Exam2 2015 Flashcards
(208 cards)
1
Q
Describe the location and function of SLGT-1 and SLGT-2
A
SLGT-1: Na+ symport of glucose and galactose into intestinal cells (and kidney proximal straight tubule, but only 10%). ATP dependent.
SLGT-2: Na+ symport of glucose and galactose for renal reabsorption (proximal convoluted tubule, 90% reabsorption in kidney). ATP dependent.
2
Q
Describe the location and function of GLUT-5
A
Facilitative FRUCTOSE transporter in the brush border membrane lining the lumen. Transports fructose INTO intestinal cells.
Energy and substrate-INDEPENDENT
3
Q
What are the net products of anaerobic glycolysis (3)?
What type of phosphorylation does it utilize?
A
- )Lactate
- ) 2 ATP produced.
- ) No net NADH.
Substrate-level phosphorylation.
4
Q
______ stimulates glucose transport into muscle and adipose cells utilizing which transport protein?
A
Insulin, GLUT4
p.197 BRS
5
Q
Insulin does not significantly stimulate the transport of glucose into tissues such as…(3)
A
Liver, brain, and RBCs
6
Q
What are the roles of GLUT1 and GLUT2?
A
GLUT1: Can transport glucose into the brain WITHOUT the need for insulin.
GLUT2: Liver. Transport based on concentration gradient. Glucose in, and to the blood.
7
Q
Where are hexokinase and glucokinase found?
Describe their Vmax, Km, and regulation.
A
- ) Hexokinase: In ALL tissues.
- Low Km (high affinity); i.e. works under low [glucose].
- Low Vmax.
- Regulated by its product, G-6P (feedback inhibition). - ) Glucokinase: Found in LIVER and PANCREAS.
- High Km (low affinity); i.e. functions only at HIGH [glucose].
- High Vmax: Removes glucose quickly.
- Regulation via F6-P and GKRP.
8
Q
What is the purpose of phosphorylating glucose?
A
To prevent glucose form leaving the cell (polar groups cannot pass through the membrane).
9
Q
What are five ways PKB mediates insulin signaling?
A
1.) Active PKB helps in the translocation of GLUT4 glucose transporters to cell
surface in myocytes and adipocytes
2.) PKB inactivates glycogen synthase kinase-3 (GSK-3) to stimulate
glycogen synthesis
3.) PKB activates transcription factors that promote the expression of genes
involved in adipocyte differentiation
4.) PKB promotes cell survival by inactivating proapoptotic proteins
5.) PKB may activate protein phosphatase 1 (PP-1) by phosphorylating its G subunit.
Signal Transduction, #38
10
Q
What is the name for enzymes that link sugars?
A
Glycosyltransferases
11
Q
What two sugars make up sucrose and with what type of linkage? Is it reducing? Why?
A
Glucose + Fructose in an alpha–1,2 linkage.
Not a reducing sugar because both anomeric carbons are used
12
Q
What type of polysaccharides are indigestible for humans? Example?
A
ß-1,4 glycosidic linkages – e.g. Cellulose.
13
Q
What keeps the pH of the mouth optimum for salivary amylase activity? Acidic or alkaline?
A
Bicarbonate keeps mouth alkaline for optimum salivary amylase activity.
14
Q
What sugars are digested in the mouth by salivary amylase? What types of sugars are not digested?
A
Starch and glycogen are digested in the mouth by salivary amylase. Disaccharides are not digested in the mouth by salivary amylase. #9, Lecture 10.
15
Q
Where and how are disaccharides digested in the human body?
A
By disaccharidases — enzymes in the membrane-bound BRUSH BORDER (mucosal lining) MUCOSAL CELLS in the INTESTINAL LUMEN. #11
16
Q
What is the fate of monosaccharides when they arrive into the intestinal lumen?
A
Monosaccharides are absorbed by transmembrane proteins of the brush border on the luminal surface of the mucosal lining in the upper jejunum, then released into the PORTAL SYSTEM – LIVER.
17
Q
What transports galactose and glucose into intestinal mucosal cells? What is its mechanism?
A
SGLT-1: Active, energy-dependent process that requires the concurrent uptake of Na+ ions.
p.169 Lipp
18
Q
What transports fructose into intestinal mucosal cells? What is its mechanism?
A
GLUT-5: Energy- and sodium-independent monosaccharide transporter.
p.169 Lipp
19
Q
What is the role of GLUT-2?
A
It transports monosaccharides (galactose, glucose, and fructose) from the intestinal mucosal cells into the PORTAL CIRCULATION.
p.169 Lipp
20
Q
All digestible carbohydrates are absorbed before material enters the ________.
A
Large intestines.
21
Q
________ and _______ regions absorb most of the monosaccharides, where they are transported through the ________ into the _______.
A
- Duodenum and upper jejunum
- Through the portal system, into the liver.
22
Q
In what tissues are the SLGT present?
A
SLGT-1 and SLGT-2 are present for absorption in the KIDNEY and LIVER.
23
Q
1.) Give a description (location, special circumstances, etc.) and the 2.) function for GLUT-1
A
- ) Widely distributed in fetal tissues. As adults, expressed at highest levels in RBCs and the BBB. Low in adult muscle. NOT INSULIN DEPENDENT
- ) Responsible for the low-level of basal uptake required to sustain respiration in cells.
24
Q
1.) Give a description (location, special circumstances, etc.) and the 2.) function for GLUT-2
A
- ) Expressed by renal tubular cells and small intestinal epithelial cells that transport glucose, liver cells and pancreatic β cells.
* In the basolateral membrane of intestinal cells to ensure sugar exits into the blood when blood glucose levels are low* - ) Is a high-capacity and low-affinity isoform.
- Transports glucose into/out cells
- Can transport Glu, Gal and Fructose out into portal circulation based on gradient
25
1.) Give a description (location, special circumstances, etc.) and the 2.) function for GLUT-3
1. ) Expressed mostly in NEURONS (where it is believed to be the main glucose transporter isoform) and in the PLACENTA. Transports glucose INTO these tissues.
2. ) Is a high-affinity isoform.
26
1.) Give a description (location, special circumstances, etc.) and the 2.) function for GLUT-4
1. ) Found in adipose tissues and muscle (skeletal muscle and cardiac muscle).
2. ) Is the INSULIN-REGULATED GLUCOSE TRANSPORTER (increased under insulin): translocation from intracellular membrane compartments to the cell surface in adipocytes and skeletal/cardiac muscle. Responsible for insulin-regulated glucose uptake and storage.
* Uniporter with gradient*
27
In which intestinal disease can there be lower lactase activity in the intestinal mucosa?
Cystic fibrosis.
28
In what condition can the body not produce enough digestive enzymes?
