Week 3 Skildum- Folate, Cobalamin (B12), Cholesterol, Glycogen Metabolism Flashcards
(168 cards)
1
Q
How is dietary folate taken up from the diet?
A
Green leafy vegetables, liver, legumes, yeast, and fortified flour.
2
Q
What is the vitamin precursor for folate?
A
Folate
3
Q
What are the three parts of a complete folate molecule?
A
- Pteridine ring 2. PABA 3. Glutamate
4
Q
What two molecules is folate reduced to?
A
Folate is reduced to dihydrofolate (FH2), and reduced again to tetrahydrofolate (FH4 or THF).
5
Q
What enzyme reduces Folate to Dihydrofolate (FH2)?
A
Dihydrofolate Reductase a.k.a. DHFR
(with NADPH)
6
Q
What enzyme reduces Dihydrofolate (FH2) to Tetrahydrofolate (FH4/THF)?
A
Dihydrofolate Reductase a.k.a. DHFR
(with NADPH)
7
Q
What happens to Folate’s poly-glutamate “tail”?
A
It is digested in the gut down to mono-glutamate.
8
Q
Why is Dihydrofolate reductase (DHFR) an important drug target?
A
It is involved in the anti-inflammatory response.
Blocking DHFR consequently blocks DNA synthesis.
9
Q
What three drugs target Dihydrofolate reductase (DHFR)?
A
- Methotrexate (cancer & rheumatoid arthritis)
- Trimethoprim (antibacterial)
- Pyrimethamine (antimalarial)
10
Q
What is the major form of Folate in the blood?
A
N5-tetrahydrofolate (5-Methyl THF)
11
Q
Where is Folate reduced to the N5-methyl tetrahydrofolate form?
A
Intestinal epithelial cells
12
Q
What is the most oxidized form of THF?
A
5-Formyl THF
(HC=O)
13
Q
What is the most reduced form of THF?
A
5-Methyl THF
(CH3)
14
Q
What AA is degraded to donate Formate for the modication of THF?
A
Tryptophan donates one carbon in the form of Formate to modify THF.
15
Q
In the addition of one carbon from formate,
FH4 + formate → ???
A
N10-formyl FH4
(requires ATP,also produces water)
16
Q
10-Formyl THF is reduced to what molecule in a reversible reaction?
A
5,10-Methenyl THF
(produces H2O)
17
Q
5,10-Methenyl THF is reduced to what molecule in a reversible reaction?
A
5,10-Methylene THF
(requires NADPH)
18
Q
5,10-Methylene THF is reduced to what molecule in an IRREVERSIBLE reaction?
A
5-Methyl THF
(requires NADH)
(also known as the “Methyl Trap” reaction)
19
Q
FH4+ histidine → ???
A
5,10-Methenyl THF
(FH4+ histidine → 5-Formimino THF (FIGLU)
FIGLU + NH4+→ 5,10-Methenyl THF)
Note: In folate deficiency FIGLU accumulates.
20
Q
What AA is the most most important and most abundant contributor to the one carbon pool for the reduction of folate?
A
Serine
21
Q
FH4+ serine → ???
A
5,10-Methylene THF
22
Q
What enzyme and cofactor is needed to catalyze the reaction of FH4 + serine → 5,10-Methylene THF?
A
Serine hydroxymehtyltransferase and PLP
23
Q
What are the 5 sources of the one-carbon pool in the modification of THF?
A
Serine, glycine, choline, histidine, and formate.
24
Q
What are the four products of the one carbon donations in the modification of THF?
A
- Thymidine nucleotide
- Purine bases
- Methionine
- S-adenosyl methionine
25
What reaction does Thymidylate Synthase (TS) catalyze?
Thymidylate synthase (TS) reduces a methylene carbon to methyl during its transfer from dUMP to dTMP.
(Cofactor for this reaction is oxidized, producing FH2)
26
After being oxidized to Dihydrofolate (FH2), the cofactor for Thymidine nucleotide synthesis reacts with Folic acid and DHFR (NADPH + H+) to produce what molecule?
Tetrahydrofolate (FH4), which can then react with serine and serine hydroxymethyltransferase to regenerate the original cofactor.
27
What reaction does Methotrexate target?
