Biochemistry - Post Mid-term Flashcards
1
Q
What is another name for GAG’s?
A
Mucopolysaccharides
2
Q
What are GAG’s?
A
Long, unbranched chains of negatively charged sugars
* Repeating disaccharide units
3
Q
What are proteoglycans?
A
Many GAG’s linked to a protein chain
95% sugar, 5% protein
4
Q
What is a proteoglycan monomer?
A
Central core protein
* Many disaccharide units linked via trihexoside bond
5
Q
Are GAG’s positively or negatively charged?
A
Negative – contributes to the bottle-brush structure (slippery mucus + synovial fluid)
6
Q
Which of the GAG’s is NOT sulfated?
A
Hyaluronic acid
7
Q
Where is hyaluronic acid synthesized?
A
Integral plasma membrane protein (other GAG’s in the rER)
8
Q
What is a proteoglycan aggregate?
A
Long, central strand of hyaluronic acid & proteoglycan monomers
- NOT covalently bound
- Use link proteins
- Aggregate can function as shock absorber
9
Q
Where is proteoglycan aggregate assembled?
A
Extra-cellular space
* Proteoglycans synthesized intracellularly
10
Q
What is found at position 1 & 2 of GAG disaccharides?
A
1: acid sugar (glucuronic or iduronic acid)
2: amino sugar (N-acety-amino sugar)
11
Q
Where are most GAG’s found?
A
Extracellularly
EXCEPT: Heparin – found in mast cells lining the lungs, liver & skin
12
Q
Who is sulfated more: heparin or heparan sulfate?
A
Heparin
13
Q
A deficiency of GAG’s can lead to:
A
OA
14
Q
What is the function of heparin?
A
Anti-coagulant
* Can prevent clotting during surgery
15
Q
What is warfarin?
A
Synthetic vitamin K; slower acting than heparin
16
Q
Describe the synthesis of a proteoglycan monomer.
A
- Core protein enters rER
- Protein O-glycosylated @ serine by glycosyl transferases in Golgi
- Trihexisode linkage (xylose, galactose, galactose) formed & UDP-glucuronic acid and UDP-amino sugars used to synthesize disaccharide units
17
Q
Who sulfates GAG’s?
A
PAPS (phospho-adenosyl-phospho-sulfate)
18
Q
Why is sulfation of GAG’s important?
A
Make the GAG’s even more negatively charged
19
Q
A defect in sulfation can lead to…
A
Chondrodystrophy (disorder of development and maintenance of skeletal system)
20
Q
Which GAG is unsulfated?
A
Hyaluronic acid
21
Q
What is a glycoprotein?
A
90% protein; 10% sugar (attached in O- or N- glycosylation)
22
Q
Where is hyaluronic acid found?
A
Synovial fluid
Vitreous humor of eye
* Shock absorber, lubricant (not covalently attached to protein)
23
Q
Which 2 GAG’s are found in cartilage?
A
Chondrotin sulfate
Keratin sulfate
24
Q
Where is dermatin sulfate found?
A
Skin, vessels, heart valves
25
Where is heparan sulfate found?
Basement membranes (more acetylated glucosamine than heparin)
26
Where is keratan sulfate found?
Cartilage, bone, cornea
27
Where is chondriotin sulfate found?
Cartilage, bone, heart valves
28
Which is the most abundant GAG?
Chondrotin sulfate
29
Which plasma protein is not a glycoprotein?
Albumin
30
What are the functions of glycoproteins?
Cell surface recognition, antigen presenters, mucins
31
What are mucins?
Glycoproteins with 80% sugars
* Long protein core, negatively-charged NANA or sialic acid linked to amino sugars
* Attract water; resistent to proteolysis by digestive enzymes
32
Are the sugars in blood group proteins N- or O-linked?
O-linkage at serine or threonine residues
33
Describe O-glycosylation
Step-by-step linkage of activated sugarts
| * First sugar linked to -OH group (serine or threonine or hydroxylysisne during procollagen synthesis)
34
Describe why O-glycosylation is special for collagen synthesis.
Sugar linked to -OH group of hydroxylysisne during procollagen synthesis
35
What is the only exception to the O-glycosylation rule?
Self-glycosylation of tyrosine residue performed by glyocgenin during glycogen synthesis
36
Describe N-glycosylation
Does not individually link sugars directly to the protein chain
* Uses dolichol-PP
* Sugar precursor attached to N of ASPARAGINE
37
N-glycosylated proteins can contain...
1. Complex oligosaccharides
| 2. High-mannose
38
Can glutamine be involved in N-linked glycosylation?
NO - only asparagine
39
Which lipid is used as a precursor for N-glycosylation?
Dolichol-PP
40
How many mannose residues are found in the finished sugar precursor in N-linked glycosylation?
9
41
Complex N-glycosylation proteins include:
N-acetylglucosamine, NANA, L-fucose
42
In what form is activated mannose during N-glycosylation?
GDP-mannose
43
Which are the X-linked lysosome storage diseases?
Hunter disease
| Fabry disease
44
Are lysosomal enzymes O- or N- glycosylated?
N -- mannose-6-p
45
Which enzyme is deficient in the sphingolipidoses Tay Sachs, Fabry, Gaucher and Niemann-Pick Disease, metachromatic leukodystrophy, respectively?
```
Tay Sachs Disease: hexosaminidase A
Fabry Disease: alpha-galactosidase
Gaucher Disease: glucocerebrosidase
Niemann Pick Disease: sphingomyelinase
Metachromatic: aryl sulfatse
```
46
Which compounds accumulate in Tay Sachs, Gaucher, Fabry, Niemann-Pick Disease, & metachromatic leukodystrophy, respectively?
Tay Sachs Disease: GM2
Gaucher Disease : glucocerebrosides
Fabry Disease: globosides (ceramide trihexoside)
Niemann-Pick Disease Type A and B: sphingomyelin
Metachromatic: sulfatide
47
Describe the differences between Niemann-Pick Disease Type A and Type B.