Kwashikor (protein malnutrition).
29
Lactose intolerance can increase with _______.
Age
30
Describe 2˚ lactase deficiency
Due to intestinal injury – Lactase activity is first to be lost, and last to be recovered.
31
________ is the end product of glycolysis in cells with mitochondria and an adequate supply of oxygen.
Pyruvate
| p.185 Lipp
32
In β cells of the pancreas, glucokinase functions as a __________, determining the ______ for _________.
glucose sensor, determining the threshold for insulin secretion.
p.188 Lipp
33
What is normal glucose concentration in mM?
[Glucose] = 5mM
34
It which types of tissues is glycolysis carried out predominantly under anaerobic conditions? Give six examples.
Tissue lacking or low in mitochondria – e.g. Lens, cornea, kidney medulla, testes, leukocytes, and RBCs.
35
What are the causes for cellular and metabolic acidosis?
1. ) Cellular: Increased H+ due to the inability to reconstitute ATP in the mitochondria.
2. ) Metabolic: Buildup of lactate due to the inability of pyruvate to continue metabolism in the mitochondria.
36
1. ) Measuring lactic acid levels can be a measure of which three conditions?
2. ) What are normal lactic acid levels?
1. ) Myocardial infarction, pulmonary embolism, shock.
| 2. ) Normal [lactate] ≈ 0.5 – 1 mM
37
1. ) What are the preferred locations of the Glycerol 3-P shuttle?
2. ) What is the ultimate energy yield and from what?
1. ) Skeletal muscle and brain.
| 2. ) 2 ATP from ETC (complex II), i.e. FADH2
38
1. ) What are the preferred locations of the Malate-Aspartate shuttle?
2. ) What is the ultimate energy yield and from what?
1. ) Liver, heart, and kidney.
| 2. ) 3 ATP from ETC (complex I)
39
All GLUT receptors operate with a _______ transport mechanism via ____________ that runs ________ a concentration gradient.
Passive transport mechanism via FACILITATED DIFFUSION that runs DOWN a concentration gradient.
40
What are the five cofactors (from vitamins) needed for the PDH complex?
1. ) TPP (Thiamine pyrophosphate): Thiamine (Vit B1)
2. ) Lipoic Acid
3. ) Coenzyme A : Pantothenic Acid
4. ) FAD+: Riboflavin (Vit B2)
5. ) NAD+: Niacin (Vit B3)
41
Acetyl-CoA cannot form ______ and is considered _______.
Cannot form GLUCOSE and is considered KETOGENIC.
42
What is the most common biochemical cause of congenital lactic acidosis? How is it acquired?
PDHC deficiency via X-linked E1 alpha gene.
43
What are the three main importances of citrate?
1. ) Source of Acetyl-CoA for cytosolic synthesis of FAs.
2. ) Inhibits PFK-1 (glycolysis RLS).
3. ) Activates acetyl-CoA carboxylase (RLS of FA synthesis).
p. 214 Lipp
44
Which substrate is the rate-limiting concentration in the TCA cycle?
[OAA]
45
What is normal fasting blood sugar?
70-110mg/dL
46
What is normal post-prandial (PP) blood sugar (2hrs after a meal)?
Normal PPBS is less than 120mg/dL (6.6mmol/L) 1-2hrs after meal – Most normal people are less than 100mg/dL by 2hrs PP.
47
What is the low cutoff for hyperglycemic FBS?
126mg/dL
48
What is an A1c value that indicates diabetes? FBS?
| Oral? Give normal values as well.
DM: A1c ≥ 6.5 N: ≈5
DM: FBS ≥ 126 N: ≤ 99
DM: Oral ≥ 200 N: ≤ 139
49
What is the main gluconeogenic organ? When does it not take place there and why?
1˚ organ = LIVER.
- Kidney cortex: During periods of severe hypoglycemia during liver failure.
- Small intestine: Under high protein/fasting/renal failure.
50
What are the major gluconeogenic precursors during a long-term fast? Where do they come from?
Gluconeogenic AAs: Alanine (Ala) and Glutamine (Gln) from hydrolysis of tissue proteins, e.g. muscle degradation.
51
1. ) What is the first bypass reaction in gluconeogenesis? Energy required? Anything special about this rxn?
2. ) What cofactor does it require?
3. ) Regulation? How and why.
1. ) Pyruvate —> OAA (via pyruvate carboxylase) *Requires 2 ATP* – It is special because OAA must be first converted to Malate in order to exit the mitochondria (into the cytosol), then converted back to OAA by Malate DH. Followed by Decarboxylation of OAA to Phosphoenolpyruvate by PEPCK (requires 2 GTP).
2. ) Biotin
3. ) Positive allosteric regulation by Acetyl-CoA because increased Acetyl-CoA indicates a metabolic state in which increased OAA synthesis is necessary, e.g. Fasting, when OAA is used for synthesis of glucose by gluconeogenesis.
52
1. ) What is the second bypass reaction in gluconeogenesis and where does it take place? Energy required?
2. ) What cofactor does it require?
3. ) Regulation? How and why.
1. ) F 1,6-bisP to F 6-P via F 1,6-bisPtase in the cytsol.
2. ) No cofactor.
3. ) Inhibited by AMP (low energy) and F 2,6 -bisP. Activated by ATP (high energy) and glucagon (decreases [2,6 -bisP]).
* Reciprocal effects in glycolysis*
53
1. ) What is the third bypass reaction in gluconeogenesis and where does it take place? Energy required?
2. ) What cofactor does it require?
3. ) Regulation? How and why.
1. ) G 6-P to Glucose via G 6-Ptase in the ER membrane. No energy required.
2. ) No cofactor (H2O added).
3. ) No regulation.
54
What is the Cori cycle?
Cori cycle recycles Lactate from muscle to liver for
| gluconeogenesis by converting lactate to pyruvate via LDH.
55
How does Glucagon help to maintain blood glucose homeostasis?
Glucagon, which is secreted from the pancreatic α-cells, inhibits the production of F2,6-bisP. Without a high enough concentration of F2,6,- bisP, PFK-1 in glycolysis is not stimulated and the bypass reaction of F 1,6-bisPtase in gluconeogenesis can become active.
56
What is the effect of insulin on gluconeogenesis? How?
Insulin (opposes glucagon) decreases gluconeogenesis by increasing the [F 2,6-bisP], thereby increasing glycolysis through PFK-1.
57
What is the effect of cortisol on gluconeogenesis (3)?
Opposes insulin –
1. ) Degrades TG from adipose to create GLYCEROL (gluconeogenic) and FAs.
2. ) Degrades muscle protein to produce gluconeogenic AAs.
* 3.) ***Stimulates PEP carboxykinase (PEPCK)*** in gluconeogenesis.
