAc2 on properly folded glycoprotein.
- ) Further trimming and processing (extension) in GOLGI to generate complex-type N-glycan on mature glycoprotein.
5
Q
- ) What is enzyme is defective in the disease CDG la? What is its normal function? Which steps of N-glycosylation is it associated with?
- ) What disease is associates with a defect in the 5th step of N-glycosylation? Where does it occur?
- ) What is the major distinction between the two diseases?
A
- ) PMM2 (phosphomannomutase) enzyme in the FIRST STEP. It normally transforms Man-6-P –> Man-1-P.
- ) CDG II in the GOLGI apparatus.
- ) CDG I involves the SYNTHESIS of glycoprotein, CDG II involves the PROCESSING of glycoproteins.
6
Q
What drug prohibits initial precursor synthesis in N-glycosylation?
A
Tunicamycin
7
Q
Compare glycoproteins vs. proteoglycans in terms of main constituents, charge, and structure/components (5 things each)
A
Glycoprotein:
- Primarily protein (protein + some CHO)
- CHO may be negatively charged
- Short chains
- Branched
- No repeating disaccharide units (oligosaccharides)
Proteoglycans:
- Primarily carbohydrate (CHO + some protein)
- CHO chains ALWAYS negatively charged
- Long chains
- Linear
- Negatively charged REPEATING disaccharide units (GAGs)
8
Q
- ) What comprises the repeating unit of a GAG?
- ) How many classes of GAG are based on this repeating unit?
- ) What are the constituents of a proteoglycan?
- ) Most proteoglycans will have an amino sugar that has been _____.
A
- ) An acidic sugar and an N-acetylated amino sugar (repeated x100’s in a GAG).
- ) Six
- ) Protein + GAG
- ) Sulfated (37:30 lecture 24)
9
Q
What is the only class of GAG that is NOT covalently attached to a protein?
A
Hyaluronic acid
10
Q
List the tissue distribution for each of the following GAGs:
- ) Chondroitin sulfate
- ) Keratan sulfate
- ) Hyaluronic acid
- ) Dermatan sulfate
- ) Heparin
- ) Heparin sulfate
A
- ) Chondroitin sulfate: Cartilage, tendon, bones
- ) Keratan sulfate: Cartilage, cornea, bone
- ) Hyaluronic acid: Joint and ocular fluids, cartilage
- ) Dermatan sulfate: Skin, heart valves, blood vessels
- ) Heparin: Intracellular in MAST CELLS
- ) Heparin sulfate: Cell surfaces, basement membranes
12
Q
Where are proteoglycans commonly found (4)? Why?
A
Found in joints, vitreous humor of the eye, arterial walls, and cartilage.
They are found in these places because: Due to the negative charges, GAGs repel one another and are surrounded by a water shell. When compressed, water in between the GAG is squeezed out. When released, GAGs go back to the extended hydrated state. THIS PROPERTY provides resilience to synovial fluid of joints and vitreous humor of the eye.
13
Q
- ) Which blood types can type A donate to?
2. ) Receive?
A
- ) A, AB
2. ) A, O
14
Q
Which blood types can type B donate to? Receive?
A
- ) B, AB
2. ) B, O
15
Q
- ) Which blood types can type AB donate to?
2. ) Receive?
A
- ) AB
2. ) AB, O
16
Q
- ) Which blood types can type O donate to?
2. ) Receive?
A
- ) A, B, AB, O
2. ) O
17
Q
Explain the difference between CDGs (congenital disorder of glycosylation) type 1 and 2
A
CDG Type-1: Defects in assembly within the ER. Errors in ADDING glycans, and will contain a lesser number
CDG Type-2: Defects in Golgi processing. Number of glycans will normal, but the structure/order will be different
18
Q
What is the most common CDG?
A
CDG 1a: Phosphomannomutase (PMM2) deficit. (CDG 1a; Mannose 6-P –> Mannose 1-P) Accounts for 70% of all CDG syndromes
19
Q
What are MPSs (mucopolysaccharidosises)?
A
-Mucopolysaccharidosis-
Inherited lysosomal storage diseases where defective or missing hydrolytic enzymes cause large amounts of GAGs to accumulate, causing permanent, progressive cellular damage that affects appearance, physical abilities, and in most cases, mental development.
20
Q
What are some outward manifestations of MPS (8)?
A
Coarse facial features, thick lips, an enlarged mouth and tongue, short stature, abnormal bone size or shape, enlarged organs such as liver or spleen, hernias, and excessive body hair growth.
21
Q
_______ must first be removed before exoglycosidases can act.
A
N- and O-sulfate groups
22
Q
An unusual feature of Heparan Sulfate degradation is that this process also involves a _______. Explain.
A
Synthetic step: After N-sulfate removed, the nonacetylated glucosamine must first be N-acetylated using acetyl-CoA before a N-acetylglucosaminidase can cleave this residue.
23
Q
Describe MPS-II (Mucopolysaccharidosis-II)
- ) Name
- ) Deficient enzyme
- ) Role of deficient enzyme
A
- ) Hunter Syndrome (X-linked)
- ) Iduronic acid-2-sulfatase
- ) Removes a sulfate
24
Q
Describe MPS-I (Mucopolysaccharidosis-I)
- ) Name
- ) Deficient enzyme
- ) Role of deficient enzyme
A
- ) Hurler Syndrome
- ) Alpha-iduronidase
- ) Removes iduronic acid
25
Describe I-cell disease (Inclusion-cell disease):
1. ) Name
2. ) Cause
3. ) Pathology
4. ) Symptoms
1. ) Mucolipidosis
2. ) Autosomal recessive disease in which MULTIPLE acid hydrolases are missing from the lysosomes. *The defect is in the SORTING of proteins destined for lysosomes (which occurs in Golgi)*
3. ) Accumulation of glycolipids and mucopolysaccharides in lysosomes lead to large inclusion in cells (thus, I-cell).
4. ) Coarse facial features, skeletal abnormalities, mental retardation, heart valve and respiratory problems.
26
In I-cell disease, where do the proteins intended for lysosomes end up?
The end up in the plasma because the enzyme (acid hydrolase) that adds a phosphomannose (which is recognized by Man-6-P-receptor that sends protein where it needs to go) is missing.
27
Describe Hyaluronic Acid (HA or Hyaluranan). What is it degraded by?
An anionic, non-sulfated GAG that is not covalently attached to any protein. It acts as a scaffold for the assembly of proteoglycans in cartilage (e.g. CS Aggrecan). It is degraded by hyaluronidases (endoglycosidases).
28
Where is HA found? What happens when it is lost?
HA is present in the synovial fluid of the joints to provide compressibility, and its loss is implicated in the DEGENERATIVE JOINT DISEASE of OSTEOARTHRITIS.
29
What is the difference between gram positive and gram negative bacteria in terms of cell walls?
Gram positive: Multiple layer of peptidoglycan.
| Gram negative: Single layer of peptidoglycan (though they have an OUTER LAYER THAT SURROUNDS THE PEPTIDOGLYCAN).
30
What are the repeating peptidoglycan units in bacterial cell walls
N-Acetylglucosamine (NAG) linked to N-Acetylmuramic acid (NAM), aka SIALIC ACID. The NAM is linked to a series of unusual amino acids, and include lysine and D-alanine.
31
What causes the rigidity of a bacterial cell wall? i.e. Describe the peptidoglycan cross-linking.
A transpeptidase cross-links a lysine via the pentaglycine bridge to a D-alanine on the adjacent chain of another peptidoglycan.
32
How does penicillin work?
It inhibits the transpeptidase that cross-links the peptidoglycan repeating units of the bacterial cell wall.
33
What would lysozyme do to bacterial cell walls?
It would cleave the link between N-Acetylglucosamine (NAG) and N-Acetylmuramic acid (NAM)
34
1. ) Peptidoglycan synthesis resembles the ___________ of ________ synthesis.
2. ) A _____ is involved in the synthesis of the disaccharide unit
1. ) Resembles the DOLICHOL PHOSPHATE CYCLE of N-Glycan synthesis.
2. ) Carrier phosphate
35
______ is a component of the topical antibiotic Neosporin. What does it do to peptidoglycan synthesis in bacterial walls?
Bacitracin: It inhibits the recycling of the carrier phosphate, and thus inhibits production.
36
How does Vancomycin function as an antibiotic? It may be the last line of defense against ________.
It inhibits the transfer of GAGs to the peptide acceptor.
| It may be the last line of defense against Staph aureus.
37
What are some treatment strategies for MPS (3)? Explain.
1. ) Hematopoietic stem cell transplantation (HSCT, or bone marrow transplant): Allows individuals to produce endogenous enzyme. *Recommended for MPS I (H, H/S) < age 2 or 2.5 years, with normal to moderate cognition.
2. ) HSCT + Enzyme replacement therapy (ERT): May augment enzyme availability after HSCT.
3. ) ERT: Does not cross the blood-brain barrier, and thus do not correct the mental retardation. Intrathecal administration has been proposed. *MAY BENEFIT PATIENTS WILL ALL FORMS OF THE DISEASE*
38
What are the four main functions of lipids?
1. ) Major form of stored energy
2. ) Membrane structure and function
3. ) Cell signaling
4. ) Insulation
39
What types of solvents are lipids soluble in? Give 2 examples
Non-polar solvents, e.g. chloroform, ether.