Methotrexate is a folate analog that inhibits DHFR. Prevents the cofactor in thymidine nucleotide synthesis from being regenerated.
Conclusion: kills cancer cells and other rapidly dividing cells because they do not get the amount of deoxynucleotides required for replication.
28
What reaction does the drug 5-Fluorouracil target?
5-Fluorouracil is a uracil analog that inhibits thymidylate synthase (TS). Prevents thymidine nucleotide synthesis.
29
Why does a dietary deficiency of Folate result in Megaloblastic Anemia?
Blood cells cannot synthesize enough DNA to replicate their chromosomes in the abscence of folate (reduced availability of nucleotides).
The few cells and remaining cells grow large because they can't divide until they replicate their genomes. These megaloblastic cells are most apparent in the bone marrow, but they can also be seen in circulating blood.
30
How does folate get from the gut to hepatocyte cells?
1. Folate is reduced to 5-Methyl THF in intestinal epithelial cells and enters the blood.
2. Blood from the intestines goes to the liver via the portal vein.
3. Proton Coupled Folate Transporters (PCFT) transfer folate from the blood into hepatocytes.
31
Folate deficiency before and during pregnancy is associated with what condition?
Spina bifida.
Causes neural tube defects.
Patients who are planning to get pregnant should take folate supplements daily starting one month before getting pregnant and up to three months after conception.
32
How is dietary Cobalamin (vitamin B12) taken up from the diet?
Vitamin B12 (cobalamin) is found in meat, eggs, and dairy.
33
How is dietary vitamin B12 (cobalamin) transported from the stomach to the liver?
1. Dietary vitamin B12 first binds to **R-binder** proteins secreted in the stomach.
2. R-binder proteins bind to **Intrinsic factor** which allows the complex to be absorbed by **receptors** in intestinal epithelial cells.
3. **Transcobalamin II** proteins bind to the complex and transport it through the blood to the liver and other tissues.
4. Complex disassociates in the liver and Vitamin B12 is stored in complex with **Cubillin**.
34
What condition results from a deficiency in Vitamin B12 (Cobalamin)?
Pernicious Anemia.
(megaloblastic anemia plus neurological problems)
35
What are some clinical features/symptoms of Cobalamin (Vitamin B12) Deficiency or Pernicious Anemia?
* Anemia
* Big beefy tongue
* Autoimmunie gastritis
* Atrophy of parietal cells
* Numbness
* Ataxia
36
Metabolism of Cobalamin (Vitamin B12) is important for the production of what two molecules?
1. Succinyl CoA (TCA substrate)
2. Methionine (essential AA)
37
What form of Cobalamin is required for the production of Succinyl CoA?
Adenosylcobalamin : Cobalamin bound to an adenine nucleotide.
38
What form of Cobalamin is required for the synthesis of Methionine?
Methylcobalamin: cobalamin bound to a methyl group.
5-Methyl THF + Cobalamin → Methylcobalamin
39
Describe the Cobalamin Reaction 1.
| (production of Succinyl CoA)
Methylmalonyl CoA + Adenosylcobalamin →
Succinyl CoA
* Methylmalonyl CoA mutase catalyzes the rxn
* rearranges the carboxylic acid to form succinyl CoA (branched chain to straight chain)
* Adenosylcobalamin is not consumed in the rxn.
40
Describe Cobalamin Reaction 2:
Production of Methionine
Homocysteine + Methylcobalamin → Methionine
* Catalyzed by methionine synthase
* transfer of methyl group from methylcobalamin to homocysteine
* methylcobalamin is regenerated by accepting a methyl from a fully reduced 5-Methyl THF.
41
Mutations in methionine synthase can result in what condition?
Hyperhomocysteinemia
42
What problems is hyperhomocysteinemia linked to?
Cardiovascular and Neurological
43
Hyperhomocysteinemia can result from deficiency in what three things?
1. B12 (cobalamin) deficiency
2. Methionine synthase
3. Vitamin B6 (pyridoxal phosphate) deficiency
44
Where does the sulfur for cysteine synthesis come from?
Dietary methionine
45
Methionine can bind to an adenosine nucleoside to become what important molecule?