58
1. ) How do odd-chain FAs contribute substrates to gluconeogenesis?
2. ) Even-chain?
3. ) Acetyl-CoA?
1. ) They can be converted to succinyl-CoA (a TCA intermediate) and go on to become OAA, which feeds into gluconeogenesis.
2. ) Even-chain FAs (most fats) cannot make glucose. They do, however, provide ATP and NADH for its synthesis.
3. ) Acetyl-CoA (the end product of fat metabolism) is NOT a gluconeogenic precursor. It does, however, act as an allosteric activator of gluconeogenesis.
59
What is the total energy consumption of gluconeogenesis and where?
```
2 ATP – Pyruvate carboxylase
2GTP – PEPCK
2 ATP – Glycerate Kinase
2 NADH – G-3-PDH
#35
```
60
What is the main source of energy for gluconeogenesis under fasting conditions?
Fats —> C16 ≈ 130 ATP.
| *FA ox –> TCA –> ETC –> ATP*
61
What acts as an allosteric activator for the pyruvate carboxylase enzyme of gluconeogenesis?
Acetyl-CoA
62
Describe how glycogen is liberated into the blood stream?
```
Converted to G 6-P using ATP, then G 6-Ptase catalyzes its conversion into glucose.
#43
```
63
1. ) What is Type 1a Glycogen Storage Disease (name and cause)?
2. ) What is the presentation/symptoms (4)?
3. ) Treatment?
1.) Type 1a: Von Gierke Disease – Caused by deficient G 6-Ptase.
2.) a.) Severe fasting hypoglycemia (lethargy, seizures, brain damage).
b.) Hepato-renomegaly – increased liver glycogen stores, but normal glycogen structure.
c.) Hyperlipidemia: OAA gets backed up because no gluconeogenesis, thus, in TCA, the buildup of OAA pushes it towards Acetyl-CoA production – Which is then used to make Triglycerides. *Infants often have doll-like appearance due to excess adipose in cheeks.
d.) Hyperuricemia: Due to increased production of nucleic acids.
3.) No fasting – Frequent meals and nocturnal infusion of glucose or uncooked cornstarch.
#44
64
What is the affect of ethanol metabolism on gluconeogenesis?
```
Ethanol metabolism produces large quantities of NADH. High [NADH] favors Lactate production via LDH, and also favors Malate production via Malate DH (forces OAA Malate equilibrium towards malate). These effects result in a DECREASE IN PRECURSORS FOR GLUCONEOGENESIS.
*Increase in Lactate = metabolic acidosis = hyperventilation (respiratory compensation)*
#51
```
65
Why is methanol dangerous to drink?
Because it is metabolized to formaldehyde, which is toxic to the optic nerve, can produce blindness, and can be fatal in high doses.
66
What ratio does alcohol metabolism increase? What are the effects (5)?
Increased NADH/NAD+ ratio
1.) Inhibition of gluconeogenesis by removing precursors (increases risk of hypoglycemia).
2.) Inhibition of FA oxidation cycle = fatty liver and increased TGs.
3.) TG increase = increased VLDL = *Hyperlipidemia*
4.) Decrease in TCA cycle = increased Acetyl-CoA = ketone bodies = ACIDOSIS.
5.) Increased lactic acid = acidosis —> *Increased acidity can decrease URIC ACID excretion, leading to GOUT (deposition of uric acid in joints).
#52
67
What are six symptoms of alcoholic hypoglycemia?
```
Agitation, impaired judgement, combativeness, confusion, tachycardia, lactic acidosis.
#53
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68
1. ) What stimulates glycogenolysis in muscle tissue (3)?
| 2. ) Why can't it release glucose into the blood?
1.) Ca2+, AMP, and epinephrine.
2.) It lacks G 6-Ptase
#7
69
1. ) What is another name for Type 1 muscle fibers? Color, why?
2. ) Which organelle does it have a lot of?
1. ) Slow oxidative fibers; Red fibers (due to lots of myoglobin for O2 delivery).
2. ) Mitochondria
70
1. ) What is another name for Type 2 muscle fibers? Color, why?
2. ) Which organelle does it have less of than red fibers?
1. ) Fast glycogenic fibers; white fibers (due to less myoglobin because they perform anaerobic metabolism).
2. ) Less mitochondria.
71
1. ) Where is most of the bodies glycogen stored? i.e. the *single* largest [glycogen]?
2. ) What is it regulated by?
1. ) Liver (10% of its weight).
| 2. ) Regulated by insulin/glucagon, blood glucose, epinephrine.
72
What is the functional difference between storing glycogen in the liver vs. storing it in muscle?
Liver storage is for glucose release into the blood (blood-glucose homeostasis), muscle storage is for muscle use ONLY (energy for contraction), is does not/cannot release it into the blood because muscle tissue lacks G 6-Ptase.
73
1. ) What is the main enzyme in glycogen synthesis? Explain how it adds glucose.
2. ) Where does this occur?
1.) Glycogen synthase – UDP glucose is used to add glucose units to the NON-REDUCING (non-anomeric) end of an EXISTING glycogen polymer (alpha-1,4 linkages).
2.) In the CYTOSOL.
#17
74
1. ) What causes branching in glycogen and where?
| 2. ) What is the purpose of branching in glycogen (3)?
1. ) Branching enzyme – alpha-1,6 linkages ≈ every 6-8 residues.
2. ) Increases number of sites for synthesis and degradation, increases number of non-reducing end available for degradation when needed, increases solubility.
75
Give an example of a branched glycogen and an unbranched glycogen.
Amylopectin – has branches.
Amylose – Straight chain; less branches.
#18, p.246 Lipp
76
Explain the allosteric and covalent regulation of Glycogen Synthase.
Allosteric – Activated by G 6-P, both liver AND muscle (well-fed state).
Covalent – Active when dephosphorylated, inactive when phosphorylated via HORMONAL REGULATION by glucagon/insulin.
#21
77
What is the difference between activated and inactivated glycogen synthase? What are the forms called?
```
Active – dephosphorylated = Glycogen synthase a or I.
Inactive – phosphorylated = Glycogen synthase b or D.
#22
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78
1. ) By inhibiting which molecule does insulin increase glycogen synthesis?
2. ) What affect does this have on glycogen synthase and how?
1. ) GSK3
| 2. ) Glycogen synthase is dephosphorylated (activated) by PP1.
79
What mutation causes muscle GSD 0? What is affected?
| What is the main symptom? Onset?
GYS1 gene; deficient Glycogen synthase.
Impairs the heart's ability to efficiently pump blood. Increased risk of cardiac arrest and sudden death. *particularly after physical activity*
-Onset typically early in childhood.