A: infantile, deadly
B: late childhood onset - no neurodegen
48
What is the most common lysosomal storage disorder?
Gaucher
49
What is a sphingolipid?
Lipid with sphingoside alcohol
50
What is a ceramide?
Sphingosine + fatty acid
51
What are 2 types of sphingolipids?
1. Glycosphingolipids (Ceramide + carb)
| 2. Spingophospholipids (sphingomyelin) (Ceramide + phosphorylcholine)
52
The enzyme required for lipolysis is
Hormone sensitive lipase
| Active when phosphorylated -- epinepherine
53
The first enzyme in the activation of fatty acids is:
Thiokinase (fatty acyl coA synthetase)
| * Requires 2 ATP
54
The 2 enzymes and shuttle required to transport fatty acyl coA across the mito membrane...
CPT1 (inhibited by malonyl-CoA -- product of TAG synthesis)
CPT2
Carnitine shuttle
55
Who inhibits CPT1?
Malonyl CoA (product of TAG synthesis)
56
The 4 steps of beta-oxidation of fatty acids
1. Oxidation - FAD - MCAD
2. Hydration
3. Oxidation - NAD+
4. Cleavage
57
A 16 C fatty acid will be broken into...
8 acetyl CoA's
7 FADH
7 NADH
58
An MCAD deficiency results in:
Fasting hypoglycemia
Hypoketosis
Increase serum fatty acids
Increase dicarboxylic acids in urine
59
Jamacian vomiting sickness is a result of eating an unripe ackee fruit...
Hypoglycin A (MCAD inhibitor)
60
Oxidation of odd-chain FA's requires 2 cofactors
Biotin (proprionyl coA carboxylase) & B12 (methylmalonyl coA mutase)
61
This syndrome results from defective peroxisomal biogenesis...
Zellweger syndrome
62
This sydrome results from inability to metabolize branched chain FA's (alpha-oxidation)
Refsum disease (phytanyl coA alpha-hydroxylase)
63
This is a small pathway of FA oxidation (and its product can be elevated w/ a beta-oxidation deficiency)
Omega-oxidation (dicarboxylic acids)
64
The 3 enzymes required for ketogenesis are...
1. Tholase (acetoacetyl coA)
2. HMG coA synthase (HMG coA)
3. HMG coA lyase (acetoacetate)
65
Which enzyme of ketogenesis is also used in cholesterol synthesis?
HMG coA synthase (cytosol-cholesterol; mito-ketogenesis)
66
For the utilization of ketone bodies, the key enzyme is:
Thiophorase (NOT present in liver)
| Acetoacetate --> acetoacetyl coA
67
DKA results from
```
Inadequate insulin (more likely in DM1)
* Acetone breath from excessive ketogenesis
```
68
Name the two main sites of fatty acid de novo synthesis in humans.
1. Liver
| 2. Lactating mammary gland
69
Where does fatty acid synthesis take place within the cell?
Cytoplasm
70
What are the 2 essential (dietary) fatty acids?
1. Omega-6: Linoleic acid
| 2. Omega-3: alpha-linolenic acid
71
Who is the precursor to arachidonic acid?
Omega-6, linoleic acid
72
When is fatty acid synthesis likely to occur?
After a high carbohydrate meal
73
Which metabolic condition leads to high citrate levels in liver mitochondria?
High carbohydrate diet
74
What is the fate of increased citrate?
Trasported to the cytosol
75
What enzyme & co-factors are necessary for the reaction citrate --> acetyl coA?
ATP, coA
* Enzyme: citrate lyase
* Occurs in cytosol
76
Which enzyme in the mitochondria is inhibited by high levels of ATP during fatty acid synthesis?
Isocitrate DH
77
What are the 4 methods to generate acetyl coA in the mitochondria?
1. PDH
| 2. Degradation: FA, ketone bodies, AA's
78
Describe the cellular location and the reaction catalyzed by the malic enzyme!
* Liver cytosol
Oxaloacetate --> Malate --*--> Pyruvate
* Generates NADPH
* Irreversible reaction
79
What is the rate-limiting enzyme for fatty acid synthesis?
ACC (acetyl-coA carboxylase)
Acetyl CoA --> malonyl CoA
80
What 3 cofactors does acetyl coA carboxylase require?
Biotin, CO2, ATP
81
What 2 molecules can be used to carboxylate acetyl coA to malonyl coA?
1. CO2
| 2. Bicarbonate (HCO3-)
82
In what form is acetyl coA carboxylase active/inactive? Who promotes allosteric activation/inactivation?
Active: polymer>dimer (CITRATE)
Inactive: dimer>polymer (PALMITOYL COA)
83
Describe the allosteric, hormonal & long-term activation of ACC.
* Polymerized-form
1. Citrate
2. Insulin (de-phosphorylates)
3. High carb, low fat diet
84
Describe the allosteric, hormonal & long-term inactivation of ACC.
* Dimer-form
1. Palmitoyl coA / long chain fatty acyl coA's
2. Glucagon, NE/E (phosphorylates - cAMP)
3. High fat diet, fasting, glucagon
85
Which form of FAS is active?
Dimer
86
What is the name of the multifunctional enzyme that catalyzed 7 different reactions in fatty acid synthesis?
FAS (fatty acid synthase)
87
The synthesis of palmitate from malonyl coA requires...
14 NADPH
| 7 ATP
88
How many carbons are in malonyl coA?
3 C
89
Briefly describe the process of palmitate synthesis from malonyl coA?
2 arms: acetyl coA (sulfhydrl) condensing arm added to the ACP (acyl carrier peptide) arm which has malonyl coA (CO2 released)
90
What are 2 typical modifications of palmitate, once formed? Where does these modifications occur?
1. Chain elongation (ER -- add malonyl CoA's or mito -- reversal beta-oxidation)
2. Desaturation at C's 5, 6, 9 (ER)
91
What makes linoleic & alpha-linolenic acid essential?
