Biochemistry-Endterm Flashcards
1
Q
Inborn errors of metabolism
A
Monogenic disease but can be polygenic.
Leads to changing in an enzyme in a primary pathway or in a secondary pathway
Treat through diet restrictions
2
Q
Disorders of amino acid metabolism
A
- Phenylketonuria
- Urea cycle enzymes
- Hypergylcinemia
3
Q
Disorders of carbohydrate metabolism
A
- Glycogen storage disease
- Diabetes
- Galactosemia
4
Q
Disorders of lipid and lipoprotein metabolism
A
- Familial hypercholesterolemia
- Tangier disease (HDL deficiency)
5
Q
Disorders of purine and pyrimidine metabolism
A
- Lesch-Nyhan syndrome
- ADA
- SCID
6
Q
Hormone disorders
A
- Thyroid diseases
- Androgen resistance syndrome
7
Q
Nutritional disorders
A
- Obesity
- Problems in transporting folate
8
Q
Organelle diseases
A
-Mucopolysaccharidosis in lysosomes
9
Q
Tissue disorders
A
- Collagen diseases
- Muscular dystrophies
10
Q
Systemic disorders
A
-Hemophilia
11
Q
Marfans syndrome
A
Autosomal dominant condition due to a defect in fibrillin on the FBN1 gene located on chromosome 15
Affects:
- Cardiovascular system (weak heart+blood vessels)
- Ocular problems
- Skeletal system: spine, chest & joints
12
Q
Major criteria for diagnosing Marfans syndrome
A
- Enlarged aorta and tear in aorta
- Skeletal problems
- Family history
- Dislocation of lens
13
Q
Minor criteria for diagnosing Marfans syndrome
A
- Loose joints
- Short sightedness (myopia)
- Unexplained stretch marks
14
Q
Akhenetons Marfans syndrome
A
- Long face and fingers
- Slit-like eyes
- Arachnodactyl: spider-like fingers
- Wide hops
- Protruding belly
15
Q
Fibrillin
A
Major component of microfibrils. Need 3 fibrillin to make a microfibril. Serves as a substrate for elastin
16
Q
2 mutations of FBN1
A
- In-frame mutation (missense)
- Premature termination (nonsense)
17
Q
Diagnosing Marfans syndrome
A
- Reliable reverse transcriptase PCR
- Next generation sequencing
18
Q
Reliable reverse transcriptase PCR
A
Single cell genotyping
19
Q
Next generation sequencing
A
Take the patients DNA and make specific primers to check if the patient has Marfans syndrome
20
Q
Treating Marfans syndrome
A
There is no treatment
Can take beta blockers to reduce stress on the aorta
Gene therapy is also an option but not reliable
-Would use ribozymes and RNA anti-sense technology to reduce mutant FBN1
21
Q
Hemophilia
A
Condition in which a person is unable to form a stable clot
Phenotype: easily bruised, prolonged bleeding
Can lead to death since person will have an internal hemmorhage
X-linked recessive inheritance
Three types of hemophilia: A, B, C
22
Q
Hemophilia A
A
Absence or almost no clotting factor 8
23
Q
Factor 8
A
Serves as a coenzyme to change X to Xa in the clotting cascade (tense reaction)
Produced by the HEMA gene
24
Q
HEMA gene
A
Located on X chromosome on position 28
2 mutations of HEMA gene:
- Point mutation: less severe as have some activity of factor 8
- Inversion: severe
25
Hemophilia B
Lack of clotting factor 9
26
Detecting mutations in hemophilia
Amplify the factor 8 and 9 genes by PCR. Then screen by restriction fragment length polymorphism analysis (RFLP) or repeat sequence polymorphism
This will show the genotype and the transition of it through generations
27
Treatment of hemophilia
- Replacement therapy: injecting the clotting factors
- Desmopressin: an analogue of the diuretic vasopressin found to increase the levels of clotting factor 8 slightly. Used when there is a minor surgery
- Gene therapy: not effective as the clotting factors are too big
28
Cystic fibrosis
An autosomal recessive condition that affects the exocrine glands. People with cystic fibrosis have thick mucus and high levels of chlorine in their sweat.