S-adenosylmethionine (SAM)
donates methyl groups to numerous substrates including precursors to neurotransmitters (e.g. norepinephrine \> epinephrine, guanidinoacetate \> creatinine, nucleotides \> methylated nucleotides, etc).
46
What is the only metabolic fate of 5-Methyl THF?
To lose its methyl to cobalamin.
47
What is the methyl trap hypothesis?
Cobalamin deficiency results in functional folate deficiency because all the folate gets "trapped" as 5-methyltetrahydrofolate.
48
What is glycogen?
- polymer of glucose
- glucose storage molecule for most cell types
49
What tissues is glycogen most important in and why?
* Heart and Skeletal Muscle
* Serves as a buffer for glucose-6-phosphatase for use within the cell.
* Liver
* serves as a glucose buffer for the blood
50
How do defects in glycogen metabolism often present?
Fasting hypoglycemia
and
Muscle pain during exercise
51
What are the two types of carbon-carbon bonds in glycogen?
1-4 bonds: Bonds between the 1 and 4 carbons (make linear chains)
1-6 bonds: Bonds between the 1 and 6 carbons (make branch points)
52
Bonds between what carbons make linear chains in glycogen?
1-4 bonds
53
Bonds between what carbons make branch points in glycogen?
1-6 bonds
54
How does glucose get trapped in the cell?
By phosphorylation.
Hexokinase converts glucose --\> G6P which can't leave the cell.
55
What is UDP-glucose?
A "charged up" form of glucose that can be broken and recovered to make new carbon-carbon bonds.
* glucose \>\> G6P
* hexokinase & ATP
* G6P \>\> G1P
* phosphoglucomutase
* G1P \>\> UDP-glucose
* UDP glucose pyrophosphorlase & UDP
56
What molecule makes the first bond to glucose to begin the glycogen chain?
Glycogenin
57
What protein does insulin signal to **dephosphorylate** glycogen synthase (which activates the enzyme to start glycogen synthesis)?
Protein phosphatase-1
58
In the absence of insulin, what molecule is active and phosphorylates glycogen synthase (inactivating the enzyme and inhibiting glycogen synthesis)?
Glycogen Synthase Kinase-3
59
What enzyme adds UDP-glucose to the growing glycogen chain?
Glycogen synthase
60
In what direction does elongation of the glycogen chain occur?
The direction of elongation is towards the #4 carbon.
Elongation continues linking glucose in 1-4 bonds undtil the chain is about 11 units long.
61
Branching enzyme (glycosyl 4 → 6 transferase) cleaves a piece of the glycogen chain off and attaches it to what #carbon?
Branching enzyme attaches the piece of glycogen to the #6 carbon creating 1-6 glycosidic linkage branches.
62
What are the key enzymes in glycogen synthesis?
Glycogen synthase & Branching enzyme (a.k.a. 4:6 transferase)
63
A mutation in what enzyme leads to GSD 0, and the subsequent failure to make any glycogen?
Glycogen synthase
64
A mutation in what enzyme leads to GSD IV, Anderson disease?
Branching enzyme (4:6 transferase)
65
What advantages does the branching of glucose provide?
* Many opportunities to access glucose
* Makes more active ends so glycogenolysis and glycogenesis can happen VERY rapidly
* does not rely on the expression of new genes
* increases solubility
66
What are the key enzymes in glycogen degradation (glycogenolysis)?
Glycogen phosphorylase
&
Debranching enzyme complex
(4:4 transferase & alpha-1,6-glucosidase)
67
What does glycogen phosphorylase do?
Cleaves units of glucose from glycogen chains and adds inorganic phosphate to make G1P.
68
When is phosphorylase no longer able to cleave glucose from glycogen chains?
When it gets within four units of a branch point.
69
What are the two enzymes in the Debranching enzyme complex? What do they do?
* 4:4 transferase
* cleaves a 1:4 glycosidic bond and transfers three glucose units to the end of another chain in a 1:4 bond.
* alpha-1,6-glucosidase
* hydrolyzes the remaining glucose's 1:6 bond to release glucose
70
Why can't glycogen phosphorylase cleave within four units of a branch point?
The enzyme becomes sterically hindered near the branch point and can't get ahold of it.
71
Mutations in what enzyme cause GSD V (McArdles disease)?