They have double bonds beyond C # 9
92
Name 2 ways to form NADPH.
1. PPP
| 2. Malic enzyme (malate --> pyruvate)
93
Glucose is to glycogen, as fatty acids are to:
TAG
94
Why is palmitoyl CoA the feedback inhibitor of ACC & not palmitate?
Palmitate has detergent character to cell membranes
95
Where in the human cell are long chain fatty acids elongated, in the FA synthase complex or in the ER or in mitochondria? Where in the cell are fatty acids desaturated? Which enzyme is involved?
In humans, fatty acids are elongated and desaturated in the ER using their activated form as fatty acyl CoA.
The enzyme involved in desaturation contains cytochrome b5.
96
Is docosahexaenoic acid (DHA 22:6, 3) synthesized in humans from linoleic acid, from -linolenic acid, or from arachidonic acid? Why is DHA so important?
DHA is synthesized in humans from linolenic acid3 family.
Linoleic acid (18:2) and arachidonic acid (20:4) are of the 6 family and cannot be used.
DHA is needed in the fetus and infants for brain and visual development and later
on in adults for general brain metabolism.
97
List the 4 major sites of TAG synthesis in humans.
1. Liver
2. Fat
3. Lactating mammary gland
4. Intestinal mucosa
98
Discuss 2 ways glycerol-3-phosphate can be formed.
1. Glycerol --*glycerol kinase*--> glycerol-3-p
| 2. DHAP --*NADH*--> glycerol-3-phosphate
99
Why is TAG synthesis in the intestinal mucosa cells simplified?
TAG --*panc lipase*--> MAG --*2 acyl coA*--> DAG, TAG (no need for phosphatidyl intermediate)
* Necessary b/c intestinal mucosa cells have to resythesize a large amount of dietary TAG's
100
What is unique about TAG synthesis in the liver?
Can pick up free glycerol in the blood (glycerol kinase) --> glycerol-3-phosphate
101
What is the intermediate in TAG synthesis in the liver & fat?
Lysophosphatidic acid
102
Desaturation of fatty acids requires:
1. Cytochrome B5
2. Desaturase
3. NADPH-cytochrome B5 reductase
103
Which fatty acid is generally used to synthesize eicosanoids?
Arachidonic acid (precuror: Linoleic acid - omega-6)
104
How many carbons in an eicosanoid?
20
105
What cells DO NOT synthesize eicosanoids?
RBC's
106
Which cell type synthesizes mainly prostacyclin and which cells synthesizes mainly thromboxane?
Prostacyclin: endothelial cells
Thromboxane: platelets
107
Which phospholipase can be used for direct release of arachidonic acid out of phospholipid membranes?
Phospholipase A2 (cleaves FA in position 2 of the glycerol backbone)
108
Which hormone inhibits the release of arachidonic acid by inhibition phospholipase A2?
Cortisol (glucocorticoid)
109
How can eicosanoids act?
Locally
1. cAMP
2. PLA2 (inc. Ca)
110
Describe the relationship between phospholipase C, PIP2, IP3 & DAG
PLC cleaves PIP2 to generate IP3 & DAG
111
Within the cell, arachidonic acid resides at _____ postion of the membrane phospholipids.
C-2
| * Hence, PLA2 cleaves phosphatidylinositol
112
Who cleaves PIP2 to generate arachidonic acid?
PLA2
113
NSAID's
COX-1 & COX-2 inhibtors
114
Cortisol
PLA2 + COX-2 inhibitor
115
Celecoxib
Celebrex (selective COX-2 inhibitor)
116
Which NSAID is an IRREVERSIBLE inhibitor of COX?
Aspirin
117
Who promotes COX-2?
Cytokines, endotoxin, tumor promotors, growth factors
118
Differentiate between COX-1 & COX-2.
COX-1
* Constiutive, all tissues
* Normal physio fx: gastric secretion, renal blood flow, homeostasis
COX-2
* Non-constituitive (liver, macrophages) in response to immune response
* Increased prostaglandin synthesis --> PAIN, HEAT, REDNESS, HEAT, SWELLING, FEVER
119
Induction of COX-2 results in:
Pain, heat, redness, swelling, fever
120
Aspirin reversibly/irreversiby in COX by...
1. Irreversibly
| 2. Acetylating a serine residue in the active site
121
Differentiate between TXA2 & PGI2
TXA2: vasoconstriction/platlet aggregation
PGI2: vasodilation/decreased platlet aggregation
122
The 2 effects of 81 mg aspirin:
1. Reduced TXA2 synthesis (dec clotting)
| 2. NO significant effect on PGI2
123
To overcome the irreversible inhibition by low dose aspirin...
Synthesize more COX
124
Why does low dose aspirin not affect prostaglandin, but affect thromboxane?
Prostagland - vascular endothelium (can synthesize more COX1)
Thromboxane - eunucleated platlets -- must wait 7-10 days before NEW platlets are synthesized
125
Who is responsible for bronchoconstriction?
Thromboxane
126
How might dietary fish oil prevent inflammation?
Omega-3 --> EPA --> TXA3 & PGI3 (reduced clotting)
127
The immediate precursors to PGI2 & TXA2 are:
PGG2 --> PGH2
128
Leukotrienes are secreted during...
Allergic/hypersensitivity reactions
129
Who uses LTA?
- Mast cells
| - Eosinophils
130
LTA --> LTC?
Addtion of the tripeptide glutathione
131
Who are the cysteine-leukotrienes?
LTC, LTD, LTE
132
LTC, LTD, LTE ...
Increase vascular permeability, and lead to severe bronchoconstriction, vasoconstriction & lung edema
133
The enzyme responsible for leukotriene synthesis:
lipoxygenase
134
3 possible treatments for asthma:
1. Steroids / inhibit release arachidonic acid
2. Lipoxygenase inhibitor
3. Cysteinyl-leukotriene receptor antagonists
135
Would you expect COX-2 in platlets?