It is diagnosed within the first month of life
29
Rates of cystic fibrosis
Highest in Europe and lowest in Asia
30
Cause of cystic fibrosis
Caused by a defect in the CFTR gene which is located in chromosome 7. CFTR gene is responsible for producing the CFTR protein
31
CFTR protein
Helps transport chlorine and sodium in epithelial cells by hydrolyzing ATP to transport the ions
Without the protein, thick mucus accumulates in the body leading to respiratory insufficiency and systemic obstruction
32
Mutations of CFTR gene
Most common mutation is the delta F508 mutations. However, there are a lot more mutations
Mutation means that there is no ATP hydrolysis for chlorine transport
33
Delta F508 mutation
Caused by a deletion of 3 nucleotides on exon 10 which results in the deletion of phenylalanine at position 508.
34
Classes of CFTR mutation
Six classes and each class has a different severity level
35
Class 1
Can’t produce the protein so need to find a way to fix protein synthesis
36
Class 2
No trafficking of proteins so need to correct protein folding
The delta F508 mutation belongs to this class
37
Class 3
No protein function so need to restore channel conductance
38
Class 4
Less protein function so need to restore channel conductance
39
Class 5
Less protein production so need mature protein and correct misplicing
40
Class 6
Less stable protein so need to stabilize it
41
Cystic fibrosis and sweat glands
Normally, sodium chloride carry water to skins surface and then is tea sorbet back in the body
In the case of cystic fibrosis, the sodium chloride is not reabsorbed leading to the skin to be salty
Also, when a person exercises, they experience fatigue, nausea, dizziness, etc.
42
Screening cystic fibrosis
Done by:
- Mutation testing
- Sweat test
- Immunoreactive trypsinogen
43
Mutation testing
At birth, babies are screened for cystic fibrosis. Common mutations are detected however less common ones aren’t detected
44
Sweat test
Is the gold standard for diagnosing cystic fibrosis. Chlorine levels in the sweat is 5 times higher than in normal sweat. This allows for the diagnosis of cystic fibrosis in hound children and in adults
45
Immunoreactive trypsinogen
Mucus blocks the pancreatic ducts so trypsinogen can’t go to the intestine. However, if a person tests positive for this test, should also do the sweat test as well
46
Treating cystic fibrosis
Can’t treat it but can alleviate symptoms
Can use CFTR modulators to correct the defective function of the CFTR protein. However, it only works for a couple of mutations
If the lungs are severely damaged, then a lung transplant is required
47
Nucleotides
Composed of a nitrogenous base, sugar, and phosphate group (either 1,2, or 3)
48
Purine
Nitrogenous bases that are made of fused rings
49
Pyrimidine
Nitrogenous bass that is made of a single ring
50
Roles of nucleotides
- Carry activates metabolic intermediates (UDP-glucose)
- Part of coenzyme structures (NAD, FAD)
- Energy currency
- Secondary messenger signals
51
Nucleoside
Base and sugar. No phosphate groups
52
Adenyalte kinase
Enzyme responsible for turning AMP into ADP and vice versa. Uses ATP to help in the conversion.
So AMP+ATP -> 2 ADP
53
Guanylate cyclase
Changes GMP to GDP with the help of ATP
54
ATP helps change...
- GDP to GTP
| - CDP to CTP
55
De novo purine synthesis
Ribose 5 phosphate (from PPP) is changed to PRPP by PRPP synthetase with the help of magnesium and ATP
PRPP is changed to amido PRT by GPAT and this is the rate limiting step.