40
Give the two major classifications of lipids with description and examples (2, and 3)
1. ) Storage lipids (e.g. triacylglycerols, cholesterol esters): Neutral lipids. Can be stored INTRAcellularly as lipid droplets (e.g. in adipose).
2. ) Membrane lipids (e.g. phospholipids, cholesterol, glycolipids): Amphipathic (both polar and nonpolar groups on the same molecule)
41
Which fatty acid does 16:0 stand for?
Palmitic acid
42
Which carbons (i.e. what number) in fatty acids are labeled alpha, beta, and omega?
```
Alpha = Carbon #2
Beta = Carbon #3
Omega = Last carbon in the fatty acid chain
```
43
List the number of carbons present in each of the following fatty acid classifications:
1. ) Short chain FA (SCFA):
2. ) Medium chain FA (MCFA):
3. ) Long chain FA (LCFA):
4. ) Very long chain FA (VLCFA):
1.) Short chain FA (SCFA): 22 carbons
44
Lactating mammary glands produce mainly which type of chain length fatty acid? Why?
MCFA, because these are easier to digest by infants.
45
____ fatty acids (as long as _____) have been observed in the CNS, particularly in myelin.
VLCFA (as long as 34 carbons).
46
Most mammalian fatty acids have _____ numbers of carbons.
Even numbers of carbons.
47
What is the numeric notation for Stearic acid?
18:0
48
Name two monosaturated fatty acids, with their numeric notation
* Monosaturated = 1 double bond*
1. ) Palmitoleic (16:1)
2. ) Oleic (18:1)
49
List three polyunsaturated fatty acids (PUFA) and their numerical notation. Where do we get these from and what are they called as a result of where we get them?
Polyunsaturated = 2 or more double bonds
1. ) Linoleic acid (18:2)
2. ) Linolenic acid (18:3)
3. ) Arachidonic acid (20:4)
* Humans cannot synthesize polyunsaturated fatty acids, and thus, we must acquire them from plants or animals. As a result, they are called ESSENTIAL FATTY ACIDS*
50
1. ) Functional groups are always in a _____ configuration around the double bonds in fatty acids.
2. ) How is the other configuration achieved?
1. ) Cis configuration
| 2. ) Trans configuration is achieved by hydrogenation. TRANS DO NOT OCCUR NATURALLY.
51
1. ) How does chain length affect melting points in fatty acids?
2. ) How do kinks (double bonds) affect melting points in fatty acids?
1. ) MP increases with length
| 2. ) MP decreases with # of double bonds.
52
_____ fatty acids are liquid at room temp, example?
Unsaturated: Olive oil
53
What are triacylglycerols?
Three fatty acids attached by ester linkages to a backbone of glycerol.
54
What method and compound is needed to remove a fatty acid from triacylglycerols (TAGs)?
Hydrolysis using lipases
55
What general class of lipids are glycerols part of?
Glycerolipid
56
The major form of our dietary fat (>___%) comes from what kind of lipids?
>90% comes from triacylglycerols
57
Why is fat stored more efficiently than glycogen?
Glycogen requires a great deal of water to store, fat does not.
58
Where are fat droplets stored in the body?
Adipocytes
59
Fat digestion begins in the _____ by what? Digestion continues in two places, where and by what?
Begins in the mouth by LINGUAL LIPASE.
| Digestion continues in the stomach (by gastric lipase).
60
What is the optimum pH for lingual and gastric lipases, and what length of TAGs do they function on?
pH 4-6. They act on TAGs with short and medium chain FA (e.g. milk fat).
61
Lingual and gastric lipases are lacking in _____ and in adult patients with which two disease?
Lacking in INFANTS, and adults with CYSTIC FIBROSIS and PANCREATIC INSUFFICIENCY.
62
______ fatty acids are directly absorbed into the bloodstream from the stomach.
Short chain fatty acids (SCFA)
63
Digestion of TAGs with LCFA occurs in the ______ by _______.
Occurs in the DUODENUM by PANCREATIC LIPASE
64
_______ in the stomach breaks up TAGs into small fat globules.
Peristalsis
65
______ and _____ neutralizes chyme.
Hepatic and pancreatic HCO3-
66
What is cholecystokinin? Where is it produced, what does it do?
It is a hormone produced by, and released from the intestinal I-cells. It regulates the gallbladder to release bile, and the pancreas to release its enzymes.
67
What does secretin do? Where does it come from?
Produced by the intestinal L-cells. Stimulates secretion of bicarbonate from the pancreas.
68
1. ) What is emulsification? Where does it occur?
| 2. ) Emulsification is achieved with the help of (2 things)?
1. ) Emulsification increases the surface area of lipids so pancreatic lipase acts on a larger surface area. It occurs in the duodenum.
2. )
a. ) Bile salts: Detergent property.
b. ) Peristalsis: Mechanical mixing.
69
Bile salts are derivatives of what? How is it different from its derivatives and what is the purpose of these differences?
Cholesterol. It is partly polar, with hydroxyl groups in order to conjugate them to amino acids like GLYCINE or TAURINE
70
Bile salts are made by the ____, and stored in the ______.
Made by the liver, stored in the gall bladder.
71
Describe the action of pancreatic lipase
Hydrolyzes triacylglycerols at positions 1 and 3. Thus forming 2-monoacylglycerol and TWO LCFAs (absorbed in the ileum).
72
______ stabilizes the binding of lipase to its substrate. It is secreted at a _____ and is activated by ______
Pancreatic colipase. It is secreted as a zymogen and is activated by trypsin.
73
_____ is an inhibitor of pancreatic lipase (weight loss drug)
Orlistat
74
1. ) Describe the structure of phospholipids
| 2. ) Where are phospholipases released from and what do they do?
1. ) Fatty acids at the one and two carbon positions, and a phosphate group at the third carbon position.
2. ) Released from pancreas in pancreatic juice, they hydrolyze phospholipids into fatty acids and other lipophilic substances.
p. 330
75
1. ) What is a phospholipase?
2. ) Describe the actions of the four different kinds
3. ) Where are phospholipases produced?
1. ) It is an enzyme that hydrolyzes phospholipids at certain positions
2. )
a. ) Phospholipase A1: Hydrolyzes the fatty acid at carbon 1.
b. ) Phospholipase A2: Hydrolyzes the fatty acid at carbon 2.
c. ) Phospholipase C: Hydrolyzes the phosphate at C3 proximal to the phosphate.
d. ) Phospholipase D: Hydrolyzes distally to the phosphate, leaving it intact, leaving behind diacylphosphatic acid.
76
1. ) Dietary and biliary phospholipids are mainly digested by ________
2. ) Where does it cleave and what are the products?
1. ) Phospholipase A2
| 2. ) Cleaves the FA at C2, releasing ARACHIDONIC ACID and lysophospholipids.
77
Fatty acids and lysophospholipids are absorbed in the _____ from ______.
Absorbed in the ILIUM from MIXED MICELLES
78
1. ) What does cholesterol esterase do?
2. ) Where does it come from ?
3. ) What increases the activity of this enzyme?
1. ) It removes the fatty acid at the 3 position of cholesterol, leaving behind cholesterol and fatty acid.
2. ) Pancreas
3. ) Bile salts
p. 330
79
Where is free cholesterol absorbed?
It is absorbed in the duodenum and jejunum.
80
What is colipase?
A protein coenzyme required for optimal enzyme activity of pancreatic lipase.
81
What is contained within mixed micelles?
20-30 molecules of...
Fatty acids, cholesterol, monoacylglycerol, and lysophospholipid.
Also fat soluble vitamins: Vitamins A, D, E, and K.
82
How does the micelle cross the brush border into the enterocyte?
THEY DON'T. Micelles are in dynamic equilibrium between micelle breakdown and formation (micelles --> monomeric molecules in aqueous phase), and this allows THE MONOMERIC LIPIDS to cross membrane. *It is the MONOMERIC LIPID that is actually absorbed into the enterocyte*
83
What do bile salts do within the context of lipid absorption?
They increase the concentration of the monomeric lipid molecules in the unstirred aqueous layer that are available for absorption,
84
Free cholesterol is absorbed via _____ in the _____ and _______
Via NPC1-L1 protein in the DUODENUM and JEJUNUM.
85
What lipids are absorbed in the proximal 2/3 of the ileum (3)?
fatty acids, 2-monoacylglycerol, and lysophospholipids
86
1-2.) What happens to bile salts after they have emulsified fat for digestion (2 general steps)?
3.) When is the name of this bile acid circulating process?
1. ) They are deconjugated and absorbed via ILEAL BILE ACID TRANSPORTER into the TERMINAL ILEUM.
2. ) Bile acids are then transported to the liver where they are reconjugated and recirculated.
3. ) Enterohepatic circulation of bile
87
Describe the location and function of cholecystokinin (CCK), i.e. what what does it act on, what does it cause to happen.
- Produced by the I-cells in the duodenum and jejunum.
- It acts on:
a. ) The gall bladder to release bile, and...
b. ) Exocrine cells of the pancreas (Exocrine pancreas: release bicarbonate and enzyme to release pancreatic lipase. Endocrine function releases insulin and glucagon into the blood stream), phospholipase, cholesterolesterase, etc.
88
Pancreatic secretion is ______ controlled...by what and how (2 things)
Hormonally, by CCK and secretin.
1. ) CCK: -Produced by the I-cells in the duodenum and jejunum.
- It acts on:
a. ) The gall bladder to release bile, and...
b. ) Exocrine cells of the pancreas (Exocrine pancreas: release bicarbonate and enzyme to release pancreatic lipase. Endocrine function releases insulin and glucagon into the blood stream), phospholipase, cholesterolesterase, etc.