COX-2 synthesis is induced. Protein synthesis is not possible in platelets and therefore one would not expect COX-2 in platelets.
136
What is the effect of low dose apirpin on COX?
COX-1 on platelets -- unable to synthesize thromboxane
137
What is the function of prostaglandins?
1. Gastric protection (+ mucus, - acid)
| 2. Renal BP regulation
138
Compare the 2 to the 3 series of PG & TX.
PGI2 = PGI3
TXA2 > TXA3
* Hence, a diet rich in omega-3's will favor prevetion of blood clotting due to weaker TXA3
139
Why will a diet a diet rich in omega-3's favor prevention of blood clotting?
Weaker TXA3
140
Name the intermediate that is formed in the linear pathway from arachidonic acid in the synthesis of leukotriene A4.
5-lipoxygenase forms 5-HPETE
141
LBTB4 ...
acts mainly as chemo-attractant for neutrophils in blood
142
LTC4 lead to...
Severe bronchioconstriction
143
Name the components of the slow reacting substance of anaphylaxis (SRS-A). Is SRS-A stronger or weaker than histamine?
SRS-A contains LTC, LTD and LTE. It is much more potent than histamine.
144
Which molecule is linked to LTA4 in order to form LTC4?
Tripeptide glutathione
145
Why are LTC, LTD and LTE named cysteinyl-leukotrienes?
All contain covalently bound a cysteinyl-group that originated in glutathione.
146
Describe the anti-inflammatory action of glucocorticoids related to inhibition of release of arachidonic acid.
Corticosteroids inhibit the release of arachidonic acid by inhibition PLA2 & also COX-2
147
Compare the actions of PGE to PGF2
Vasoconstriction is performed by PGF 2
| Vasodilation is performed by PGE2
148
Name four major functions or usages of cholesterol!
a. Cholesterol modulates the correct fluidity of the plasma membranes
b. Cholesterol is used only in the liver for synthesis of primary bile acids
c. Cholesterol is used for steroid hormone de novo synthesis only in the adrenal cortex, ovaries and testes.(not in the liver)
d. An intermediate of cholesterol synthesis is used in the skin for the formation of vitamin D (process needs UV light)
149
In which cells does cholesterol synthesis mainly take place? In which cell compartment? Why are mitochondria needed?
Cholesterol synthesis takes place mainly in the hepatocyte and in cells of the adrenal cortex and in the brain.
* Takes place in cytosol; mito needed for citrate (citrate lyase)
150
What are the 3 major sources of liver cholesterol?
1. Diet
2. Lipoproteins (HDL, LDL)
3. De novo synthesis
151
The liver sends cholesterol 3 places. What are they?
1. Secrete in HDL/VLDL
2. Free cholesterol in bile
3. Bile salts/acids
152
What percentage of dietary fat is cholesterol?
10% (Majority is TAG's)
153
The key regulated enzyme in cholesterol synthesis...
HMG CoA reductase
154
HMG CoA reductase is regulated by...
Negative: glucagon, AMP kinase, high cholesterol diet, cholesterol, statins
Positive: insulin
155
HMG CoA reductase is activated when phosphorylated/dephosphorylated
Dephosphorylated
156
Cholesterol has how many C's?
27
157
The side products of cholesterol synthesis are...
1. Dolichol & Ubiquinone (IPP & FPP)
| 3. Protein prenylation (GPP & FPP)
158
Why are so many pyrophosphates needed in cholesterol synthesis?
Necessary to make the intermediates soluble in the cytosol
159
What is the location of the key enzyme of cholesterol synthesis?
ER membrane-bound
160
What is the paradox associated with statin use?
Statins reduce the amount of cholesterol produced by competitively inhibiting HMG CoA reductase
* The decreased cholesterol paradoxically causes upregulation of the enzyme (by release of SREBP, which binds to SRE region of HMG coA reductase gene & increases transcription)
161
HMG CoA reductase is regulated by intracellular/extracellular cholesterol.
Intracellular cholesterol
162
What is the acronym for the protein released when intra-cellular cholesterol is low?
Sterol regulatory element binding protein (SREBP)
163
Who activates SREBP?
SCAP
164
Statins have 4 major effects
1. Increased LDL receptor on cell surface
2. Increased uptake of LDL from serum
3. Decreased serum cholesterol
4. Increased HMG CoA reductase transcription -- SREBP (paradox)
165
In the liver, a high concentration of cholesterol...
Leads to degradation of HMG CoA reductase by the ubiquination system in proteasomes
166
Low intracellular cholesterol leads to...
1. Upregulation of LDL receptors
| 2. Synthesis of cholesterol
167
Which enzyme promotes the storage of cholesterol esters?
ACAT
168
SLOS (Smith Lemli Opitz Syndrome)
* Auto recessive cholesterol synthesis problem
* Deficiency of 7-dehydrocholesterol reductase
* X double-bond formation, ring B, partially deficient
169
The difference between Hunter syndrome & Hurler syndrome
Mucopolysaccaridoses
* Hurler: iconidase
* Hunter: iconidate
* Both lead to build-up of dermatin & keratin sulfate
* Hunter --> no occular problems
170
True/False. Cholesterol can be metabolized by humans
False -- ring structure cannot be metabolized
171
Elimination of cholesterol
Cholesterol --> Bile acids --> Feces
172
Cholesterol is modified by intestinal bacteria to form...
1. Cholestanol
| 2. Coprostanol
173
The rate limiting enzyme of bile acid synthesis is: (mention products & regulation)
7-alpha-hydroxylase
* Products: cholic acid & chenodeoxycholic acid
* +: cholesterol
* -: cholic acid
174
What is the difference between bile acids & bile salts?
Bile salts are bile acids conjugated with glycine or taurine.
* Bile salts are much more effective at solubilizing lipids than bile acids
175
What are the 2 major bile salts?