9 more reactions form inosine monophosphage (IMP)
In general, the nitrogenous base is added to the sugar which is PRPP
Low PRPP means that the de novo synthesi
56
IMP
IMP can be changed to GMP and AMP. ATP is required to make GMP and GTP is required to make AMP
Feedback inhibition of the products leads to stoping of the reaction of IMP
57
PRPP synthetase regulation
Activated by inorganic phosphate
Inhibited by purines since already have a lot of purines in the body so don’t need to make more
58
Regulation of GPAT
PRPP activates the enzyme in a positive feedback manner
Purines inhibit the enzyme
59
Salvage pathway
Taking free nitrogenous bases and changing them into nucleotides
Have two enzymes:HGPRT and APRT
Uses PRPP so depletes the supply of PRPP
60
HGPRT
Changes hypoxanthine to IMP and guanine to GMP
61
APRT
Changes adenine to AMP
62
Creating deoxyribonucleotides
Need to convert ribonucleotodes into deoxyribonucleotides by reducing it at the 2’ end
Reduction is carried out by ribonucleotode reductase
Creates the correct amount of each deoxyribonucleotides by binding to specific allosteric sites
63
Ribonucletoide reductase
Needs ribonucleoside diohospahte as a substrate
After ribonucleotide reductase reduces, it becomes divided so need to reduce it again and this is done by thioredoxin
64
Thioredoxin
Regulated by thioredoxin reductase
65
De novo pyrimidine synthesis
The nitrogenous ring is first created and then it attaches to PRPP.
Orotic acid is added to PRPP by orotate phospho-ribosyl tranferase to form orotic monophosphate (OMP)
OMP is changed to UMP by orotidine carboxylase and releases carbon dioxide
UMP is further metabolized into the different pyrimidine bases
66
Purine nucleotide cycle
Need it to replenish the supply of TCA molecules.
AMP is changed to adelynosuccinate which is then converted back to AMP. Whole process is done by adenylate kinase
Aspartate is changed to fumarate (TCA intermediate) and this cycle can continue since large reservoir of aspartate in the cell and can get more from the bloodstream
67
If no purine nucleotide cycle...
Then muscles become very fatigued
68
Pyrimidine metabolism
Happens readily in humans
69
Purine matabolism
Can’t be done by human cells so turned into uric acid as a waste product
70
Breaking down AMP
Changed into adenosine by nucleotidase
Converted to inosine by adenine deaminase
71
Breaking down IMP
Converted into inosine by nucleotidase.
Changed to hypoxanthine by PRP.
Hypoxanthine changed to xanthine by xanthine oxidase
72
Breaking down GMP
Converted into guanosine by nucloeotidase
Changed into xanthine by guanine deaminase
73
Breaking down XMP
Changed into xanthosine by nucleotidase
Changed into xanthine by PRP
74
Uric acid
Formed by xanthine oxidase
Soluble at alkaline pH in its anionic form
When uric acid precipitates, it leads to gout
75
Xanthine oxidase
Is a bifunctional enzyme
- Changes hypoxanthine to xanthine
- Changes xanthine to uric acid
76
Gout
Inflammatory joint disease mostly located in the distal parts of the body since low temperature leads to low solubility
Caused by the formation of uric acid crystals
77
Treatment of gout
- Inhibiting xanthine oxidase by drugs such as allopurinol
- Dialysis removal of uric acid
- Taking in a low purine diet
78
Breakdown of dietary nucleic acids
Broken down by nucleases in the GI tract
| Nucleotides consumes do not form the nucleotides that are in our body
79
Free radical
Any molecule that has an unpaired valence electron
80
Atmospheric oxygen
Is a biradical but it highly unreactive since it’s electrons are in two different orbitals
Can also take electrons one at a time and can be excited to move its electron to a higher orbital (same orbital as first electron) to form the singlet oxygen
81
Reactive oxidative species (ROS)
Free radicals and non-radicals derived from oxygen
82
Reactive nitrogen species (RNS)
Free radical and non-radicals derived from nitrogen
83
Reactive species and their half-lives
Have an inversely proportional relationship
The hydroxyl radical has the lowest half-life (10 to the power of -9) which means its barely found as a free radical
84
Endogenous sources of ROS
- Mitochondrial respiratory chain (main source of ROS)
- Xanthine oxidase
- NADPH oxidase
- Cyclo-oxygenase
85
Exogenous source of ROS
- Pollutants
- Radiants
- Smoking
86
Restoration to make ROS
The Q cycle gives off one superoxide radical as well as complex 1. Since we always need respiration to make energy, this production of radicals is unavoidable
87
Phagocytes to produce ROS
Phagocytes are able to men their killing liquid by a series of reactions
- Oxygen is changed to superoxide radical by NADPH oxidase
- The superoxide radical is changed to hydrogen peroxide by superoxide dismutase
- Hydrogen peroxide is changed to perchlorate (killing substance) by myeloperoxide
88
If defect in NADPH oxidase...