80
What mutation causes liver GSD 0? What is affected?
| What is the main symptom? Onset?
GYS2 gene, autosomal recessive. Deficient glycogen synthase. Causes hypoglycemia after long periods of fasting — Ketosis may occur from fat breakdown —> Acetyl-CoA. *Improves when food is eaten*
-Onset typically in infancy.
81
Describe GSD type IV: What is its name, deficiency, 2˚ symptoms (-osis), type of glycogen it makes.
Andersen disease – Deficient branching enzyme. Leads to abnormal glycogen structure with long outer branches. *Amylopectinosis: Decrease in amylopectin-branched glycogen = insoluble glycogen*
-Failure to thrive (declining growth and mental development).
-Hepatosplenomegaly
-Progressive cirrhosis
-Muscle hypotonia
-Death usually by 5 years of age.
#33
82
What is the initial primary product of glycogenolysis?
Glucose 1-P from a 1-4 linkage.
83
1. ) Describe the action of phosphorylase in glycogenolysis
| 2. ) Coenzymes?
1.) Cleaves alpha-1,4 linkages from non-reducing ends until it reaches four glucose units from a branch point (then the debrancher acts).
2.) Coenzyme – Pyridoxal phosphate (the active form of Vit B6) (Vit B6 at the active site).
#40
84
Describe the bifunctionality of the debranching enzyme
1.) 4:4 Transferase – Transfers three glucose unit from one branch to another branch (all alpha-1,4), leaving behind one alpha-1,6 glucose.
2.) 1:6 Glucosidase – Hydrolyzes the single alpha-1,6 glucose left behind into free glucose.
#42, p.248 Lipp, p.193 BRS
85
1. ) _______ activates glycogenolysis mainly in muscle.
| 2. ) _______ activates glycogenolysis in the liver.
1.) Epinephrine.
2.) Glucagon
#44
86
What is the glucagon/insulin ratio when fasting?
High
87
What act as allosteric inhibitors for glycogen phosphorylase and where?
Glucose 6-P (well-fed state) – inhibits in muscle and liver.
Glucose – liver; acts as a glucose "sensor."
ATP (high-energy) – Muscle and liver.
88
What act as allosteric activators for glycogen phosphorylase and where?
AMP (low energy) – Muscle
Calcium – Muscle: Activation of phosphorylase b = increased glycogenolysis.
*Ca2+ binds calmodulin*
89
Describe Type II GSD
1. ) Cannot degrade ______, thus, _____ accumulates in _______. How is this unique?
2. ) Where its effects are seen. Symptoms?
3. ) Treatment?
Type II (Pompe Disease) – Acid Maltase Deficiency
Lysosomal acid alpha-1,4-glucosidase deficiency (GAA)
1.) Cannot degrade lysosomal glycogen
• Accumulation of glycogen in lysosomes
**Only Glycogen Storage disease that is Lysosomal Storage disease**
2.) Generalized: Liver, Muscle and Heart
-Normal blood glucose
• Normal glycogen
• Muscle Weakness
*Cardiomegaly (Pompe affects “the pump”)*
3.) Gene therapy* available (Myozyme)
90
In Type II GSD, myofibrils are _____________, leading to eventual muscle tissue destruction.
```
Myofibrils are replaced with glycogen.
#57
```
91
Describe Type III GSD: What is deficient?
1. ) What abnormalities result from the deficiency?
2. ) Clinical manifestations (3)?
3. ) Treatment (2)?
4. ) What population is most susceptible?
Type III (Cori Disease): Debranching enzyme deficiency.
1.) Accumulation of an abnormally structured
glycogen having very short outer chains
2.) Clinical manifestations: Hepatomegaly,
fasting hypoglycemia, myopathy.
3.) Treated with frequent high carbohydrate meals with cornstarch supplements.
-A high protein diet is also effective as this drives gluconeogenesis
4.) Autosomal recessive:
1:5,400 North African Jews (1:35 carriers N.African Jews)
#58
92
What is a mnemonic to remember Types III and IV GSD?
"ABCD": Anderson (IV) – Branching, Cori (III) Debranching.
93
Describe Type V GSD: Deficiency?
Normal ______ enzyme.
1.) Clinical presentation (4).
Type V – McArdles Disease: Skeletal muscle phosphorylase deficiency (myophosphorylase).
*Normal liver enzyme*
1.) Muscle cramps with exercise.
-No rise in blood lactic acid after exercise.
-Myoglobinemia and myoglobinURIA (myoglobin in urine; brownish color).
-High level of muscle glycogen – i.e. normal structure.
#60
94
Describe Type VI GSD: Deficiency?
* ______ milder than in Type 1a*
- Extreme _______.
Type VI – Hers Disease: Liver phosphorylase deficiency.
*Hypoglycemia milder than in Type 1a*
-Extreme hepatomegaly.
#61
95
Which GSD(s) leads to abnormal glycogen structure?
```
Type IV (Andersen): Loss of branching.
Type III (Cori): Loss of debranching.
```
96
Where is the 1˚ location for fructose metabolism? What is its transporter?
Liver – GLUT-5 (non-insulin dependent)
97
How does fructose promote insulin secretion?
IT DOESN'T
| p.264 Lipp
98
What is the first enzyme in the metabolism of fructose? Describe its kinetics (Km and Vmax), its product, and location. Does it bypass any regulatory steps?
Fructokinase – Present in liver, kidney, and small intestine. *NOT PRESENT in SKELETAL MUSCLE, ADIPOSE, or RBCs*
- Low Km (high affinity), high Vmax.
- Produces F1-P.
- Bypasses PFK-1.
99
1. ) What is the first intermediate in fructose metabolism? What effect does it have on glycolysis?
2. ) What other compound has a similar effect?
1. ) Fructose 1-Phosphate: It inhibits formation of the GKRP complex (glucokinase regulatory protein).
2. ) F 6-P
p. 189 Lipp, L11 #24
100
Compare the rate of fructose metabolism to that of glucose
```
Fructose metabolism more rapid than that of glucose.
#8
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101
Describe the action of aldolase B, where it is found, and how its energy production differs from Fructokinase.
```
Aldolase B cleaves F 1-P to DHAP and glyceraldehyde.
It produces less ATP than the Fructokinase pathway.
#8
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102
Describe the action of Triose Kinase
```
Phosphorylates Glyceraldehyde to Glyceraldehyde 3-P *using ATP*
#8
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103
Describe the mechanism of fat (TG) synthesis from fructose (four steps)
Glyceraldehyde —> Glycerol —Aldol DH—> Glycerol 3-P (using glycerol kinase, which is not in adipose tissue) —> backbone for TGs.
104
What are the metabolic consequences of Aldolase B deficiency (aka ______)? Clinical presentation? Treatment?