1. Glycocholic acid/glycochenodeoxycholic acid
| 2. Taurocholic acid/Taurochenodeoxycholic acid
176
The major organic components of bile...
1. Phosphatidylcholine (lecithin)
| 2. Bile salts
177
What is the fate of bile salts & acids?
97% are recycled by portal circulation
178
The action of intestinal flora on bile salts...
1. Remove taurine/glycine
| 2. Convert primary bile salts into secondary bile salts by removing hydroxyl (deoxycholic acid & lithocholic acid)
179
Cholelithiasis is caused by...
1. Deficiency of lecithin (phosphatidylcholine) &/or bile salts
* Causes cholesterol in bile to precipitate in the gall bladder
180
The difference between cholesterol gallstones vs. black pigment gallstones
Chol: cholesterol
| Black pigment: bilirubinate (less common)
181
4 treatments for cholelithiasis
1. Surgery
2. Chenodeoxycholic acid (chenodiol)
3. Shock wave disintegration
4. Contact exposure methyl-tert-butyl ether
182
If a gallstone obstructs the ampulla of Vater...
Acute pancreatitis
183
What are the 4 functions of bile acids?
1. Excretion of cholesterol in feces
2. Solublize cholesterol (prevent precipitation in bile)
3. Emulsify dietary TAG's for pancreatic lipase
4. Intestinal absorption of fat-soluble vitamins (ADEK)
184
Who are the 4 fat-soluble vitamins?
A, D, E, K
185
What is the difference between primary and secondary bile salts?
Secondary bile salts are de-conjugated (glycine & taurine) & de-hydroxylated
* deoxycholic acid + lithocholic acid
186
Many ____ coenzymes are used in cholesterol synthesis.
NADPH
187
What is the broad concept of cholesterol synthesis?
The concept is to form a five-carbon building block that is used six times to form
a 30 carbon molecule.
188
What is the 5-carbon building block of cholesterol synthesis & how is it formed?
isopentenyl-PP (IPP). It is formed by
| decarboxylation of mevalonyl-PP.
189
Lipoproteins contain a phospholipid monolayer/bilayer?
Monolayer (mostly PC)
190
What is needed for the appropriate function of lipoproteins?
Apo-lipoproteins
191
Chylomicron release from intestinal mucosal cells requires...
Apo B-48
192
VLDL release by the liver requires...
Apo B-100
193
In order to be taken up by the liver, IDL's & chylomicron remnants require...
Apo E
194
VLDLS are cleaved to... What is the fate of these molecules?
IDL's by LPL
| * 50% to the liver; 50% cleaved by HTLG to LDL
195
What is the difference between hepatic lipase and lipoprotein lipase?
LPL -- capillaries of heart, adipocytes
| Hepatic lipase -- capillaries of liver
196
What is the fate of LDL's?
70% to the liver
| 30% extra-hepatic -- steroid synthesis, cell membranes
197
An unfortunate consequence of high serum LDL...
oxLDL --> invade macrophages via SR-A1 --> foam cells
198
3 risk factors for coronary heart disease (with respect to LDL)
1. Foam cells
2. LDL-pattern B (smaller / can be trapped in ECM)
3. LP (A)
199
What is Lp (a)?
Covalently bound (disulfid bond) to apo-B-100
* Structural analog to plasminogen & can compete with plasminogen for binding to fibrin
* Reduce removal of blood clots & could trigger MI/Stroke
200
How do the various lipoproteins separate using gel electrophoresis after a fast?
1. Chylomicrons stay at origin (s travel furthest
201
Abnormal lipoprotein metabolism can be divided into...
1. Hyperlipidemia
- -HyperTAG -- 1, 4, 5
- -HyperChol -- 2, 3
2. Hypolipidemia
- -Hypoalphalipoproteinemia
- -Abetalipoproteinemia
202
Hypertriacylglycerolemias lead to ... (serum)
TAG blood values
203
What is the difference between Hyperlipidemia I, IV, V
I: chylomicrons (a-LPL; b-APO C-2; c-LPL inhibitor)
IV: VLDL (common) (LPL deficiency)
V: VLDL & chylomicrons
204
What is the difference between hyperlipidemia 2 & 3?
2A- Familial hypercholesterolemia - defective LDL receptor - elevated LDL
2B- elevated LDL & VLDL
3 - dysbetalipoproteinemia - high remnants (IDL & chylo remnants)
Homo - APO E-2 -- less effective (E rhymes with 3)
205
Statins can be used to treat ...
Hyperlipidemia 2A
206
Differentiate between statins & bile acid sequesterants...
Statins -- competitive inhibitors of HMG CoA reductase (inc LDL receptor syn & paradoxically increase HMG CoA reductase transcription)
Bile acid sequesterants -- excrete bile acids/salts in feces; liver makes more, thus lowering cholesterol
207
What does the liver use cholesterol for?
Synthesis of bile salts/acids
208
4 major components of bile
1. Conjugated bile salts
2. PC
3. Free cholesterol
4. Conjugated bilirubin
209
T/F There is a storage form of nitrogen in humans
False
210
What are the 3 ways to contribute to the amino acid pool in the body?
1. Protein synthesis / turnover
2. Dietary
3. AA synthesis (non-essential)
211
What area the 2 major ways AA's are used in the body?
1. Catabolism (urea, C-skeleton)
| 2. Synthesis of N-containing compounds
212
What are several N-containing compounds?
Heme, creatine, neurotransmitters, purines, pyramidines
213
What are the dietary essential amino acids?
```
P-phenylalanine
V-valine
T-threonine
T-tryptophan
I-isoleucine
M-methionine
H-histadine
A-argininine
L-leucine
L-lysine
```
214
Which are the 3 conditional non-essential amino acids?
1. Cysteine (methionine)
2. Tyrosine (phenylalanine)
3. Arginine
215
What are the 2 major methods of protein degradation?
1. Lysosome (extra-cellular/cell-surface proteins)
| 2. Proteasome/ubiquitination -- proteins syn. by cell
216
What are the 4 ways proteins are turned over in the body?