2. ) Secretin: Produced by duodenal S cells in response to chyme activity. Stimulates bicarbonate secretion by the pancreas.
89
What happens mixed micelle lipids after arriving to the enterocyte?
They are resynthesized and repackaged (TAG, PPL, cholesterol esters) into chylomicron, which go out into lymphatic circulation.
90
What can impair lipid digestion/absorption?
- Pancreatic insufficiency: cystic fibrosis, pancreatic cancer.
- Cholestasis (decreased bile flow): Gall stones.
- Inflammatory bowel disease: Celiac sprue (gluten, wheat, and barley sensitivity), Crohn disease (autoimmune disease of intestines)
- Bowel resection: Cut out length and affect area of resorption.
91
Lipid malabsorption interferes with absorption of what important coenzymes?
Fat soluble VITAMINS A, B, E, and K.
92
If you can't release bile, intestinal enzymes, or have some kind of intestinal damage, what are the medical consequences (3 things)?
Steatorrhea:
a. ) Increased fecal excretion of TAG
b. ) Foul smelling, loose, fatty stools
c. ) Fecal incontinence
93
What is a glycoconjugate?
"Glycoconjugate" is the general classification for carbohydrates covalently linked with other chemical species such as proteins, peptides, lipids and saccharides. Glycoconjugates are formed in processes termed glycosylation.
94
What are the precursors to De novo fatty acid synthesis (3)?
Acetyl CoA, NADPH, ATP
| p.345
95
Where can acetyl CoA come from?
Carbohydrates, amino acids
96
1. ) What is the first fatty acid made de novo (with numeric nomenclature)?
2. ) How is this activated to become substrate for future FAs?
3. ) What becomes the substrate for all future fatty acids?
1. ) Palmitic acid (16:0)
2. ) By elongation (addition of carbons), and by desaturation (addition of cis double bonds)
3. ) Palmitoyl CoA (activated palmitic acid)
pp. 350-351
97
What are the two major sources of NADPH for fatty acid synthesis?
1. ) Hexose monophosphate shunt (PPP): Two NADPH produced for each molecule of glucose that enters the pentose phosphate pathway.
2. ) Malic enzyme: The cytosolic conversion of malate to pyruvate also produces cytosolic NADPH (and CO2).
p. 350
98
Describe the three phases of fatty acid synthesis (with two sub-steps each)
1.) Phase 1: Cytosolic entry of acetyl CoA
-Acetyl CoA is made in the mitochondria (by pyruvate dehydrogenase reaction)
-Citrate shuttle is used for its transport to cytosol (acetyl CoA cannot cross mitochondrial inner membrane)
2.) Phase 2: Generation of malonyl CoA
-Activated carrier of two carbon units
-Acetyl CoA carboxylase generates malonyl CoA
3.) Phase 3: Fatty acid chain formation
-Fatty acid synthase, a 7 enzyme complex + Acyl carrier protein (ACP)
-Palmitic acid is the end product
STARTS on p.347
99
What causes citrate to be transported out of the mitochondria and into the cytoplasm, instead of being metabolized by the TCA cycle.
Citrate accumulates in mitochondria due to high [ATP] and [NADH] that inhibit isocitrate dehydrogenase (enzyme that metabolizes citrate in TCA cycle)
p.346
100
What stimulates citrate lyase to breakdown citrate in the cytoplasm to form the precursors for FA synthesis?
High levels of glucose and insulin cause ATP citrate lyase to convert citrate into Acetyl CoA and oxaloacetate
101
What compounds inhibit ATP citrate lyase?
Polyunsaturated fatty acids (PUFA) and LEPTIN inhibit ATP citrate lyase.
102
1. ) How is acetyl CoA activated in phase 2 of FA biosynthesis?
2. ) What activates the enzyme used in this step?
3. ) What inactivates the enzyme used in this step?
4. ) Why is this step very significant?
1. ) The enzyme acetyl CoA carboxylase adds CO2 (usually in the form of bicarbonate or carbon dioxide) to acetyl CoA, thus generating MALONYL CoA.
2. ) Activated by citrate and insulin
3. ) Inactivated by LCFA, PUFA, glucagon, epinephrine, and AMP (signifies a low energy state).
4. ) It is the committed and RATE-LIMITING STEP of FA synthesis.
103
1. ) What type of reaction is used to convert acetyl CoA to malonyl CoA?
2. ) This reaction is _____-dependent (hint: it is a vitamin)
3. ) What is the main function of the above vitamin and what other enzymes are also dependent on it?
1. ) Carboxylation
2. ) Biotin-dependent
3. ) Biotin functions as a CO2 carrier for several important reactions involving the following enzymes: Acetyl CoA carboxylase, pyruvate carboxylase, propionyl CoA carboxylase.
104
Describe the salient features of fatty acid synthase
Fatty acid synthase (a 7 enzyme complex that acts AS A DIMER) a dimer with two identical polypeptide chains that are arranged HEAD TO TAIL (each polypeptide monomer contains ALL SEVEN activities and an ACP, i.e. acetyl protein carrier).
105
Fatty acids are synthesized from the ____-end to the ____-end.
Omega-end (methyl end), to the alpha-end (carboxylic acid end).
106
Describe phase 3 of fatty acid synthesis (7 steps)
1. ) ACP-SH (of fatty acid synthase complex) binds acetyl-CoA via AT (Acetyl CoA:ACP Transacylase)
2. ) Acetyl-CoA transferred to Cys-SH, which now comprises the OMEGA end (leaving a free ACP-SH available).
3. ) ACP-SH now binds Malonyl-CoA via MT (malonyl CoA:ACP Transacylase)
* Elongation Steps 4-7*
4. ) Acetate from Cys transferred to ACP group in a CONDENSATION REACTION (loss of CO2). Now a four-carbon group with TWO CARBONYL GROUPS, alpha and beta (beta needs to be removed).
5. ) ß-carbonyl removed via REDUCTION REACTION.
6. ) Enol formed in a DEHYDRATION reaction.
7. ) Enol reduced into a four-carbon chain that now is beginning to resemble a fatty acid.
* **THIS MUST BE REPEATED SEVEN TIMES (with two carbons added each time), in order to get the desired 16 carbon chain***
5. )
107
What are the four crucial reaction types involved in fatty acid synthesis?
1. ) Condensation
2. ) Reduction
3. ) Dehydration
4. ) Reduction
108
1. ) When a FA reaches the 16C length, intrinsic ______ activity of FAS releases the _______.
2. ) Where does the fatty acid end up after this step?
1. ) Intrinsic THIOESTERASE 1 activity of FAS releases the PALMITATE.
2. ) It is transferred to a molecule of water (hydrolysis) and into the aqueous medium of cytoplasm.
109
Explain when/how shorter chain length FA (8-12C) are made in mammalian FA synthesis
In lactating mammary epithelial cells, Thioesterase II, a discrete cytosolic protein, hydrolyzes shorter chain leng FA (8-12C) from the FAS complex.
110
What is the substrate for odd-chain and branched-chain FA?
Propionyl CoA (3C), as opposed to Acetyl CoA (which is 2C). Thus, when you add two C's at a time, you end up with an odd number of C's.
111
How are branched-chain FAs made in the FAS?
By initiating FAS with CoA derivatives of BRANCHED-CHAIN KETO ACIDS (products of Leu, Ileu, and Val).
112
What is required for the two reduction reactions in the FAS?
Energy (reducing equivalent) in the form of NADPH
113
How many levels is FA synthesis regulated at? Describe the regulation of FA synthesis and how it is achieved.
Regulated at three levels:
1. ) ATP:Citrate lyase --> Induced by glucose/insulin
2. ) Acetyl CoA carboxylase (most stringently regulated enzyme in FAS): Short-term regulation via allosteric regulation, and covalent modification. Long-term regulation via gene expression, e.g. High carb/low fat diet = increased acetyl CoA carboxylase activity, Fasting of high fat diet = supressed endogenous synthesis is supressed because of reduced acetyl CoA carboxylase activity.
3. ) Fatty acid synthase: Regulated with a long-term gene expression mechanism --> Insulin and feeding INCREASE fatty acid synthase activity, while PUFA and fasting DECREASE it.
114
Describe the short-term allosteric regulation of acetyl CoA carboxylase (ACC)...3 things
1. ) ACC is inactive as a dimer, and is active as a polymer
2. ) Citrate promotes polymerization of ACC
3. ) LCFA-CoA's inhibit polymerization.
115
Describe the long-term covalent modification regulation mechanism of acetyl CoA carboxylase:
1. ) What covalent modification activates/inactivates ACC?
2. ) What enzymes are involved and what is their mechanism?
3. ) There is an ATP dependent step, what is it and what is it mediated by?
4. ) What regulates the above step?
* **FAS requires LOTS OF ENERGY, therefore, under LOW ENERGY CONDITIONS, FAS IS INHIBITED**
1. ) ACC is inactive when phosphorylated, and active when dephosphorylated.
2. ) Insulin activates PROTEIN PHOSPHATASE, which in turn DEPHOSPHORYLATES ACC to the active form
3. ) AMP-dependent kinase (AMPK) converts active ACC (dephosphorylated) into the inactive ACC (phosphorylated).
4. ) Glucagon, epinephrine, AMP, and cyclic AMP activate AMPK, and are therefore NEGATIVE REGULATORS.