```
Aldolase B Deficiency (aka Hereditary Fructose Intolerance – HFI): Increased F 1-P = Decrease in Pi and ATP = Increased AMP = Decreased Gluconeogenesis (due to increased AMP) and Glycogenolysis (due to decreased Pi).
*HYPOglycemia, HYPERuricemia (and lactic acidosis), HEPATIC FAILURE, DEATH*
Treatment: Remove dietary fructose AND SUCROSE.
#10, p.265 Lipp
```
105
Explain how large amounts of fructose can cause gout and hypertension.
1. ) As fructose is metabolized, ATP is depleted and converted to AMP (ATP —> ADP —> AMP). AMP —> Uric acid (AMP Deaminase) —> GOUT.
2. ) Uric acid blocks eNO synthase —> Decrease in [NO] (vasodilator) = HYPERTENSION.
106
Explain how fructose can cause metabolic syndrome
```
F 1-P leads to formation of pSer-IRS-1 (inactive form of the insulin signal) = Insulin insensitivity = METABOLIC SYNDROME.
#14
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107
How does fructose increase VLDL and cause obesity?
F 1-P —> Glyceraldehyde 3-P —> Pyruvate —> Acetyl-CoA —> Citrate (TCA) —> Cytosolic Citrate —> —> fats —> VLDL.
*Deposition of fats and increase in VLDL causes obesity*
#15
108
Which organ tissue utilizes sorbitol metabolism for energy? (8)
Lens, retina, liver, kidney, placenta, RBCs, ovaries, and seminal vesicles.
p.267 Lipp, #25
109
1. ) Explain how the liver, ovaries, and seminal vesicles utilize fructose via sorbitol.
2. ) Why would this pathway be used?
1. ) Glucose —> Sorbitol (via Aldose reductase) —> Fructose (via Sorbitol dehydrogenase) —> Metabolism.
2. ) This pathway provides a means to produce fructose from glucose WITHOUT USING ATP.
p. 267 Lipp, #25
110
How is glucose —> fructose different in the lens, nerve, and kidney vs. in the seminal vesicles, liver, and ovaries?
```
Lens, nerve, and kidney have low or absent Sorbitol dehydrogenase.
#25
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111
Explain the effects of hyperglycemia on the cells of the lens, nerve, kidney, seminal vesicles, liver, and ovaries (four 'steps').
Does this have any correlation with the symptoms of DM (5 things)?
1. ) Insulin not required for the entry of glucose into these cells.
2. ) Large amounts of glucose may enter these cells in the case of hyperglycemia.
3. ) Large amounts of glucose (+ NADPH) = Increased Sorbitol production; which cannot pass through the cell membrane, and remains in the cell (exacerbated when sorbitol DH is low or absent, as in the retina, lens, and kidney).
4. ) Sorbitol accumulation causes STRONG OSMOTIC EFFECTS = SWELLING due to WATER RETENTION.
* In DM – This may lead to cataract formation and macular edema (poor vision), peripheral neuropathy, and microvasculature problems including nephropathy and retinopathy*
p. 267 Lipp, #25
112
1. ) What is the linking bond present in Lactose? What two subunits does it link?
2. ) What enzyme catalyzes its digestion and where is it present?
1. ) Lactose = Galactose + Glucose via ß-1,4 linkage.
2. ) ß-Galactosidase (Lactase) – Present in Brush Border of intestines (jejunum).
p. 269 Lipp, #29
113
Galactose must be ______ before it can be further metabolized. How is the achieved?
Phosphorylated – Galactokinase + ATP.
| p.269 Lipp, #31
114
What is the cause of non-classical galactosemia? What does it lead to (metabolic and clinical)
```
Galactokinase deficiency – Leads to GALACTITOL accumulation via aldose reductase.
-Causes galactosemia and galactosuria. Can lead to cataract formation.
#32
```
115
What is the cause of classical galactosemia (and what is the genetic basis)? Metabolic and clinical consequences?
Treatment?
Uridyltransferase deficiency (autosomal recessive, seen in homozygotes) – Increase in Gal 1-P, as well as Gal seen in blood and urine.
-Can cause mental retardation in infants and needs immediate treatment (part of NY screening panel).
-Liver and kidney damage (jaundice).
-Treat by removing dietary galactose (and, therefore, FRUCTOSE).
#33, p.270 Lipp
116
What hormone stimulates lactose synthesis in lactating females?
```
Prolactin.
#35, p.272 Lipp
```
117
1. ) What enzyme is used in the synthesis of lactose? What are its constituent parts?
2. ) What stimulates its activity?
3. ) What is a women's hormonal state post-pregnancy (i.e. what hormone is reduced)?
1.) LACTOSE SYNTHASE (UDP-galactose:glucose galactosyltransferase): Made up of...
-Protein A (ß-D-Galactosyltransferase; used in most tissues to synthesize N-linked glycoproteins), and...
-Protein B (alpha-lactalbumin; found only in lactating mammary glands).
2.) Prolactin.
3.) Low-progesterone —> I'm not sure I understand the relevance of this...
#35, p.272 Lipp
118
Why do hyperglycemia and hypergalactosemia lead to ophthalmological complication?
```
Both of the aldohexoses, glucose and galactose, can be reduced to their corresponding alcohols, sorbitol and galactitol, by aldose reductase leading to an osmotic effect in the retina (water retention and blurry vision) as well as other ophthalmologic complications such as retinopathy, cataracts etc.
#39
```
119
What are the three main functions of the PPP?
1.) NADPH synthesis (for lipid reductive biosynthesis, cytochrome p450 rxns, etc.)
2.) Ribulose 5-P synthesis (used in nucleotide synthesis).
3.) Metabolism of 5C sugars and interrelationship between carbohydrate pathways, i.e. the PPP is an important way for ODD-CHAIN CARBOHYDRATES TO INTEGRATE.
#16
120
What are the steps and products (and uses for the products) of the 1st part of the PPP (aka the _____ phase). What enzymes are used at each stage?
Part 1 – Oxidative Phase: Irreversible steps.
a.) G 6-P —> 6-PG via G 6-P DH. Produces 1 NADPH used for fatty acid reductive biosynthesis and cytochrome p450 reactions.
b.) 6-PG —> Ribulose 5-P via PG-DH. Produces 1 NADPH and CO2.
c.) Ribulose 5-P —> to Ribose 5-P via isomerase. Product is Ribose 5-P; used for NUCLEOTIDE SYNTHESIS.
#7
121
1. ) Which enzyme is the primary regulator of the oxidative part of the PPP?
2. ) What inhibits this reaction and by which type of inhibition?
1.) Glucose 6-Phosphate Dehydrogenase.