1. Oxidative damage
2. Denaturation - hydrophobic core exposed
3. Ubiquination - ATP dept.
4. PEST (proline, glutamate, serine, threonine) sequences -- short 1/2 life
217
T/F Ubiquination is an ATP dependent process
True
218
What is the fate of ubiquitin post-proteasome?
Recycled
219
What can result from an inappropriate release of lysosome components from WBC's into the joints?
Inflammatory disease
220
What is the pH environment of the lysosome?
Acidic
221
Where do most AA's release their amino groups as ammonia?
Liver
222
What is the fate of NH3?
Detoxified to urea
223
What are amino acid carbon skeletons used for?
1. GNG
| 2. Burned in TCA cycle
224
Urea made in the liver is transported to the __________ for excretion.
Kidney
225
How can the kidneys excrete ammonia as ammonium ions?
Glutamine (glutaminase ion)
226
What are 2 examples of non-protein nitrogenous substances excreted by the kidney?
1. Uric acid (purine degrad)
| 2. Creatinine (creatine degrad)
227
What is the major nitrogenous product excreted in the urine?
Urea (86%)
228
Describe the reaction: glutamine --> glutamate + NH4+
Glutaminase (kidney)
229
How are amino acids absorbed at the intestinal brush border?
Secondary active transport
| Na/K gradient; portal vein w/ own gradient
230
What is one major cause of renal stones in children?
```
Cystinuria (COAL)
C- cystine
O- ornithine
A- arginine
L- lysine
* Cystine excreted and urine, can precipitate & cause stones
```
231
What disease results from a defect in transport of neutral amino acids, i.e. tryptophan?
Hartnup's disease
| * Can result in NAD+ deficiency (pellagra)
232
From what amino acid do you synthesize NAD+?
Tryptophan
233
What disease results from the lack of NAD+?
Pellagra
234
Tissue protein catabolism results in ...
Amino acids (amino group off, or to anthoer alpha-keto acid)
2. Alpha keto acid
3 & 4 -- pyruvate/glucose (glucogenic); acetyl coA (ketogenic)
235
Differentiate between:
Essential vs. Non-essential AA
Glucogenic vs. Ketogenic AA
Essential: cannot be synthesized by human
Glucogenic: substrates for GNG (pyruvate) or TCA intermediate
Ketogenic: acetoacetate, acetyl CoA, acetoacetyl CoA
236
What are the 2 major ketogenic AA's?
Leucine, Lysine (acetoacetyl-CoA)
237
What 2 AA's can be used to make alpha-ketoglutarate?
Glutamate, glutamine
238
What types of amino acids can be used to make succinyl coA?
BCAA's (isoleucine, valine)
239
What 2 AA's can be used to make fumerate?
Phenylalanine, tyrosine
240
What two amino acids can be used to make oxaloacetate?
Asparagine, aspartate
241
What AA can be used to make pyruvate?
Alanine
242
What enzyme catalyzes the reaction involving alanine?
Alanine -*ALT + B6*-> Pyruvate
| * Amino group transferred to alpha-ketogluterate to form glutamate
243
The glucose-alanine cycle involves what two organs?
Muscle (form pyruvate) & liver (GNG)
244
The major transport AA during starvation...
Alanine
245
Is the reaction between alanine & ALT reversible?
Yes
246
What enzyme is often used for the treatment of leukemia?
Asparaginase (reduced availability of asparagine inhibits tumor growth)
247
3 enzymes are capable of incorporating free ammonia.
1. Glutamate DH
2. Glutamine synthetase
3. CPS I
248
Where is glutaminase active?
Renal tubule/liver
249
Where is glutamine synthetase active?
BRAIN & endothelial cells of the hepatic vein
250
Which enzyme is particularly helpful in picking up free ammonia in the brain?
Glutamine synthetase
251
The reversible reaction in glutamate metabolism...
```
Glutamate DH (liver-oxidation)
Reverse reaction (uses free ammonia) to make glutamate
```
252
The enzyme Glutamate DH requires...
NAD+
253
The enzyme AST requires...
PLP (B6)
254
The metabolism of aspartate...
Aspartate --> Asparagine (asparagine synthetase -- uses free glutamine, not ammonia)
255
The 3 major disorders of Phe/Tyrosine metabolism:
1. PKU 1 (PAH), Maternal, 2 (malignant - BH2 reductase) -- mousey urine
2. Alkaptonuria -- homogentisic acid oxidase -- dark urine
3. Tyrosinemia -- cabbage urine -- fumerylacetoacetate hydrolase
256
The 2 major disorders of branched chain AA deficiency...
1. MSUD - branched chain alpha-ketoacid DH (+ B1) -- ketosis + maple syrup urine
2. Methylmalonic aciduria (methylmalonyl CoA mutase + B12) -- seizures, encepholapthy
257
What is homocystinuria?
Cystathione beta-synthase deficiency
| * Disruption of C/T (collagen!) -- osteoporosis, lipid deposits
258
What are the 2 fates of homocystein?
1. Recycled to methionine
| 2. Sulfur delivered to serine to form cysteine
259
Transamination reactions require...
PLP (Vitamin B6)
260
How is NH3 transported from peripheral tissues?
1. Glutamine
| 2. Alanine
261
Transamination reactions, in general, use this as an amino acceptor...
Alpha-ketogluterate
262
What is the fate of urea from the liver?
75% - kidney
| 25% - gut / ureases & proteases
263
The urea cycle has 2 N donors
1. Glutamate (ammonia)
| 2. Aspartate
264
Where does the urea cycle take place?
Liver (1 & 2 - mitochondria; 3-5 - cytosol)
265
The major regulated enzyme of the urea cycle.
CPSI (requires NAG n-acetyl glutamate)
266
N-acetylglutamate (NAG) formation can be stimulated by...
Arginine
267
For which congenital hyperammonemia disorder is it not kosher to give arginine?