116
Name four negative regulators of FAS
Glucagon, epinephrine, AMP, cyclic AMP.
117
What is the initial substrate for the elongation of FA? Give numeric nomenclature as well.
Palmitate (16:0)
118
Where do the elongation steps of FAS occur? Describe the elongation steps of FAS, including location, enzymes, and reducing equivalents (four things)
* The elongation steps occur in either SMOOTH ER or MITOCHONDRIA*
1. ) Palmitate is activated to palmitoyl CoA by Acyl-CoA synthetase (using ATP).
2. ) Same four reactions in FAS are repeated, i.e. condensation, reduction, dehydration, reduction.
3. ) ELONGASE (enzyme) uses either malonyl CoA (smooth ER) or acetyl CoA (mitochondria) as the 2-carbon donor.
4. ) NADPH supplies reducing equivalents
119
Where does elongation of fatty acids occur? What enzymes are used?
Occurs in SMOOTH ER (malonyl CoA) and in MITOCHONDRIA (acetyl CoA)
120
If the numeric nomenclature for a FA includes ∆9, what does this signify?
That there is a double bond between carbons C9 and C10.
121
1. ) What is desaturation of a FA?
2. ) Where on the FA can/does it occur?
3. ) What carries out this process and in what location within the cell?
4. ) What types of omega fatty acids are possible for humans to make?
1. ) Formation of double bonds
2. ) ∆4, ∆5, ∆6, ∆9
3. ) Desaturases within the ER
4. ) Omega 9 or less
122
Polyunsaturated Fatty Acids (PUFAs) are formed only through a combination of _____ and _______.
Through a combination of ELONGATION and DESATURATION reactions.
123
Desaturation of FA involves what three proteins? What is each role?
1. ) NADH-Cytochrome b5 reductase: FAD to FADH2
2. ) Cytochrome b5: Fe3+ to Fe2+
3. ) Desaturase: Stearyl CoA to oleyl CoA
124
_______ induces ∆9-desaturase, but represses ______.
Dietary cholesterol induces, but REPRESSES OTHER DESATURASES.
125
Describe the general structure of triacylglycerol
Usually contain a saturated FA on C1, an unsaturated FA on C2, and is variable on C3.
126
What are the precursors for triacylglycerol?
Glycerol 3-P and fatty acyl CoA
127
How are TAGs typically stored?
Stored mostly in adipose tissue, but also in lipoproteins circulating in serum (dLDL)
128
What are the two ways the body can synthesize Glycerol 3-P...enzymes, location (3)?
Liver:
a. ) From dihydroxyacetone phosphate (DHAP) using the enzyme glycerol-P-dehydrogenase. REQUIRES NADH.
b. ) From glycerol, using GLYCEROL KINASE.
Adipose tissue: Only from DHAP, because glycerol kinase is absent in adipose tissue.
129
How is TAG synthesis regulated in the liver, i.e. activation and inhibition of enzymes (3)?
1. ) GPAT and MGAT are activated by insulin (high-energy state), inhibited by AMP-activated kinase (low-energy state).
2. ) PAP (lipin1) gene is induced by fasting, cAMP and glucocorticoids and is inhibited by insulin.
3. ) DGAT expression is induced by insulin.
130
Deficiency of what compound is associated with congenital generalized lipodystrophy (absence of adipose tissue and fatty liver)?
Deficiency of AGPAT2
131
This overexpressed compound is the target for cancer research
AGPAT2
132
What enzymes are involved in TAG synthesis in the small intestine (2)?
1. ) MGAT: monoacylglycerol to diacylglycerol
| 2. ) DGAT: diacylglycerol to TRIacylglycerol
133
Which enzyme involved in TAG synthesis is being targeted as a treatment for obesity?
DGAT
134
Complete oxidation of one molecule of palmitic acid (16:0) can yield how many ATP?
129 ATP
135
Fat is stored in adipose tissue, but is oxidized in which part of the cell, in which organs (2)?
In the MITOCHONDRIAL MATRIX of LIVER and MUSCLE
136
No FA oxidation occurs in the ______, or in cells that lack ______.
No FA oxidation occurs in the BRAIN, or in cells that lack mitochondria (e.g. RBCs).
137
What enzyme generates fatty acids from triacylglycerol in adipocytes (activation and inhibition)? What hormones regulate its function (3)?
Hormone-sensitive lipase (a G-couple protein receptor): It is ACTIVATED (phosphorylated) by ACTIVE PROTEIN KINASE in response to EPINEPHRINE and GLUCAGON via a G-protein coupled receptor.
It is INHIBITED by INSULIN.
138
How are released FAs transported to liver and muscle?
By SERUM ALBUMIN
139
1. ) _____ from from released FAs is used for gluconeogenesis in the liver.
2. ) What two specific portions from the above compound are used for gluconeogenesis?
1. ) Glycerol
| 2. ) DHAP and glyceraldehyde 3-phosphate
140
Describe the ß-oxidation pathway
1. ) # of carbons intended for
2. ) Where is occurs
3. ) Action
1. ) Major pathway for <20C
2. ) Occurs in MITOCHONDRIA of LIVER and MUSCLE
3. ) Involves oxidation of ß-carbon (C3 from carboxyl end) to release acetyl CoA
141
Describe the omega oxidation pathway:
1. ) # of carbons intended for
2. ) Where is occurs
3. ) Action
1. ) Minor pathway used normally for SCFA substrates (<6C)
2. ) Occurs in the ER
3. ) Makes dicarboxylic acids by oxidating the OMEGA END
142
Describe alpha-oxidation pathway of FA:
1. ) # of carbons intended for
2. ) Where is occurs
3. ) Action
1. ) Minor pathway with no energy yield (removal of carboxyl group on PHYTANIC ACID...a branched acid)
2. ) Occurs in PEROXISOMES.
3. ) Removal of carboxyl group on PHYTANIC ACID...a branched acid
143
Describe the peroxisomal ß-oxidation pathway of FAs:
1. ) # of carbons intended for
2. ) Where is occurs
3. ) Action
1. ) VLCFA (>20C)
2. ) Peroxisomes
3. ) Produces slightly less energy than mitochondrial system
144
Describe phase 1 of ß-oxidation degradation (3 steps)
Phase 1: Transport of FA into mitochindria
1. ) Activation of FA to acyl CoA
2. ) Transfer of FA to Carnitine (carrier)
3. ) Carnitine shuttle employed to transport FA into mitochondria.
p. 357
145
Describe phase 2 of ß-oxidation of FA (4 steps). How does this resemble FA synthesis?
Phase 2: Repeated cycles of 2-carbon removal.
1. ) Dehydrogenation (Reduction)
2. ) Hydration (Dehydration)
3. ) Dehydrogenation (Reduction)
4. ) Thiolysis (Condensation)
146
1. ) Where does activation of FA to ACYL CoA occur?
2. ) Where/what is its catalyzing enzyme?
3. ) What are the reactants and products, and what does it take to convert reactants to products (i.e. what is the energy state of this reaction?)
1. ) Reaction takes place in the cytosolic phase of the outer mitochondrial membrane.
2. ) Acyl CoA synthetase on outer mitochondrial membrane.
3. ) Fatty acid + CoA --> Acyl CoA via TWO EXERGONIC REACTIONS (ATP to AMP + PPi, and then PPi to 2Pi).
147
Acyl CoA synthetases are found in what three places?
1. ) ER
2. ) Outer mitochondrial membrane
3. ) Peroxisomal membrane
148
The activation of FA to Acyl CoA consumes the equivalent of how much energy?
Two ATP
149
Where does fatty acid synthesis occur in humans (3 places)?
1. ) Liver
2. ) Lactating mammary glands
3. ) Adipose tissue (to a lesser extent than the previous two)
p. 345
150
Once Acyl CoA is within the intermitochondrial membrane, how does pass through the inner mitochondrial membrane, which is impermeable to CoA?
Through the formation of Acyl Carnitine (addition of Acyl CoA to carnitine) and release of CoASH.
151
What are the main sources of carnitine (3)?
1. ) Diet (meat)
2. ) Limited synthesis in liver and kidneys from lysine and SAM
3. ) Heart and skeletal muscle cannot make carnitine, but have high affinity uptake.
152
1. ) What enzymes carry out the forward and reverse reaction of adding carnitine to fatty acyl CoA?
2. ) _____ and ______ can cross the IMM without the help of carnitine.
1. ) Carnitine palmitoyl transferase (CPT)
a. ) CPT-1 in OMM (foreward)
b. ) CPT-2 in IMM (reverse)
2. ) Short and medium chain acyl CoAs
153
1. ) What is the rate-limiting step in fatty acid oxidation?
| 2. ) What is the regulator for this step and through which method?
1. ) CPT-1 (p.357)
| 2. ) Malonyl CoA (negative allosteric regulator), a product of fatty acid synthesis
154
When _____ is low, CPT-1 can be active in fatty acid synthesis
Malonyl-CoA
155
Describe the step for regulation of CPT-1 (3)
1. ) ACC converts acetyl CoA into malonyl CoA
2. ) Malonyl CoA inhibits CPT-1
3. ) AMP (low energy) inhibits ACC and stimulates the breakdown of malonyl CoA to acetyl CoA
156
Each cycle in phase 2 of FA ß-oxidation contains which four steps?
1. ) Oxidation (double-bond formed), FADH2 formed
2. ) Hydration, H2O used
3. ) Oxidation, NADH formed
4. ) Lysis, CoA used
157
Each cycle in phase 2 of FA ß-oxidation yields what 3 products?