2.) NADPH competitively inhibits.
#8
122
In the PPP, _____ and ______ can be made without the use of ______.
-Fructose 6-P and Glyceraldehyde 3-P
-Without the use of ATP.
#16
123
1.) Regarding the PPP – Transketolase, which requires ______, tranfers _____-carbon units.
Transaldolase transfers ______-carbon units.
2.) What does transketolase directly form? Transalsolase
1.) Transketolase requires thiamine pyrophosphate, transfers TWO-carbon units.
Transaldolase transfers THREE-carbon units.
2.) Transketolase: F 6-P
Transaldolase: F 6-P
p.280 Lipp
124
What are the products of the non-oxidative reactions in the PPP? Is it irreversible or reversible.
2nd part (non-oxidative pathway): Reversible.
1. ) F 6-P
2. ) Glyceraldehyde 3-P
125
In the PPP, no ______ is used or made. It is _______ in all cells, and occurs in the ______ of the cell.
- ATP
- Ubiquitous
- cytosol
126
The PPP is the only source of _______ for _______ cells.
The only source of NADPH for RBCs.
127
What are ROS and how are they formed?
-ROS (reactive oxygen species) = Partial reduction of molecular oxygen.
-Formed by exposure to UV, or by interaction with transition metal ions, as occurs within the ETC.
#18
128
The danger from H2O2 largely comes from its ___________________.
```
Ready conversion to the reactive 'hydroxyl radical (OH•)'
#18
```
129
What are the dangers of H2O2?
Attack on membranes, deformation of cytoskeleton, lysis, and hemolytic anemia.
130
What is the reduced form of glutathione? How is it made? i.e. what enzyme, cofactors?
G-SH = reduced glutathione.
| It is made by: (NADPH + Glutathione Reductase) + G-S-S-G (oxidized form) —> G-SH + (NADP+)
131
How does glutathione reduce H2O2? i.e. what enzyme, cofactors?
```
(G-SH [reduced form] + Glutathione Peroxidase) + H2O2 —> 2H2O + G-S-S-G (oxidized form)
#20
```
132
What organ would be affected by a G-SH deficiency and how?
```
Enlarged spleen due to deformed RBCs from oxidized RBC membrane proteins.
#21
```
133
What does G-SH do in proteins?
Maintains reduced state of -SH groups in proteins *including Hb*, preventing oxidation to S-S and denaturation.
#21
134
G-SH oxidation (reduction of ROS) is catalyzed by the ______-containing enzyme __________. Where does this occur?
```
SELENIUM-CONTAINING enzyme GLUTATHIONE PEROXIDASE. In the mitochondria and cytoplasm.
#15
```
135
The amino acid ______ contained in glutathione is converted back to its reduced form using the enzyme _______, along with the cofactor ______ – without which you will end up with _______.
- Amino acid *CYSTEINE*
- Enzyme GLUTATHIONE REDUCTASE
- Cofactor NADPH, without which you will end up with ROS.
136
The oxidized form of glutathione is represented as ______, and is called _______.
G-S-S-G, i.e. Disulfide Glutathione.
137
1. ) What is the consequence of G6PD deficiency pertaining to RBCs?
2. ) What is the medical outcome?
1. ) Less G6PD = Less NADPH = Less G-SH (less cell detox of ROS). G-SH helps maintain the reduced state of membrane proteins, e.g. -SH groups, and Hb in RBCs.
- Oxidation of the -SH groups in Hb leads to the formation of denatured proteins that form insoluble masses called Heinz Bodies that attach to RBC membranes.
2. ) Leads to hemolysis and hemolytic anemia = JAUNDICE.
* Additional oxidation causes RBCs to become rigid, and they are removed from circulation by spleen and liver*
138
What form does Hb take when there is deficient G6PD?
```
met Hb
#22
```
139
What is the genetic basis for G6PD deficiency?
```
X-linked
#24
```
140
Damaged RBCs are removed by ______ in the ______ and ______.
```
By macrophages in the spleen and liver.
#25
```
141
When the Hb in RBCs is oxidized, _______ bonds are formed and it becomes _______.
-Disulfide bonds
-metHb
#25
142
What are three causes for G6PD deficiency? Indicate the most common cause.
1.) Oxidant drugs (mnemonic – AAA = antibiotics, antimalarials, and antipyretics) – e.g. Amoxicillin. *NOT acetamenophin*
2.) Favism: From a stupid bean.
3.) Infection: *Most common precipitating factor* Inflammatory response to infection results in the generation of free radicals in macrophages.
#26
143
What is the clinical presentation of G6PD deficiency?
```
Hemolytic anemia and jaundice.
#26
```
144
What drugs can precipitate G6PD deficiency (3 types)? What other weird thing can cause it?
```
AAA —> Anti-malarial: Primaquine.
Antibiotics: Sulfonamides – UTIs (gantanol, gantrisin), PCP (pneumocystic pneumonia) in HIV positive patients.
Antipyretics - NOT ACETAMINOPHEN.
*MOTHBALLS*
#27
```
145
What two conditions (and their presentations) are linked to Thiamine (Vit _____) deficiency?
Thiamine – Vitamin B1
1.) Beriberi: Heart failure.
2.) Wernicke Encephalopathy: Often associated with alcoholics due to poor nutrition.
-Symptoms: Ataxia, ocular abnormalities, mental disorder of disproportionate memory loss and confusion.
#36
146
What are the four possible pathways of G6-P, and through what intermediates (if applicable)?
1.) Gluconeogenesis – Glucose
2.) Glycolysis – F6-P
3.) PPP
4.) Glycogen – G-1P
#38
147
Of the lipid types, ________ are most prone to ROS damage.
```
Polyunsaturated FAs
#11
```
148
What is the main product of DNA oxidation by ROS?
```
Oxidized GUANOSINE
#11
```
149
Glutathione peroxidase requires what cofactor? To do what?
```
Selenium – To reduce H2O2 (G-SH gets oxidized to G-S-S-H).
#15
```
150
RBCs are totally dependent on ____________ for their supply of NADPH.
the pentose phosphate pathway
| p.283 Lipp
151
1. ) Mutations of which enzyme can lead to ALS? What harmful substance is elevated in this case?
2. ) What are the mitochondrial, cytoplasmic, and extracellular versions of this enzyme?
1.) -Super Oxide Dismutase (SOD).
-Elevated O2•- (ROS super-oxide radical).
2.) Mito: MnSOD
Cyto: CnZnSOD
EC: CuZnSOD
152
The mitochondrial CyP450 system is active is _______ tissues, such as...(4).
Steroidogenic tissues, such as placenta, ovaries, testes, and adrenal cortex.
p.284 Lipp
153
Cyto P450 uses ______ to perform _______ reactions.