Muscle Glycogen Phosphorylase
| (muscle cells lose structure and shape)
72
Mutations in what enzyme cause GSD VI (Hers disease)?
Liver Glycogen Phosphorylase
| (causes fasting hypoglycemia)
73
Deficiency in what enzyme results in GSD III?
Deficiency in 1,6-glucosidase activity of the Debranching Enzyme Complex
74
Glycogen metabolism is controlled by the phosphorylation of what two enzymes?
* Glycogen Phosphorylase
* active when phosphorylated
* Glycogen Synthase
* active when dephosphorylated
75
In the fed state, are glycogen phosphorylase and synthase phosphorylated or unphosphorylated?
Both are unphosphorylated.
Phosphorylase = inactive
Synthase = active
76
In the fasted state, are glycogen phosphorylase and synthase phosphorylated or unphosphorylated?
Both are phosphorylated!
Phosphorylase = active
Synthase = inactive
77
Describe how glucagon signaling activates glycogen phosphorylase.
Glucagon → cAMP → Protein Kinase A → phosphorylates glycogen phosphorylase kinase (active) → phosphorylates glycogen phosphorylase (active) → glycogenolysis → glucose
\*Ca2+/Calmodulin dependent kinase also phosphorylates glycogen phosphorylase kinase (active)
78
Describe how glucagon signaling inactivates glycogen synthase.
Glucagon → cAMP → Protein Kinase A → phosphorylates glycogen synthase (inactive)
\*Glycogen synthase kinase-3 also becomes active in the presence of glucagon and inactivates glycogen synthase.
79
Describe how epinephrine inactivates glycogen synthase in a hepatocyte (fasted state, alpha pathway).
Epinephrine → Phospholipase C → DAG → Protein Kinase C → phosphorylates glycogen synthase (inactive)
OR
Epinephrine → Phospholipase C → IP3 → Ca2+/Calmodulin dependent kinase → phosphorylates glycogen synthase (inactive)
80
Describe how insulin activates glycogen synthase in a hepatocyte and skeletal muscle cell.
Prevents it from being phosphorylated!
Insulin → IRS-1 → PI3K → PDK → PKV (Akt) → phosphorylates glycogen synthase kinase-3 (inactive)
&
PKV (Akt) → phosphorylates protein phosphatase-1 (active)
SAME in both hepatocyte & skeletal muscle!!!!
81
Describe how epinephrine activates glycogen phosphorylase/inactivates glycogen synthase in a skeletal muscle cell (fasted state, beta pathway).
Epinephrine → cAMP → Protein Kinase A → phosphorylates glycogen phosphorylase kinase (active) → phosphorylates glycogen phosphorylase (active) → glycogenolysis → glucose
&
Protein Kinase A → phosphorylates glycogen synthase (inactive) → inhibits glycogenesis
82
What Glycogen Storage Disease is characterized by normal glucose tolerance, exercise intolerance, cardiac and muscle hypertrophy, as well as sudden cardiac arrest?
GSD 0 - Glycogen synthase deficiency
83
What clinical conditions are present in GSD I (deficiency in glucose-6-phosphatase)?
* Fasting hypoglycemia
* lactic acidosis
* Hepatomegaly due to glycogen accumulation
* Hyperuricemia
* Hyperlipidemia
\*\*Patient would be woozy and dizzy in exercise before experiencing muscle pain.
84
How can GSD I (von Gierke disease) be treated?
Avoid fasting by frequent feeding
Eating uncooked cornstarch (takes a long time to digest)
85
What glycogen storage disease is characterized by fasting hypoglycemia, ketoacidosis, hyperlipidemia, hepatomegaly, and elevated ALT/AST?
GSD III (Cori disease)
86
What is the treatment for GSD III (Cori disease)?
Frequent high carbohydrate meals.
AVOID fasting state.
(typically grow out of GSD IIIb)
87
What glycogen storage disease is characterized by a failure to thrive, hepatomegaly, liver failure, and is often fatal?
GSD IV - Deficiency of branching enzyme 4:6 - transferase.
88
What are common symptoms of GSD V (deficiency in muscle glycogen phosphorylase)?
Late childhood onset of exercise intolerance, myoglobinuria after exercise.
Increased creatinine kinase and ammonia after exercise due to AA metabolism from muscle breakdown.