1. ) 1 FADH2
2. ) 1 NADH
3. ) 1 acetyl CoA
158
A deficiency of MCAD causes what metabolic disorder? Describe what deficiencies this leads to.
Hypoketotic hypoglycemia: Leads to deficiency of both ATP and acetyl CoA (which are needed for gluconeogenesis because Acetyl CoA is the OBLIGATORY ALLOSTERIC ACTIVATOR of PYRUVATE CARBOXYLASE [PC]).
159
MCAD deficiency leads to low acetyl CoA, which leads to low _____
Ketone bodies (hypoketonia)
160
What are two diagnostic markers for MCAD deficiency?
1. ) C8, and C10 carnitine accumulation in blood and urine
| 2. ) Dicarboxylic acids produced by omega-oxidation of MCFA in the blood and urine
161
What are the a.) causes (1), b.) mechanisms (2), and c.) consequences (3) of Jamaican Vomiting Sickness?
a. ) Caused by Hypoglycin A (toxic amino acid)
b. ) Metabolic products sequester carnitine and CoA, which inhibits ß-oxidation of fatty acids.
c. ) Sudden onset of vomiting, severe HYPOGLYCEMIA, generalized weakness, altered consciousness and death.
162
Compare and contrast FA synthesis and degradation
Chart on p.357
163
1. ) Hormonal regulation of TAG degradation (lipolysis) occurs at the level of ______ (___).
2. ) What stimulates and inhibits?
1. ) Hormone-Sensitive Lipase (HSL)
| 2. ) Glucagon/epinephrine stimulate HSL, Insulin inhibits HSL
164
The last cycle of odd-chain FA oxidation yields ______ (#C's?), which is a precursor for what?
Propionyl CoA (3C), which is a precursor for glucose (leads to gluconeogenesis) *UNLIKE EVEN-CHAIN FAs, WHICH YIELD ACETYL CoA which is not a precursor*
165
Propionyl CoA is metabolized to _______ via ________
Metabolized to SUCCINYL CoA via METHYLMALONYL CoA.
166
1. ) What deficiencies (2) cause problems in the oxidation and metabolism of ODD-CHAIN FATTY ACIDS?
2. ) What are the consequences?
1. )
a. ) Mutase
b. ) Vitamin B12
2.) Methylmalonic aciduria, Metabolic acidosis, mental retardation
167
Unsaturated fatty acids generate _______ ATP than their saturated counterparts OF THE SAME LENGTH. Why?
5 ATP less, because of the additional enzymes needed (NADPH dependent enoyl CoA reductase and isomerase)
168
VLCFA oxidation is done how? What is its energy output?
- Peroxisomal beta oxidation
- Normally produced 2 ATP NOT PRODUCED because electrons go to create water (no ETC or TCA) ***MAKE SURE THIS IS RIGHT***
169
1. ) Where does phytanic acid in humans come from?
2. ) How is it metabolized?
3. ) How much energy is produced?
1. ) Produced from chlorophyll and a component of some dairy products and fish.
2. ) Alpha-carbon MUST FIRST BE METABOLIZED, then can be metabolized by ß-oxidation
3. ) NO ENERGY PRODUCED (WHY? FIND OUT) --> No reducing equivalents produced!
170
Describe disorders of the carnitine shuttle (4)
1. ) Primary carnitine deficiency: hepatic synthesis, renal reabsorption, nutritional, transporter.
2. ) CPT-2 defects (muscle)
3. ) CPT-1 or CACT defects (lethal at a young age)
4. ) Secondary carnitine deficiency: Accumulation of acyl carnitines (inhibit renal absorption of carnitine) due to CPT-2 or CACT defects
171
How to treat carnitine deficiencies (4)?
1. ) High carb/low LCFA diet
2. ) Increase MCFA content
3. ) Limit physical activity
4. ) Carnitine supplements
172
1. ) Omega-oxidation of FA is a minor pathway unless what?
| 2. ) Explain omega-oxidation (where, how, what, products)
1. ) ß-oxidation is defective, e.g. MCAD deficiency (medium-chain acyl CoA dehydrogenase).
2. ) Omega-oxidation occurs in the ER and is carried out by the CYTOCHROME P-450 SYSTEM to yield DICARBOXYLIC ACID.
173
With an MCAD deficiency, what can one expect to find accumulated in the blood?
Medium-chain carboxylic acids (C6-C10), and their conjugates with carnitine and glycine can be found in the urine.
174
1. ) A deficiency of ________ prevents alpha-oxidation of phytanic acid.
2. ) What disease does this cause?
3. ) What are some symptoms (4)?
1. ) phytanyl CoA hydrolase
2. ) Adult Refsum Disease
3. )
a. ) Cerebellar ataxia
b. ) Peripheral polyneuropathy
c. ) Retinitis pigmentosa
d. ) Hearing loss
175
Describe the cause and symptoms of adrenoleukodystrophy (aka ______)
aka X-ALD: It is an X-linked defect in ABCD1 that transports VLCFA CoAs into peroxisomes. It causes VLCFA to build up in the brain, causing mental retardation.
176
Describe Zellweger Syndrome (pathology, syptoms)
A spectrum of disorders in the biogenesis of peroxisomes.
177
1. ) What causes Infantile Refsum Disease?
| 2. ) What are symptoms (2)?
1. ) Defect in peroxins
| 2. ) Decreased cerebral mylenation, and a loss of hearing and vision
178
1. ) Accumulation of which two ketone bodies can cause metabolic acidosis? What is their pKa?
2. ) Where do they come from?
3. ) Under what conditions does this occur and how?
1. ) Acetoacetate and D-ß-Hydroxybutyrate (both pKa 3.5)
2. ) Acetyl CoA from the LIVER MITOCHONDRIA (only made in the liver!!!)
3. ) Increased lipolysis leads to increased delivery of FA to the liver, e.g. Fasting, Type 1 Diabetes.
p. 364
179
What causes production of excess ketone bodies?
Increased FA ß-oxidation produces acetyl-CoA -- Excess acetyl-CoA in LIVER MITOCHONDRIA leads to production of ketone bodies.
180
What is a common intermediate (but used for two different things) between cholesterol synthesis and ketogenesis? Where is it synthesized in both cases?
HMG CoA:
a. ) In cholesterol synthesis, HMG CoA is synthesized in the cytoplasm.
b. ) In the formation of ketone bodies, HMG CoA is synthesized in LIVER MITOCHONDRIA.
181
Why doesn't the liver utilize ketone bodies for energy, and only exports them?
Because the liver lacks THIOPHORASE, and thus cannot catabolize ketone bodies.
182
Ketone bodies are ____ fuel for _____ and ______ during _______?
Ketone bodies are SOLUBLE fuel for MUSCLE (spares glucose) and BRAIN (after 8-12 weeks) during STARVATION.
p.364
183
How are ketone bodies used for fuel? How much energy does their metabolism produce (2 different compounds)?
They can be converted to acetyl CoA (HOW, WHERE?) --> Acetyl CoA (via the TCA cycle) can be converted to ACETOACETATE (23 ATP), and ß-hydroxybutyrate (26 ATP)
184
Acetone in the breath (from what?), gives the breath a ____ odor. When would this occur?
Acetone in the breath from KETONE BODIES NOT METABOLIZED, gives the breath a FRUITY ODOR. This occurs in patients with uncontrolled TYPE 1 DIABETES (diabetic ketoacidosis).
185
1. ) What causes Diabetic Ketoacidosis?
2. ) What are the physiologic parameters that lead to this?
3. ) What are the consequences of these parameters (a-h)?
1. ) Uncontrolled diabetes and, ultimately, increased KETONE BODIES.
2. ) Decreased insulin, increased glucagon
3. ) Glucagon effects:
a. ) Increased HSL, TAG lysis
b. ) Decreased Malonyl CoA
c. ) Increased CPT-1, FA oxidation
d. ) Increased Acetyl CoA
e. ) Increased NADH
f. ) Decreased TCA cycle
g. ) Increased PC, PEPCK
h. ) Decreased OAA and citrate
186
1. ) Nonpolar lipids, e.g. _____ (1), are found where?
| 2. ) Polar lipids, e.g. _____ (2), are found where? Describe one of their key characteristics.
1. ) Nonpolar lipids, e.g. triacylglycerols (TAGs) are used for LIPID STORAGE, mainly confined to ADIPOSE TISSUE.
2. ) Polar lipids, e.g. phospholipids, sphingolipids, are found mainly in membranes. Polar lipids are AMPHIPATHIC (contain both hydrophobic and hydrophilic domains in the same molecule).
187
1. ) Describe the composition of glycerophospholipids (3)
| 2. ) Describe the composition of sphingolipids (3)
1. ) Glycerol backbone, two FA (ester linkages), polar head group linked by PO4.
2. ) Sphingosine backbone, one FA (amide linkage), polar head group which is usually sugar(s)
188
What are five possible head groups (2 of them sugars) to be found on glycerophospholipids (aka _______)?
Glycerophospholipids (aka PHOSPHOLIPIDS)
1. ) Ethanolamine
2. ) Choline
3. ) Serine
4. ) Glycerol (sugar)
5. ) Myo-Inositol (sugar)
189
1. ) Describe the salient feature (i.e. polar head group) of the three most common phospholipids found in humans.
2. ) What is the other common name for phosphatidylcholine?