```
Uses NADPH to perform HYDROXYLATION reactions.
#27
```
154
1. ) ________ is responsible for over 50% of drug metabolism. How does it do this?
2. ) What is the other version of this?
1.) CYP3A4 – It uses NADPH (a flavoprotein) to reduce P450 + Fe3+ (to Fe2+), and ultimately hydroxylate the drug.
2.) CYP2D6
#29
155
Concerning the bactericidal use of ROS, ________ is needed to make ROS via ________.
```
NADPH is needed to make ROS via NADPH OXIDASE.
#39
```
156
1. ) What is the cause of chronic granulomatous disease?
| 2. ) What are the metabolic and clinical ramifications?
1.) CGD: NADPH Oxidase deficiency – Not able to form ROS (superoxide) in phagolysosome to kill bacteria with MYELOPEROXIDASE (HOCL).
2.) Increase in granulomas (nodules of inflammation) that have sequestered bacteria AND WERE NOT DESTROYED.
*SEVERE PERSISTENT INFECTIONS*
#40
157
1. ) Describe the linking in O-glycans
| 2. ) N-glycans?
1.) -OH group attached to Ser/Thr
2.) NH2 on Asn
#7
158
Describe the O-glycosidic linkages in collagen.
In the case of collagen, there is an O-glycosidic linkage between galactose or glucose and the hydroxyl group of hydroxylysine (HyL).
p.313 Lipp
159
____________ on the surface of red blood cells help provide the ABO blood group determinants.
O-linked oligosaccharides.
| p.313 Lipp
160
Proteins, including glycoproteins, that are destined for cellular membranes, lysosomes, or to be exported from the cell, are synthesized on _________________.
ribosomes attached to the RER.
| p.315 Lipp
161
________________ initially directs these proteins to the RER, allowing the growing polypeptide to be extruded into the lumen. Exception?
An N- terminal hydrophobic sequence.
* No consensus sequence on for O-linked, but Ser/Thr near or adjacent to Pro*
p. 315 Lipp, #9
162
Concerning synthesis of O-linked glycosides, glycosylation begins with the transfer of ______ (from _______) onto the _________________.
GalNAc (from UDP-GalNAc) onto the R-group of a specific serine or threonine.
p.315 Lipp
163
The glycosyltransferases responsible for the stepwise synthesis of the oligosaccharides are bound to the _________ of the ________.
membranes of the Golgi apparatus.
| p.315 Lipp, #9
164
In N-linked glycosylation, there is always a _______. Describe.
```
Consensus sequence: —Asn-X-Ser/Thr—
*Where X = Any amino acid EXCEPT PRO*
#10
```
165
What are three roles of N-linked glycoproteins?
1.) Antibodies — IgG.
2.) Glycoprotein IIb/IIIa on platelets (aggregation and blood clotting).
3.) gp120 (HIV).
#10
166
The synthesis of N-linked glycosides occurs in the _____ of the ______. It requires the participation of the phosphorylated form of _______ (_______), a lipid of the ______ membrane.
1. ) lumen of the RER
2. ) dolichol (dolichol pyrophosphate), a lipid of the ER membrane.
pp. 315-316 Lipp
167
During N-glycosylation, what is the unique 14-sugar oligosaccharide precursor? Where is it built?
This consists of dolichol (an ER membrane lipid) attached through a pyrophosphate linkage to an oligosaccharide containing N-GlcNAc, mannose, and glucose. *This occurs ON AND IN the ER MEMBRANE*
p.316 Lipp
168
________ inhibits N-linked glycosylation. What does it do in O-linked glycosylation?
Tunicamycin – No effect on O-linked.
| p.316 Lipp
169
What is usually the first sugar added in O-linked glycosylation? What is it added to and what type of linkage?
GalNAc in an alpha-1 linkage to Ser/Thr.
170
What is usually the first sugar added in N-linked glycosylation? What is it added to and what type of linkage?
GlcNAc in a ß1 linkage to Asn.
171
Mutations of which enzymes lead to CDGs?
Isomerase and mutase.
172
In N-glycosylation, the 14-sugar oligosaccharide precursor is transferred from the _______ to the protein by ________. This occurs where?
-From the Dolichol phosphate to the protein by OLIGOSACCHARIDE TRANSFERASE (OST).
-This occurs in the lumen of the ER. Whereas some (but not all) of the previous synthesis steps took place in the cytoplasm, attached to the ER membrane, after which it "flipped" inside to the lumen.
≈21:30 L18.
173
In N-glycosylation, the sugars are added to the nascent polypeptide in a process called _______. What does this mean?
Cotranslational synthesis of N-linked glycoproteins.
| This means that as the protein is being made, you are adding the 14-sugar N-block (oligosaccharide).
174
In N-linked glycosylation, before the protein is exported to the Golgi, it is trimmed. What is trimmed and how many sugars are present on the product that is shipped to the Golgi?
1 mannose and 3 glucoses are removed from the previously 14-sugar block. Therefore, 10 sugars are present on the product that is shipped to the Golgi.
175
1. ) Describe the final (maturation) step in N-glycosylation and where it occurs.
2. ) Where did the previous steps occur?
1. ) Further trimming and processing (extension with additional sugars) in the Golgi to generate a complex-type N-glycan on mature glycoprotein.
2. ) The previous steps occurred on the ER membrane (cytoplasm) and within the ER lumen.
176
Concerning N-glycan processing, what is the difference between the complex-type N-glycan and the high mannose-type N-glycan? What is the same in both?
1. ) Complex-type N-glycan processing takes place in the Golgi and contains NO TERMINAL MANNOSE.
2. ) High mannose-type N-glycan processing stops in the ER (does not enter the Golgi) and CONTAINS TERMINAL MANNOSES.
* Both have a COMMON PENTASACCHARIDE CORE*
177
Concerning blood typing, antibodies are present in the ______, whereas antigens are present in the _______.
Antibodies in the PLASMA, antigens in the RBC MEMBRANE.
178
Type-B blood will have what type of antibodies? Antigens?
Anti-A antigens in the plasma, B antigen on the membrane.
179
Group AB blood has what type of antibodies? Antigens?
No antibodies (universal acceptor). A and B antigens.
180
Group O blood has what type of antibodies? Antigens?
Anti-A and anti-B antibodies (can only accept from type-O). It bears the H-antigen (has no antigenic properties, so in functionally has no antigen...UNIVERSAL DONOR).
181
GAGs are attached to a _____ on a core protein covalently via a trisaccharide of ________.
```
Ser via a trisaccharide of Xyl-Gal-Gal
#27
```
182
Due to _______, GAGs assume an extended, "bottle brush" formation.
```
Due to CHARGE REPULSION.