Arginemia
268
The 5 enzymes required for the urea cycle:
1. CPSI (NAG)
2. OTC
3. ASS
4. ASL
5. ARG
269
Treatment for hyperammonemia (congenital)
1. Dialysis
2. Benzoic acid (benzyl CoA -*glycine*-> hippurate)
3. Phenylbutyrate --> phenylacetate --> phenylacetylglutamine
4. Low protein diet
270
Acquired hyperammonemia
- Porto-systemic shut of ammonia
| - Neurotoxicity
271
3 treatments for acquired hyperammonemia
1. Low protein diet
2. Lactaluslose (produces lactic acid -- can be neutralized by NH4+)
3. Neomycin (antibiotic that can reduce bacterial urease in the gut)
272
What is an antibiotic that can reduce gut urease activity?
Neomycin
273
What are the 2 prevailing hypotheses related to neurotoxicity secondary to hyperammonemia?
1. Energy (taking up TCA intermediates alpha-KG --> glutamate)
2. Neurotransmitter (decreased GABA & glutamate)
274
Parkinson's Disease
* Loss of dopamine producing cells in basal ganglia
* Admin: L-dopa (with a dopa decarboxylase inhibitor)
* Neurodegenerative movement disorders
275
Serotonin is synthesized in...
Gut, platelets, CNS
276
Pheochromocytoma
Elevated VMA & catecholamines (urinary)
* Episodic -- headache, thirst, tachy
* Adrenal medulla tumor
277
Synthesis of serotonin
Tryptophan -*BH4*-> 5 hydroxytryptophan -*AA decarboxylase*-> serotonin
278
The phenylalanine cascade...
Phe -*PAH*-> Tyr -*TH*-> L-DOPA -*decarboxylase*-> DOPAMINE -*hydroxylase*-> NE -*SAM/methylate*-> Epi
279
The degradation of catecholamines
* MAO & COMT (catechol o-methyl transferase)
* * Dopamine --> HVA (homovanillyic acid)
* * NE/E --> VMA (vanillyl acid)
280
Dopamine beta-hydroxylase requires...
Vitamin C
281
DOPA decarboxylase requires...
Vitamin B6 (PLP)
282
Carcinoid
* Tumor of serotonin producing cells in GIT
* Cutaneous flushing, diarrhea
* Increased 5-HIAA excretion in urine
283
From what is melatonin derived?
Serotonin
284
The 3 reactions requiring BH4 coenzyme
1. Phe -> Tyrosine
2. Tyr --> L-DOPA
3. Tryptophan --> 5-hydroxytryptophan
285
A deficiency of BH4...
Can result in delayed mental development + seizures
| - Treat with Neurotransmitter precursors in diet + dietary Phe restriction
286
A tetrahydrobiotin deficiency can manifest from a deficiency of 2 enzymes
1. BH2 reductase
| 2. BH2 synthesis
287
How is GABA synthesized?
Glutamate -*decarboxylase + PLP*-> GABA
288
How is histamine produced?
Histidine -*decarboxylase + PLP*->
289
The major inhibitory neurotransmitter...
GABA
290
What is the GABA shunt?
GABA --> TCA cycle
291
Histamine is a vasocontrictor/dilator
Dilator
292
In general, how do anti-histamines work?
Receptor antagonists
| * Not enzyme inhibitors **
293
2 popular examples of anti-histamines
H1 (benadryl), H2 (Zantac) blockers
294
From whom is creatine synthesized?
Arginine, Glycine & SAM
295
Where is creatine found?
Muscle, heart, brain
296
What is creatine?
Reservoir of high energy-bonds
* Accepts phosphate during rest
* Donates phosphate during contraction
297
What enzyme modulates the transition of creatine to creatine phosphate?
Creatine kinase (CK, CPK)
298
NO is synthesized from which AA & which enzyme?
Arginine (NO mARG!)
| * NO synthase (releases cirtulline)
299
What can be used as a vasodilator during an MI?
Nitroglycerin
300
Where is NO synthesized?
Endothelium of blood vessels
| * Causes vasodilation
301
The NO cascade...
Guanylate cyclase --> cGMP --> relaxation vessels --> phosphodiesterase
(Second messenger cascade)
302
What is melanin?
A polymer of pigmented molecules derived from tyrosine
303
The enzyme deficiency in albinism?
Tyrosinase (tyrosine --> melanin)
304
The more severe form of albinism
Occulocutaneous albinism
305
The tripeptide glutathione is composed of:
GCG
- glutamate
- cysteine
- glycine
306
Glutathione acts as an anti-oxidant by:
H202 --> H20 (reduced); GSH --> GSSG (reduced)
| * Important for integrity of cell membrane
307
The 2 reactions that require vitamin B12
1. Methionine synthase (homocysteine --> methionine)
| 2. Methylmalonyl coA mutase
308
The 4 AA's that can be used by the odd-chain FA oxidation
1. Methionine
2. Isoleucine
3. Valine
4. Threonine
309
Methionine synthase requires 2 vitamins
1. B12
| 2. B9 (folic acid -- methylated-THF)
310
Lack of intrinsic factor will result in...
```
Pernicious anemia (inability to take up B12)
* B9 will be tied up methylated and anemia will result
```
311
Vitamin B9 is referred to as
Folic acid
312
T/F Proks can synthesize B9
TRUE
313
What are 2 drugs that involve folic acid?
1. Methotrexate (competitive inhibitor of dihydrofolate reductase)
2. Sulfonamides (Dihydropterin synthase in proks from PABA)
314
Sulfonamides
Competitively inhibit dihydropterin synthase in proks from PABA (make folic acid)
315
Glycine & Serine can be interconverted using
B9 (folic acid) & serine hydromethyl transferase
316
The dihydrofolate reductase reaction requires
2 NADPH
317
How do we get from histidine to flutamate?
FIGlu (donates formino group to folate)
| * Deficiency in folate will result in elevated FIGlu
318
How do you test for folic acid deficiency?