1. )
a. ) Phosphatidylethanolamine: OH—CH2—CH2—NH3+
b. ) Phosphatidylcholine: OH—CH2—CH2—N+—(CH3)3
c. ) Phosphatidylserine: OH—CH2—CH*—NH3+ (COO-) <--would be coming DOWN off of starred CH*
2.) Lecithin
190
What is the other common name for phosphatidylcholine?
Lecithin
191
Describe the primary pathways of phospholipid biosynthesis (one pathway for 2 different polar groups added)
A.) When the polar group to be added is a SUGAR ALCOHOL...
1. )Phosphatidic acid is activated to CDP-DAG
2. ) Glycerol or inositol can then be added to CDP-DAG by a TRANSFERASE, which will generate...
3. ) Phosphatidylglycerol (PG) or phosphatidylinositol (PI)
B.) When the polar group to be added is a NITROGENOUS BASE...
1. ) Nitrogenous base is activated by CDP...
2. ) Then added to DAG, which will generate...
3. ) Phosphatidylcholine (PC) or phosphatidylethanolamine (PE)
192
Describe the secondary pathway of phospholipid biosynthesis (and why it is used as opposed to the primary pathway)
It is used instead of the primary pathway WHEN DIETARY CHOLINE IS DEFICIENT (choline is an essential nutrient). When choline levels are low...
-Phosphatidylethanolamine (PE) can be converted to phosphatidylcholine (PC) by transferring groups from S-adenosyl methionine (SAM)
193
What is the biosynthesis pathway used to generate phosphatidylserine (PS)? Describe
Phosphatidylserine (PS) is made by BASE EXCHANGE.
| -In this pathway, the ethanolamine from PE is exchanged for serine in order to produce PS.
194
1. ) Which type of phospholipid is important for lung function? Describe its function.
2. ) Describe it composition
3. ) What does it prevent?
4. ) What is it produced by?
1. ) A type of phosphatidylcholine (PC) called DIPALMITOYLLECITHIN (DPPC) is important for lung function.
- More than 80% of surfactant phospholipid in the extracellular fluid layer that lines the lung alveoli is DPPC
2. ) Glycerol molecule, phosphocholine on C3, and both R1 and R2 are palmitic acid.
3. ) It prevents the lung from collapsing (atelectasis) at the end of the expiration phase of breathing.
4. ) It is produced by Type 2 Alveolar epithelial cells.
195
1. ) What ratio is measured during fetal gestation to determine fetal lung capacity?
2. ) What ratio # indicates fetal lung maturity?
3. ) During what weeks of gestation does the ratio sharply increase?
1. ) Lecithin:sphingomyelin
2. ) A ratio >2 in amniotic fluid is indicative of fetal lung maturity
3. ) 31-34 weeks
196
What drug is administered to a mother shortly before delivery is fetal lung IMMATURITY is suspected?
Dexamethasone (steroid)
197
How is lung surfactant biosynthesis regulated (what general method, and what compounds [3]?
Surfactant biosynthesis is HORMONALLY REGULATED by...
1. ) Corticosteroids
2. ) Thyroxine
3. ) Catecholamines
198
Insufficiency of which phospholipid leads to a serious lung disorder? What is the lung disorder?
Insufficiency of Dipalmatoyllecithin (DPPC) leads to Infant Respiratory Distress Syndrome (IRDS)
199
A deficiency of surfactant in adults causes what lung dysfunction?
Adult Respiratory Distress Syndrome (ARDS)
200
1. ) What is CARDIOLIPIN? Describe its composition, chemical properties, location and function.
2. ) What are pathologies associated with its deficiency (3)?
1.) Cardiolipin is an ACIDIC PHOSPHOLIPID found in the INNER MITOCHONDRIAL MEMBRANE and in BACTERIAL MEMBRANE.
It is composed of two molecules of PHOSPHATIDIC ACID linked together covalently through a molecule of GLYCEROL.
2.) Anti-cardiolipin antibodies have been detected in anti-phospholipid syndrome (APS), SYPHILIS INFECTION, and in SYSTEMIC LUPUS ERYTHOMATOSUS.
201
1. ) What is Platelet Activating Factor (PAF)? Describe its composition (3) and function (2)
2. ) What does its synthesis and release do?
1. ) Platelet Activating Factor (PAF): Ester linked saturated FA at C1, Acetyl ester at C2, phosphocholine at C3.
a. ) Activates inflammatory cells
b. ) Mediates hypersensitivity, acute inflammatory and anaphylactic reactions.
2. ) Synthesis and release of PAF causes...platelet aggregation and release of serotonin (catecholamine) from platelets.
202
Describe FOUR important functions of Phosphoinositides (PI)
1. ) PIP2 is the source of TWO signaling molecules in G signaling.
2. ) PI is also an intermediate in PI 3-kinase signaling by INSULIN.
3. ) PI is a component of GPI anchors (?)
4. ) C2 of PI is esterified with ARACHIDONIC ACID (20:4), which is the precursor of eicosanoids.
203
1. ) Describe the composition of Plasmalogens.
2. ) Describe TWO important plasmalogens and where they are found.
3. ) Describe the general functions of plasmalogens (2) and which compounds their biosynthesis involves (2).
1.) In plasmalogens, O-(1-alkenyl) occurs at C-1 of glycerol
2. )
a. ) Ethanolamine plasmalogen is abundant in MYELIN
b. ) Choline plasmalogen is abundant in the HEART.
3.) Plasmalogens may serve as antioxidants and free radical scavengers. Their biosynthesis involves both PEROXISOMES and ER.
204
What two pathologies affect plasmalogen synthesis?
1. ) Zellweger syndrome
| 2. ) X-ALD
205
______ is a therapeutic target in the treatment of Alzheimer Disease and stroke (e.g. halopemide)
Phospholipase D
206
Describe the action of the following in the degradation of phospholipids, and where they are found
1. ) Phospholipase A1
2. ) Phospholipase A2
3. ) Phospholipase C
4. ) Phospholipase D
1. ) Removes FA at C1. Present in many mammalian tissues.
2. ) Removes FA at C2. Present in mammals.
3. ) Cleaves between glycerol and phosphorylated head group. Found in liver lysosomes and bacilli. It is activated by the PIP2 system.
4. ) Cleaves the head group distal to the phosphate. Found in plant and mammal tissue.
207
Phospholipase D plays a role in ______ and in _______
ß-amyloid formation and in thrombosis.
208
1. ) What is the only significant sphingophospholipid found in humans? What role does it play?
2. ) What other compound that it has an affinity for is the above compound often found coexisting with in a cell?
1. ) Sphingomyelin: Important constituent of myelin (18% protein, 76% lipid), which insulates and protects neuronal fibers.
2. ) Cholesterol
209
1. ) Describe the two steps for sphingomyelin degradation
| 2. ) What is a pathology of compromised sphingomyelin degradation (2 types)? Describe
1. )
a. ) SPHINGOMYELINASE removes phosphocholine to leave CERAMIDE.
b. ) Ceramidase cleaves ceramide to FA and sphingosine
2. ) Niemann-Pick Disease (Type A and Type B): Autosomal recessive lipid storage disorder caused by a deficiency of ACID SPHINGOMYELINASE.
a. ) Type A (<1% of normal activity): Hepatosplenomegaly due to deposition of lipids. Also deposits in CNS, can lead to ataxia and seizures. Death by AGE 2 OR 3
b. ) Type B (5% or more activity): Less severe. Bone marrow and enzyme replacement have been useful treatments.
210
What physiological/anatomical components are glycosphingolipids essential parts of (3)?
1. ) All membranes (located on outer leaflet of the plasma membrane) *FOUND IN GREATEST AMOUNTS IN NERVE CELLS*
2. ) Carbohydrate portion is an antigenic determinant for blood groups.
3. ) Serve as surface cell receptors.
211
Describe the general composition of the FOUR main types of glycosphingolipids
1. ) Cerebrosides: Ceramide + 1 or 2 sugars (galactose or glucose)
2. ) Sulfatides: Ceramide + 1 sulfated sugar
3. ) Globosides: Ceramide + ≥3 sugars with an N-ACETYLATED SUGAR
4. ) Gangliosides: Ceramide + 3 or more sugars with SIALIC ACID (NANA)
212
Describe the pathology associated with each of the following problems in sphingolipid degradation (Sphingolipidoses --lysosomal storage disorders) AND ALSO what enzyme is defective, what will accumulate as a result, and what the consequences are.
1. ) Sulfatides
2. ) Gangliosides
3. ) Globosides
4. ) Cerebrosides to Ceramide
5. ) Sphingomyelin to Ceramide
* **MUST KNOW THIS STUFF***
1. ) Metachromic leukodystrophy: Arylsulfatase deficiency causes accumulation of SULFATIDES. (not on "to-know" list)
2.) Tay-Sachs disease: Hexosaminidase A deficiency causes accumulation of GANGLIOSIDES. *Mental retardation, blindness, death by age 3...Shows up with cherry red spot on macula!!!*
3. )
a. ) Fabry's disease (X-linked): Alpha-Galactosidase A deficiency causes accumulation of GLOBOSIDES. *Skin rash (small, dark red spots on skin ---> angiokeratomas), kidney failure, pain in lower extremities, inability to sweat, clouding of cornea, hearing loss*
b. ) Sandhoff disease: ß-Hexosaminidase A deficiency causes accumulation of GM2 and globosides. *Similar to Tay, but more rapidly progressing*
4. )
a. ) Gaucher's disease (most common): ß-Glucosidase (glucocerebrosidase) deficiency causes accumulation of GLUCOCEREBROSIDES. *Hepatosplenomegaly, erosion of long bones (osteoporosis), mental retardation in INFANTILE FORM ONLY*
b.) Krabbe's disease: Galactocerebrosidase deficiency causes accumulation of GALACTOCEREBROSIDE. *Loss of myelin, mental retardation, death by age 2*
5. ) Niemann-Pick disease (A+B): Sphingomyelinase deficiency causes accumulation of sphingomyelin. *Hepatosplenomegaly, mental retardation*
* p.395 and table in notes*
213
What does prostaglandin mean?