#27
```
183
Due to ______, GAGs repel one another and are surrounded by ________.
-Negative charge
-Water shell
#28
184
_______-chain fats cannot make glucose, but do provide _____________.
-EVEN-chain fats
-But do provide ATP and NADH for its synthesis.
#33, L13
185
What ratio would you want to increase in order to release inhibition of F 1,6-BPtase during gluconeogenesis? How does this work?
Increase Glucagon/Insulin ratio.
-Insulin increases [F 2,6-BP], which is an inhibitor of F 1,6-BPtase and, therefore, gluconeogenesis. By increasing Glucagon, you reduce the [F 2,6-BP] and release inhibition of F 1,6-BP, allowing gluconeogenesis to proceed.
#39, L13
186
Describe the Km/affinity of Fructokinase for fructose? Where is it present and not present?
```
Low Km/High affinity for fructose – Present in liver, not present in MUSCLE, ADIPOSE, or RBCs.
#8
```
187
1. ) Why does aldolase a yield more ATP than aldolase b?
| 2. ) What is the difference is their possible substrates?
1.) Because aldolase a produces DHAP *AND* Glyceraldehyde 3-P, of which only glyceraldehyde 3-P goes on to produce NADH. Aldolase b produces DHAP and *glyceraldehyde,* which does not continue to produce NADH.
2.) They both can metabolize Fructose 1,6-BP, but only ALDOLASE A can metabolize FRUCTOSE 1-P, the product of fructose metabolism by fructokinase.
#8
188
How does mannose enter the glycolytic pathway?
Mannose —Hexokinase—> Man 6-P —Mannose isomerase—> F 6-P.
189
What are the body's two sources of NADPH? What is the 2nd one especially important for?
1. ) HMPS: G 6-PDH, 6-PG DH
2. ) Cytoslic Malic Enzyme: L-Malate —> Pyruvate
* Important for hepatic lipid synthesis*
190
Give the four main functions of NADPH
1. ) F.A. synthesis
2. ) Removal of ROS
3. ) Phagocytose bacteria
4. ) NO synthesis
191
Concerning ROS, what causes CVD?
```
Oxidation of LDL (lipoprotein).
#11
```
192
1. ) What enzyme is present is the peroxisomes of almost all cells?
2. ) What is unique about it?
3. ) Reactants/products
1.) Catalse
2.) Removes H2O2 WITHOUT PRODUCING FREE RADICALS.
3.) H2O2 —> 2H2O + O2
#16
193
Which two enzymes convert H2O2 to H20?
```
Catalase and GPX
#17
```
194
What are the reactants and products of SOD?
```
O2•- —> H2O2
#18
```
195
How does the kidney utilize NADPH and the cyto P450 system?
```
Hydroxylation in Vitamin D synthesis
#28
```
196
Describe the oxidation of ethanol to acetaldehyde. What is this pathway called? What does it require?
```
Ethanol oxidation in the ER utilizes the MEOS pathway which requires CYP2E1 and NADPH.
#29
```
197
1. ) What is an example of Cyt P450 induction? What does it do?
2. ) Repression?
1.) St. John Wort with Cyclosporin (anti-rejection drug) – Induction increases the rate of enzyme synthesis, increases metabolism of the drug and decreases it pharmacologic action.St. John's Wort causes sub-therapeutic levels of cyclosporin.
2.) Repression does the opposite, it represses cyt P450, thus reducing the metabolism of the drug. Results in HIGHER levels of the drug and toxicity, e.g. grapefruit and statins = higher levels of statins and rhabdomyolysis.
#32
198
What are the two phases of CYP in drug metabolism?
1.) Parent drug converted to a polar metabolite by addition of a functional group, e.g. -OH by CYP. If drug is polar enough, it will be excreted. If not, phase 2.
2.) Increased MW due to conjugation, e.g. glucuronate, acetylation.
#31
199
Describe the role of cytochrome P450 reductase. What are other necessary proteins?
```
Part of an ETC found in the ER: P450 interacts with NADPH-cytochrome P450 reductase, a flavoprotein that is necessary for the transfer the reducing equivalents to Cyt P450.
Other proteins that interact with Cyt P450: cytochrome b5, NADH-cytochrome b5 reductase, and heme oxygenase.
#26
```
200
Describe the role cytochrome P450 in drug metabolism
CYP3A4 and CYP2D6 use NADPH and Cyto P450 Reductase to transfer electrons to the Heme of cytochrome and makes the drug more polar by insertion of an OH group (Phase I).
201
Give the formula for NO synthesis
```
Arginine + NADPH +O2 —> NO + Citrulline + NADP+
#42
```
202
Explain the action of NO in dilation of smooth muscle
NO binds —> activates guanylate cyclase —> increase in cGMP —> activation of protein kinase G —> phosphorylation of Ca+2 channels —> decrease in Ca+2 transport —> decrease in Ca+2 dependent mysoin-light-chain kinase —> inactivation of smooth muscle contraction---> dilation
203
Explain the mechanism of Viagra
```
Inhibits the breakdown of cGMP (inhibits phosphodiesterase, PDE5) so that high levels of cGMP remain = high levels of vasodilation.
#43
```
204
1. ) What are the three types of NO synthase? What do they rely upon for action? Give an example of the exception.
2. ) What do they all have in common?
1.) eNOS (endothelial) and nNOS (nuclear) – Both are Ca2+-Calmodulin dependent.
iNOS (inducible) is Ca2+ independent, e.g. NO + ROS —> OH·
*iNOS is induced by bacterial lipopolysaccharides and gamma-interferon released during infections*
2.) They all required NADPH for action.
#45
205
Explain the action of NO in dilation of smooth muscle
NO binds —> activates guanylate cyclase —> increase in cGMP —> activation of protein kinase G —> phosphorylation of Ca+2 channels —> decrease in Ca+2 transport —> decrease in Ca+2 dependent mysoin-light-chain kinase —> inactivation of smooth muscle contraction---> dilation
206
Explain the mechanism of Viagra
```
Inhibits the breakdown of cGMP (inhibits phosphodiesterase, PDE5) so that high levels of cGMP remain = high levels of vasodilation.
#43
```
207
What are the three types of NO synthase? What do they rely upon for action?
```
eNOS (endothelial) and nNOS (nuclear) – Both are Ca2+-Calmodulin dependent.
iNOS (inducible) is Ca2+ independent, e.g. NO + ROS —> OH·
*iNOS is induced by bacterial lipopolysaccharides and gamma-interferon released during infections*
#45
```
208
What role does NO play in anti-platelet aggregation?
Inhibitory effect of NO on platelets is mediated by NO-induced activation of soluble guanylyl cyclase:
Anti-Aggregation.
#46