89
How is GSD V (deficiency in muscle glycogen phosphorylase) treated?
Avoid exercise
Try to build tolerance
90
What are the two purines?
Adenine & Guanine
91
What are the three pyrimidine bases?
Cytosine, Thymine (DNA), and Uracil (RNA)
92
What are some functions of nucleotides?
* DNA, RNA
* "Handles" for enzyme cofactors
* CoASH, NAD+, FAD, Adenosylcobalamin
* Energizing substrates
* UDP-glucose and CDP-choline
* Second messengers
* cAMP
* Allosteric activators
* AMP, ADP, and ATP
93
What enzyme converts Ribose 5-phosphate to 5-Phosphoribosyl 1-pyrophosphate (PRPP)?
PRPP Synthetase
| (requires ATP)
94
What two molecules allosterically inhibit PRPP synthetase?
Purine diphosphonucleosides: GDP & ADP
95
What molecule is an intermediate in purine metabolism?
Hypoxanthine
96
What is the first committed step in purine synthesis?
The transfer of an amine from glutamine by the glutamine phosphoribosyl amidotransferase.
97
Carbon and nitrogen are added from what four things to form inosine monophosphate (IMP) in purine synthesis?
THF, CO2, Glutamine, & Aspartate
98
How does IMP get converted to AMP in purine metabolism? (Hint: similar to the amine transfer in the urea cycle.)
Aspartate bonds to IMP to make adenylosuccinate (requires GTP hydrolysis).
Fumarate is cleaved off to make AMP.
99
How does IMP get converted to GMP in purine synthesis?
IMP is first oxidized to xanthine monophosphate.
Then an amine group is transferred from glutamine (requires ATP).
(IMP \> GMP \> GDP \> GTP \> RNA!)
100
In purine synthesis, how do AMP and GMP become ADP and GDP?
They are phosphorylated to diphosphates!
(AMP \> ADP \> ATP \> RNA!)
(GMP \> GDP \> GTP \> RNA!)
101
What does ribonucleotide reductase do to ADP and GDP in purine synthesis?
Adds deoxy to make dADP and dGDP, which can then be phosphorylated to dATP and dGTP.
(dADP \> dATP \> DNA!)
(dGDP \> dGTP \> DNA!)
102
What is the cofactor for ribonucleotide reductase?
Thioredoxin, which is a protein redox cofactor that can exist in reduced or oxidized states depending on cysteine sidechain sulfur atoms.
103
Why is purine salvage important?
Cells expend a lot of energy to make nucleotides. To conserve energy, there are different pathways to recycle nucleosides and bases in the cell.
104
What is the only purine nucleoside that can be directly phosphorylated back to its nucleotide in purine salvage?
Adenosine: is directly phosphorylated to AMP by adenosine kinase.
\*\*\*The other purine nucleosides must have their ribose sugars removed, then added back from PRPP, to make monophosphate nucleotides.
105
Combined Immunodeficiency is characterized by low, but not absent T-cells, chronic infections, failure to thrive, neurologic symptoms, and is caused by a deficiency in what enzyme?
Deficiency in Purine Nucleosidase Phosphorylase (PNP) is a rare cause of combined immunodeficiency.
(Unable to recycle Guanosine and Inosine nucleosides back to their free bases Hypoxanthine and Guanine)
106
Severe Combined Immunodeficiency leads to an accumulation of 2-deoxyadenosine in the blood when it is caused by a deficiency of what enzyme?
Adenosine Deaminase (ADA)
(second most common cause of autosomal recessive SCID)
107
What does the clinical presentation of SCID look like? And how is it treated?
Severely low lymphocytes.
Costochondral junction dysplasia (skeletal abnormalities seen on x-ray)
Treatment is bone marrow transplant and possible chemotherapy.
108
Lesch-Nyhan Disease (LND) is characterized by self-injurious behaviors such as biting the fingers and lips, and is caused by a deficiency in was enzyme?
Hypoxanthine-guanine phosphoribosyltransferase
(**X-linked** mnemonic: **He's** Got Purine Recycling Trouble!)
109
What are the clinical features of Lesch-Nyhan Disease?