Hormone from a sex-related gland
214
What is our most common substrate for prostaglandin (PG) synthesis, and what risks are associated with its consumption?
Arachidonic acid (arachidonate): Potent platelet aggregant and vasoconstrictor...Leads to MI and STROKE.
215
Describe the steps in prostaglandin (PG) synthesis, which enzymes and substrates are involved, and WHAT BLOCKS CERTAIN STEPS
1. ) Fatty acid is released (from cell membrane) by phospholipase A2 activity under a stimulus --> type of fatty acid depends on recent dietary intake, e.g. plants = linolenate, red meat = arachidonate, fish = eicosapentanoate.
* **THIS STEP IS BLOCKED BY CORTICOSTEROIDS (block availability of fatty acids for PG or LT synthesis), and thus have a broad anti-inflammatory benefit***
2. ) Oxidative cyclization of free arachidonic acid to yield PGG2 and PGH2 intermediates. Catalyzed by COX1 and COX2 (inducible in some tissues).
3. ) PGH2 converted to stable prostaglandin product by TISSUE-SPECIFIC PROSTAGLANDIN SYNTHASES.
p. 397
216
Describe the action of the following PGs:
1. ) PGE2
2. ) PGF2-alpha
3. ) Thromboxane A2
4. ) PGI2
1. ) Vasodilator
2. ) Vasoconstrictor
3. ) Vasoconstrictor and platelet aggregant
4. ) Vasodilator and platelet STABILIZER
217
What are the two pathways for PG synthesis?
1. ) Cyclooxygenase pathway
| 2. ) Lipoxygenase pathway
218
1. ) What substances block the lipoxygenase PG synthesis pathway, where, and how?
2. ) What is their clinical relevance?
1. ) Zileuton: Block synthesis of LEUKOTRIENES
- Lukast substances (e.g. Montelukast, zafirlukast): Blocks leukotriene action.
2. ) Zileuton and Lukasts target anaphylaxis and severe asthma.
219
Name and describe the two enzymes that convert arachidonate to PGs
1. ) COX-1 (beneficial): THROMBOTIC (coagulant). Cellular protective --> decrease erosion, decrease acid production, improve serous and mucous secretion in the gut.
2. ) COX-2: ANTI-THROMBOTIC (anti-coagulant). Associated with osteoarthritis and pain, or rheumatoid arthritis and pain.
220
Name and describe the effects (good and bad) of COX inhibitors
- Aspirin and NSAIDs block COX-1 and COX-2 (block COX-1 = BAD)
- COX-1 inhibitors control inflammation and avoid LOSS OF PROTECTION AT COX-1 SITES (cytoprotection, antacid, thrombosis)!!!
p. 397
221
1. ) What PG and enzyme would be targeted to treat inflamed tissue tissue, pain, swelling, and redness?
2. ) What type of drug would be used and what are possible adverse side effects?
1. ) COX-2, PGE2
2. ) COX-2 selective inhibitors. However, since COX-2 is ANTI-THROMBOTIC, its inhibition can induce hypercoagulation i.e. pro-MI, pro-STROKE. BECAUSE, COX-1 is not blocked and its thrombotic effects (coagulation) coupled with the vasoconstriction of COX-2 inhibition make it potentially dangerous for some patients.
222
Describe Thromboxane A2 (TXA2) -- i.e. where/how it is produced, and its effects
- TXA2 (a prostaglandin) is produced by COX-1 in ACTIVATED PLATELETS.
- Vasoconstrictor and bronchoconstrictor. It promotes adherence and aggregation of circulating platelets and contraction of vascular smooth muscle, thereby PROMOTING FORMATION OF BLOOD CLOTS (i.e. thrombi).
p. 399
223
Describe Prostacyclin (PGI2) -- i.e. where/how it is produced, and its effects (4)
- PGI2 is produced by COX-2 in vascular endothelial cells.
- Vasodilator, bronchodilator. It inhibits platelet aggregation (stabilizes and disaggregates platelets) and stimulates vasodilation, thus IMPEDING THROMBOGENESIS.
p. 399
224
Describe Prostaglandin E2 (PGE2) -- i.e. where/how it is produced, and its effects
PGE2 (stable prostaglandin):
- Local Vasodilator (thus, a PROINFLAMMATORY = pain, swelling, redness)
- Bronchodilator (PGF2-alpha, pathogenic in ASTHMA)
- Cytoprotective in GI tract
- Regulates renal blood flow (blocking PGE2 w/ NSAIDS can cause hypertension)
- Contracts uterine smooth muscle (thus, Aspirin contraindicated during labor and delivery)
225
Name and describe the effects and mechanisms of FIVE prostaglandin-related drugs
1. ) Misoprostol: PGE analog. Protects stomach lining when using NSAIDs (miso is good for your stomach).
2. ) Dinoprostone: PGE analog. Induces labor, aborts baby.
3. ) Epoprostenol: PGI2 analog. Inhaled for treatment of pulmonary HTN.
4. ) Alprostadil: PGE analog. Vasodilates, keeps PDA open (patent ductus arteriosus).
5. ) Latanoprost: PGF2a analog. Treats glaucoma (topical), discolors eye, lengthens lashes.
* **Mnemonic: M DEAL***
226
How are the effects of PGE1 and PGE2 similar/different?
They are the SAME, they just come from a different source.
227
List and describe 4 types of PG synthesis inhibitors with examples
1. ) Aspirin: IRREVERSIBLY blocks COX-1 and 2. Analgesic (pain relief), antipyretic (fever reducer), anti-inflammatory.
2. ) NSAIDs (e.g. ibuprofen): Non-selective, REVERSIBLE COX inhibitors. Same effects as aspirin.
3. ) COX-2 selective inhibitors (e.g. Celecoxib): Anti-inflammatory.
4. ) Acetaminophen: Analgesic, antipyretic, NOT anti-inflammatory.
228
What is one of the most potent stimuli for platelet activation?
Collagen
229
High dose vs Low dose Aspirin --> effectiveness?
High-dose Aspirin will block endothelial production of COX...AS WELL AS Platelet production, which is bad. Low-dose Aspirin will allow endothelium to replenish COX, while still blocking platelet COX, which is good because we don't lose the defensive COX of endothelium.
* Endothelial cells can replenish COX because they have nuclei, whereas platelets DO NOT HAVE NUCELI*
37: 15 lecture 30
230
1. ) What is/are possible adverse effects due to taking selective COX-2 inhibitors?
2. ) What supplemental drug is suggested when taking selective COX-2 inhibitors?
1. ) When taking COX-2 inhibitors for pain, swelling, redness, etc., the anti-coagulation effects of COX-2 are also blocked, thus leaving the thrombotic effects of COX-1 to predominate. This increases the risk of a cardiovascular or stroke event.
2. ) It is suggested that ASPIRIN be taken with COX-2 inhibitors to mediate the pro-thrombotic effects of thromboxane (COX-1).
231
1. ) What are the adverse effects of leukotriene C4 and D4?
| 2. ) How can these effects be mediated (2)?
1.) Bronchoconstriction, pro-inflammatory (cause leakage of endothelium and, thus, localized edema). BRONCHOCONSTRICTION AND SWELLING OF THE AIRWAYS (ASTHMA-LIKE SYMPTOMS result from overproduction of leukotrienes).
2. )
a. ) Zileuton: Blocks LIPOXYGENASE (enzyme that converts arachidonic acid to LTC precursors). Aspirin analogue in leukotrienes.
b. ) Leukasts (e.g. montelukast, zafirlukast, etc.): Blocks end-products at the receptors.
232
What are the general effects of leukotrienes C4 and D4 (4)?
Bronchoconstriction, inflammation, local edema, asthma
233
Which leukotriene receptor antagonist is used in the treatment of asthma? Side effects?
Montelukast, aka SINGULAIR. Side effects are GI distress, bleeding and hypersensitivity.
234
What is the main end-goal of lose-dose Aspirin treatment?
Less thromboxane, maintenance of prostacyclin.
235
How does cholesterol aid in the digestion of fats?
It is a precursor to BILE ACIDS and SALTS
236
High serum cholesterol is associated with what pathology?
Atherosclerosis
237
Cholesterol is the precursor to what important vitamin that binds calcium?
Vitamin D (vitamin D3 is activated form)
238
What is the daily recommended cholesterol intake for healthy people?
< 200 mg/day
239
Which meat product(s) are highest in cholesterol?
Liver
240
What does the most significant source of energy and reducing equivalents (ATP and NADPH) for cholesterol synthesis arise from?
ATP: Glucose, fats, proteins
NADPH: Oxaloacetate (cytosol) --> Malate --[*MALIC ENZYME*]--> **NADPH** and Pyruvate
PPP (HMPS)
241
Where is steroid synthesis highest in the human body (5)?