FIGlu levels
319
Folic acid is generally used for...
1 carbon transfer reactions (DNA/RNA synthesis), degradation of histadine, regeneration of methionine, serine glycine
320
A common B12 & folic acid deficiency can lead to
Megaloblastic anemia
321
Difference between NE & Epi
NE - nervous system
| Epi - functions like a hormone
322
Difference between epinepherine & cortisol
Cortisol - GNG
| Epi -- glycogenolysis
323
Which amino acid promotes both insulin & glucagon release?
Arginine
324
Glucagon release is stimulated by these amino acids
Arginine, alanine
325
Insulin release is stimulated by these amino acids...
Arginine, leucine
326
Isoniazide
Can deplete the body of PLP (B6)
| * Used for treatment of TB
327
Heme is used in...
Hemoglobin, cytochrome ETC, NO synthase, Catalase
328
Difference between heme synthesis in liver vs. bone marrow
Liver: inhibited by heme/hemein (product inhibited)
Erythroid: limited by Fe availability
329
Lead
Messes with ALADH & Zn-cofactors in ferrochelatase
330
Photosensivity will result once this compound accumulates...
HMB (hydromethylbilane)
331
Which enzymes of heme synthesis are in the mitochondria?
ALAS1/2, Ferrochelatase
332
5 porphrias
1. ALAS2 (X-linked sideroblastic anemia)
2. ALADH (Hereditary ALADH deficiency)
3. HMB Syn/PDA (Acute intermittent porphyria)
4. Congenital EPO porphyria (Uro synthase -- serious)
5. Porphyria Cutanea Tarda (Uro DC -- often due to chronic liver disease)
333
What might you not treat someone with who has porphyria?
Barbituates (can stimulate cytomchrome p450 formation)
334
Difference between direct & indirect bilirubin
```
Direct = conjugated with gluconaric acid
Indirect = unconjugated (with albumin)
```
335
Crigler-Najjer I, II & Gilber's disease
Varying levels of severity of the UDP-gluconryl transferase enzyme
336
Dubin Johnson Syndrome
Deficient ABC transporter of bilirubin into the bile
337
Jaundice occurs when serum bilirubin is > ____
2 mg/dL
338
What hormone does adipose produce?
Leptin * Appetite supressor
339
What is the difference between Type 1, 2A/B muscle fibers?
1 - red - slow twitch, rich capillary supply, decreased glycogen storage
340
Which AA's are synthesized from glucose?
Glutamate, Aspartate, Glycine
341
What is the GABA shunt?
GABA is recycled in the CNS
| * Glutamate is synthesized de novo in the brain from BCAA
342
How is acetylcholine synthesized?
Requires choline from the diet
| PE + methyl -*SAM, THF, B12*-> acetylcholine
343
Vitamin B1
1. PDH
2. Alpha-KG DH
3. BCAA DH
344
Which cytochrome p450 is important in ethanol metabolism?
CYP2E1
* In chronic alcoholics, acetaminophin is processed more by CYP2E1 --> toxic compound
* NAPQ1 --> ROS/can lead to cell death
345
What can Acetaminophin poisioning in a chronic alcoholic be treated with?
Acetadote (N-acetyl-cysteine)
346
Describe the metabolism of alcohol.
ETOH -*ADH*-> Acetaldehyde -*ALDH1(c)2(m)*-> Acetate
* NADH produced, ALDH1 active at high ETOH concentrations & also MEOS (CYP2E1) more active
347
Describe the effects of chronic alcoholism
High NADH:NAD -- unanble to carry out GNG, accumulation of lipids and fats in the liver (fatty liver)
348
Describe poisoning with methanol & ethylene glycol.
Both are substrates for ETOH DH.
* Can lead to formaldehyde & glycoaldehyde/oxalate
* Treat with ETOH or Fomepizole
* Requires bicarb/hemodialysis
349
Describe the effects of grapefruit ingestion while a patient is on statins.
Grapefruit inhibit CYP3A4 (required for statin control)
| * A patient on statins who eats grapefruit regularly can have liver damage
350
Describe the relationship between Warfarin & Phenobarbital
Warfarin unduces CYP3A4 & Phenobarbital inactivates it
| * Suddenly taking a patient off of phenobarbital can lead to massive bleeding
351
Describe LFT's
B- bilirubin
P- proteins (albumin, clotting factors, etc.)
M- metabolites (ammonia, glucose)
E- enzymes (AST, ALT, GGT, ALP)
352
Describe the pre-beta, beta, and alpha serum protein bands
pre-beta: VLDL
beta: LDL
alpha: HDL
353
Describe the alpha-1 proteins
A1-Antitrypsin
AFP (alpha-fetoprotein) -- elevated in HCC/testicular/ovarian cancer (mothers-low in Downs, high in spina bifida)
Transcortin (cortisol)
RBP (retinol)
354
Describe the band separations on serum protein electrophoresis.
Albumin, A-1, A-2, beta (includes CRP), gamma
355
Describe the alpha-2 proteins
Alpha-2-macroglobulin
Ceruloplasmin (Cu / also helpful in Fe metabolsim)
Haptoglobin (free Hb)
356
Describe the beta proteins
Transferrin
Hemopexin
Beta-lipoprotein
357
Describe the difference between serum and plasma
Serum -- no clotting factors (let blood clot, centrifuge & take the supernatant) -- preferred analysis
Plasma -- includes clotting factors -- need to have an anti-coagulant in the blood
358
Describe the gamma globulins
* Synthesized by plasma cells
* IgG - most abundant (mother--> fetus)
* IgM - infection
* IgE - allergy
* IgA - body secretions
* IgD - unknown
359
Which acute phase protein is released during inflammation? It is included in what band?
CRP (beta-globin)
360
Describe the platelet plug formation
G1A -- binds to collagen
G1B -- VWF binds to this on the platlet
G2B/3A -- allows binding of fibrinogen