* elevated uric acid in urine
* dystonia
* recurrent vomiting
* renal failure
* mental retardation
110
What does research suggest is responsible for the self-injurious behaviors associated with Lesch-Nyhan Syndrome?
Disturbance in dopamine signaling
111
During purine degradation, GMP and AMP are degraded to xanthine, which is then oxidized by xanthine oxidase to form what product?
Uric acid
112
Purine degradation can lead to precipitation of what molecule in the distal joints?
Uric acid
| (in a condition known as GOUT)
113
What enzyme does Allopurinol inhibit in the treatment of gout?
Xanthine oxidase
\*Allopurinol slows down the formation of uric acid production to enable patients to excrete uric acid before it precipitates in distal joints.
114
How is pyrimidine synthesis different from purine synthesis?
In contrast to purines, which are assembled on a ribose sugar, pyrimidine bases are first assembled then transferred to a ribose sugar.
115
Cytosolic carbamoyl phosphate synthase (CPSII) uses what molecule as an amine donor to form carbamoyl phosphate?
Glutamine
(Glutamine + CO2 + 2 ATP \>\> Carbamoyl phosphate)
uses CPSII
116
Carbamoyl phosphate bonds with aspartate to make carbamoyl aspartate, which is then cyclized to what molecule?
Orotate
(Recall from the urea cycle that elevated urinary orotic acid is characteristic of urea cycle disorders downstream from CPS-I, the closer the defect is to CPS-1, the higher the accumulation of orotic acid)
117
What two things allosterically regulate CPS II?
Allosterically inhibited by UTP
and
Allosterically activated by PRPP
118
Orate combines with what molecule to make a nucleotide, which is then decarboxylated to form uridine monophosphate (UMP)?
PRPP (5-Phosphoribosyl 1-pyrophosphate)
(same molecule used in the first committed step of purine synthesis and in purine salvage)
119
How many phosphate groups are added to UMP to make a nucleoside for RNA?
Two
UMP + P \> UDP
UDP + P \> UTP
UTP \>\>RNA!
120
How does UMP get to the dUMP → dTMP reaction?
UMP + P \> UDP
UDP + Ribonucleotide reductase \> dUDP
dUDP - P \> dUMP
121
What drug inhibits the dUMP → dTMP reaction with THF?
5-fluorouracil
122
Pryimidine degradation is unlike purine degradation in that the accumulation of pyrimidine metabolites is not what?
Not associated with any pathology!!! :)
123
What are four things cholesterol functions in?
Membranes, Bile Acids, Steroid Hormones, Vitamin D
124
What are two forms of circulating cholesterol?
Free
Esterified to a fatty acid
125
What is the precursor of cholesterol?
Acetyl CoA
126
What is the first step of cholesterol synthesis?
Three acetyl CoA's make mevalonate (6C)
127
What happens to mevalonate in the second step of cholesterol synthesis?
Mevalonate is decarboxylated to isoprenes (5C)
128
In the third step of cholesterol synthesis, how many isoprenes condense to form squalene (30C)
Six isoprenes condense to form squalene (30C)!!!
129
In the last step of cholesterol synthesis, what happens to squalene?
Squalene is cyclized and converted to cholesterol.
130
What is the key regulatory enzyme in cholesterol synthesis?
beta-hydroxy-beta-methylglutaryl CoA reductase
(HMG CoA reductase)
\*\*\*Key drug target early in synthesis (statins).
131
Cholesterol synthesis requires a ton of what?
ENERGY! (ATP & NADP)
132
What are three ways that HMG CoA reductase is regulated?
1. Transcription
2. Degradation
3. Phosphorylation
133
What happens in transcriptional regulation of HMG CoA reductase when cholesterol is abundant?
high cholesterol → SREBP + SCAP → SCAP inactive
(no transcription of HMG CoA reductase)
134
What happens in transcriptional regulation of HMG CoA reductase when cholesterol levels drop?
low cholesterol → SCAP active → cleaves SREBP DNA binding domain → nucleus to increase transcription of HMG CoA reductase
135
If there are high levels of sterols in the cell, what happens to HMG CoA reductase?
It is expelled from the membrane and degraded via proteolysis.
136
In fasted/low energy conditions, HMG CoA reductase is phosphorylated by what to become inactive?