Liver (highest), adrenal cortex, reproductive, tissues and intestines
242
What are the precursors for steroid synthesis and where do they come from?
Acetyl-CoA...from: Fat oxidation, ketogenic AA, PDH (pyruvate dehydrogenase)
243
What is the target for most cholesterol-reducing drugs? Describe
HMG-CoA reductase: Integral protein of ER membrane with catalytic domain facing cytosol.
244
What are the constituents of HMG-CoA/How is it made?
3 Acetyl-CoA via HMG-CoA synthase
245
What are two possible synthetic pathways of HMG-CoA (and where do they occur?)
```
Cholesterol synthesis (cytosolic)
Ketone body synthesis (mitochondrial)
```
246
1. ) What is the rate-limiting step of cholesterol synthesis?
2. ) What is it mediated by (and where is it located)?
1. ) HMG-CoA --> Mevalonic acid
2. ) This reaction is mediated by the enzyme HMG-CoA REDUCTASE. It is an INTEGRAL PROTEIN of the ER membrane...HOWEVER, its catalytic side faces the cytoplasm!!!
247
Explain the four methods of regulating HMG-CoA, and therefore, steroid production (i.e. method, enzymes, mechanisms and modifications).
1.) Regulation of gene expression: Sterol Regulatory Element-Binding Protein (SREBP). *Increase in cholesterol --> decrease in HMG-CoA transcription (gene expression) by binding DNA. Negative feedback mechanism.
2. ) Protein degradation: Increase in cholesterol --> increase in ubiquitin-labelling and DEGRADATION of HMG-CoA reductase.
* INCREASE IN CHOLESTEROL = INCREASED AMOUNT OF LIVER HMG-CoA REDUCTASE ENZYME*
3. ) Covalent modification via phosphorylation by AMPK (AMP-activated protein kinase) and Ptase: Phosphorylated HMG-CoA reductase = INACTIVATED.
- AMPK is activated under LOW ENERGY, high [AMP] conditions. It phosphorylates HMG-CoA reductase, thereby INACTIVATING IT and lowering cholesterol production.
- When in low energy conditions, acetyl-CoA that would be used for cholesterol synthesis is used for TCA for energy.
4. ) Hormonal regulation (STEROL-INDEPENDENT...i.e. does not depend on cholesterol):
- INSULIN and THYROXINE = UP-REGULATION of HMG-CoA expression.
- GLUCAGON and GLUCOCORTICOIDS = DOWN-REGULATION of HMG-CoA expression.
248
How do the most popular cholesterol-reducing medications work? What are they?
STATINS = COMPETITIVE INHIBITORS of HMG-CoA REDUCTASE, e.g. Lipitor (atorvastatin), Zocor (simvastatin).
-They are structural analogs of HMG-CoA, or are metabolized to structural analogs.
249
Describe the genetic deficiency in cholesterol (i.e. name of pathology, name of pathology, cause, and symptoms)
- Smith-Lemli-Opitz syndrome: An autosomal-recessive genetic deficiency in cholesterol synthesis caused by MUTATIONS IN DHCR7 gene.
- Caused by very low levels of serum and tissue cholesterol.
- It causes craniofacial abnormalities, delayed myelination, cleft palate, genital malformations, and congenital heart defects.
250
1. ) What is bile composed of (3)?
2. ) Where are bile acids/salts synthesized?
3. ) Where bile salts stored and released?
4. ) What triggers its release?
1. ) A watery mixture of organic and inorganic compounds: Organic: Phosphatidylcholine (lecithin), conjugated bile salts, and BILIRUBIN are its most important organic constituents.
2. ) In the liver
3. ) Stored in the GALLBLADDER...released to intestines when needed.
4. ) Release triggered by CHOLECYSTOKININ.
251
What is the release of bile triggered by and where is this substance produced?
Triggered by cholecystokinin released in the lower duodenum and jejunum.
252
1. ) What is bile acid composed of?
| 2. ) What is it charge status and how does this aid in its function?
1. ) Initially made from cholesterol in the liver. It is then conjugated with glycine/taurine to form BILE SALT.
2. ) Amphipathic = polar and non-polar --> Good for emulsifying fats (non-polar for fat, polar for water part).
253
1. ) What does bile help do in the gallbladder?
| 2. ) What role does it play with vitamins?
1. ) Along with phospholipids, keeps cholesterol from precipitating.
2. ) Needed for absorption and transport of fat soluble vitamins in the intestines. .
254
What is the only SIGNIFICANT way to remove cholesterol from the body?
Mixed with BILE SALTS and excreted in the feces
255
What is the relationship between bile and pancreatic lipase?
Bile emulsifies dietary triacylglycerols (fats) and renders them accessible to pancreatic lipases.
256
1. ) What is the main differences between conjugated bile acids and bile salts?
2. ) What are the two most common/prevalent PRIMARY bile acids in the body? (what does primary mean?)
3. ) What happens to make the two above acids SECONDARY, and what are their names when they've become secondary?
1. ) Bile acid = protonated, Bile salt = deprotonated
2. )
a. ) Cholic acid (primary means made in the LIVER)
b. ) Chenodeoxycholic acid (primary)
3. ) Secondary means they've lost their -OH groups...a.) becomes Deoxycholic acid, and b.) becomes Lithocholic acid
257
1. ) List the characteristics of primary bile acids (4)
| 2. ) List the characteristics of conjugated bile acids/salts (4)
1. ) Good emulsifying agents, pKa = 6 (partially ionized), Intestinal lumen pH = 6, only 50% ionized.
2. ) Amide bonds with GLYCINE or TAURINE, VERY GOOD emulsifier, pKa = 4 <-- therefore, most will be ionized in lumen, making them better amphipathic compounds and better emulsifiers.
258
The ______ use bile salts on their surface to keep them soluble: _____ faces inside, ______ faces towards the outside.
The MIXED MICELLES use bile salts. HYDROPHOBIC faces inside, HYDROPHILIC faces outside.
259
Where are mixed micelles absorbed? What is their state leading up to, and directly before absorption?
As the micelles approaches the "unstirred water layer" of the ENTEROCYTE, the micelle is constantly vacillating between a state of existence as its INDIVIDUAL components and then reforming the mixed micelle. *They are actually absorbed at the BRUSH BORDER of the enterocyte*
260
1. ) Where is cholesterol absorbed and how?
2. ) Where and how are free FA absorbed?
3. ) Monoacylglycerol and lysophospholipids?
1. ) Into the duodenum and jejunum, with its transport into the enterocyte being facilitated by Neiman-Pick Cholesterol Like Transporter (NPC1L1)
2. ) The ilium with the help of transport proteins
3. ) Passively absorbed in the ilium
261
How do fats enter the blood stream?
They are repackaged in the enterocyte as CHYLOMICRONS and secreted from enterocytes into the lymphatic system, and then enter the blood stream.
262
Describe enterohepatic circulation
>95% of bile acids and deconjugated bile salts are recirculated back to the liver via the portal system.
263
1. ) Where does bile acid synthesis occur?
2. ) What is the rate-limiting step (i.e. which enzyme is involved)?
3. ) What enzyme controls the enzyme that controls the rate limiting step, where is it located, and what does it REQUIRE?
1. ) In the liver
* **2.) 7-alpha-hydroxylase (CY7A1 = only expressed in liver)***
* **3.) Cytochrome P450 (CYP450), associated with ER, REQUIRES NADPH!!!!!***
264
1. ) What elements in the nucleus regulate bile acid synthesis?
2. ) What is the method of regulation?
1. ) Specific DNA sequences in target genes called FXR response elements (FXREs)
2. ) Inhibition in transcription of &-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile synthesis from CHOLESTEROL.
265
Conjugation of bile occurs in the ______ using _____ and ______ from _______. What is the purpose of conjugation?
Occurs in the LIVER, using GLYCINE and TAURINE from CYSTEINE. Conjugation increases the ionization of the bile salt, therefore making it a better emulsifier (more polar = better emulsification)
266
1. ) How are gallstones caused (2)?
2. ) What is the pathologic name?
3. ) What are risk factors (8)?
1.)
a.) Too much cholesterol in bile without enough bile salts or lecithin = precipitation.
b.) Gallstones from too much bilirubin from HEMOLYTIC ANEMIA CRISIS, e.g. sickle cell crisis.
2.) Cholelithiasis
3.) 5-F rule:
Fair (white skin), Fat (BMI >30), Female (estrogen), Fertile (one or more children), Forty (age >40). GENETICS ALSO (native americans and mexicans). DIABETES, rapid weight loss, fasting.
267
How can gallstones be treated (3)?
1. ) Medication to increase biliary cholesterol solubility (URODEOXYCHOLIC ACID) aka Ursodiol.
2. ) Lithotripsy: Shock wave treatment
3. ) Cholecystectomy
268
1. ) What is the point of Bile Acid Sequestrate?
2. ) What general class of drugs do this?
3. ) What are some consequences of bile acid sequestration (3)?
1. ) To sequester bile acid (so they are eliminated in stool) in order to use more cholesterol to synthesize bile acid, thereby reducing cholesterol.
2. ) Sequestrins (anion-exchange resins)
3. ) a.) Feedback repression (7-alpha-hydroxylase) lost, less cholesterol available for circulation.
b. ) Lower liver cholesterol UP-REGULATES LDL RECEPTORS
c. ) More LDL receptors means more hepatic uptake of LDL with LOWERING OF PLASMA CHOLESTEROL.