AMP-K
137
What activates AMP-K to phosphorylate HMG CoA reductase in fasted/low energy conditions to inhibit cholesterol synthesis?
AMP-K is allosterically activated by AMP and sterols
as well as
phosphorylation from AMP-activated protein kinase kinase
138
What dephosphorylates HMG CoA reductase to become active in the presence of insulin?
Phosphatases
(activated by insulin, promotes cholesterol synthesis)
139
140
What is an isoprene?
5 Carbon molecule that isomerizes
used in subsequent reactions in cholesterol synthesis
(also used in the biosynthesis of coenzyme Q)
141
Is squalene (30C) saturated or unsaturated?
Partially unsaturated
142
How many carbons are in cholesterol?
27 carbons
143
How many rings are in cholesterol?
Four
144
How many nitrogen groups are in cholesterol?
NONE!
145
What organ is the main source of cholesterol synthesis?
The cytosol of the liver.
146
What are the two form of cholesterol that the liver can export?
1. Cholesterol esters (cholesterol + FA)
2. Bile acids
147
What do bile acids/salts do?
used in digestion to emulsify dietary fat
make dietary fats solubel and accessible to lipase
148
How are bile salts recycled?
95% is reabsorbed in the small intestines and sent back to the liver as secondary bile salts (amino acid conjugates removed and hydroxyl at carbon #7 removed)
5% is excreted as feces (major loss of cholesterol)
149
How are dietary fat and cholesterol packaged by intestinal epithelial cells?
Nascent Chylomicrons \> lymph \> blood
| (bypass the liver)
150
What do HDL particles in the blood do to nascent chylomicrons to make them mature chylomicrons?
transfer ApoCii onto it
| (which activates lipoprotein lipase)
151
How is synthesized cholesterol exported from the liver?
Cholesterol is esterified to a FA \> cholesterol ester \> packaged in VLDL and secreted from the liver as nascent VLDL
152
What two additional proteins does HDL add onto nascent VLDL particles?
ApoE, and ApoCII
153
What is the function of HDL?
Tow truck/roadside repair:
* Add ApoCII and ApoE to nascent Chylomicrons and VLDL
* take cholesterol from cell membranes for reverse transport to liver (homeostasis)
154
What is an atherosclerotic plaque?
Happens when LDL not taken in by LDL receptor:
Oxidized LDL + Macrophage \>\> Large vacuole of fat (foam cell)
Build up between the endothelial and basal membrane and cause occlusion!
155
Why is the LDL receptor improtant?
Functions in endocytosis of LDL (lipoprotein particles) back into the liver cytoplasm. Mutations of the LDL receptor (6 regions) cause **familial hypercholesterolemia**!
156
What are three symptoms of familial hypercholesterolemia?
Hyperlipidemia
Premature CVD (cardiovascular disease)
Xanthomas
157
Cholesterol makes what class of hormones?
Steroid hormones
158
Where are steroid hormones synthesized?
Adrenal cortex and Gonads
159
What are the 6 steroid hormones mentioned in class?
Aldosterone, Cortisol, Testosterone, Estradiol, Progesterone, Vitamin D
160
What important enzyme catalyzes many of the reactions in steroid hormone synthesis?
p450
161
In Congenital Adrenal Hyperplasia, a mutation in Cyp21 gene causes a severe decrease in what two steroid hormones?
Aldosterone & Cortisol
(causes problems with fluid maintenance)
162
What phenotypes does Congenital Adrenal Hyperplasia cause in women and why?
Masculine characteristics: facial hair, big muscles, deep voice)
mutation causes increase in Testosterone
163
What step of steroid hormone synthesis takes place in the mitochondria?
Step 1: removal of the side chain to form pregnenolone.
(activated by protein kinase A)
164
What kind of regulation do steroid hormones act through?
Transcriptional regulation.
They diffuse through cell membranes and bind ligand activated transcription factors.
165
Vitamin D is an important regulator of what kind of homeostasis?
Calcium homeostasis!
166
Synthesis of calcitrol, a potent form of Vitamin D, requires reactions in what three organs?
Skin, liver, and kidney
| (first reaction requires UV light)
167
What kind of receptor is the Vitamin D receptor (VDR)?
A ligand activated transcription factor.
(forms a heterodimer)
168