Then can’t form bleach and will form a phagosome which will secrete substances but it won’t kill the bacteria
89
Important ROS’s
- Singlet oxygen
- Superoxide radical
- Hydrogen peroxide
- Hydroxyl radical
90
Singlet oxygen
Is selective and reacts with lipids, guanine, and amino acids (tyrosine, histidine, cysteine, and methionine)
No enzymatic defense but it can be neutralized by beta-carotene
Since singlet oxygen can kill cells, can be used in cancer therapy to kill cells
91
Superoxide dismutase
Is moderately reactive and acts as both an oxidizing and reducing agent
Reacts with iron-sulfur clusters to release free iron. Iron will react with hydrogen peroxide and form the hydroxyl radical which is really bad
In order to prevent this from happening, superoxide dismutase changes two superoxide radicals and hydrogen to hydrogen peroxide and oxygen
92
Hydrogen peroxide
Produced by superoxide dismutase and by xanthine oxidase and monoamine oxidase. Is the the only ROS that isn’t a free radical
Is generally unreactive but is highly reactive with reduced transition metals to form the hydroxyl radical. This is known as the Fenton reaction
Protect against peroxide by catalase, glutathione, and peroxidase. Glutathione (GSS) reacts with peroxide to form GSSG and this needs to be reduced and done by glutathione reductase
93
Hydroxyl radical
Formed by the Fenton reaction and by ionizing radiation. Is very reactive and reacts with all biomolecules at the site of formation.
No protection against this radical except for making it
94
Lipid peroxidation
Free radicals will attach to lipids and this will change the structure of lipids
Affects:
- Fluidity of lipids
- Causes direct toxicity
- Forms lipid oxidation products
95
Antioxidants
Antioxidants are molecules that inhibit oxidation (so reduce)
When an antioxidant reacts with a radical, it forms a radical with lower reactivity. This new radical needs to be recycled in order to use it again
96
Examples of antioxidants
Endogenous:
-Ascorbic acid, glutathione, alpha-tocopherol, uric acid
Enzymes:
-Superoxide dismutase, catalase, glutathione peroxidase/reductase
Exogenous:
-Flavanoids, alkaloids
97
Tocopherols
Also known as vitamin E
Stops chain reaction of lipid peroxidation
Has a quinone ring that stabilizes it
98
Ascorbate
Known as vitamin C
Reduces iron and copper
Cofactor for hydroxylases (ex:collagen synthesis)
Reduces radicals such as superoxide radical, hydroxyl radical
Reforms tocopherol from its radical form
99
If oxidants more than antioxidants...
High oxidation in the body and biomolecules are impaired
100
If antioxidants more than oxidants...
Impairs signaling processes which leads to growth and developmental defects
101
Acetyl CoA
Can branch into two different pathways:
- Enter the TCA cycle
- Go to fatty acid synthesis
Acetyl CoA is the major precursor of fatty acid synthesis
102
Fatty acid synthesis
Happens in the cytoplasm in three stages:
- Transporting acetyl CoA from the mitochondria to the cytoplasm
- Synthesizing Maloney CoA
- Synthesizing fatty acid
103
Transporting acetyl CoA
Acetyl CoA can’t cross the inner mitochondrial membrane due to the CoA part. So acetyl CoA and and oxaloacetate combine together to form citrate by citrate synthase. The CoA part stays in the mitochondria
In the cytoplasm, citrate lyase reconverts the citrate into oxaloacetate and acetyl CoA
104
Synthesizing Malonyl CoA
Acetyl CoA is converted to Malonyl CoA by acetyl CoA carboxylase by an ATP and magnesium and carbon dioxide. The magnesium holds the carbon dioxide
105
Acetyl CoA carboxylase
Is the rate limiting step of fatty acid synthesis so it has a lot of regulation:
- Regulation by citrate
- Regulation by fatty acid
- Regulation by G3P
- Regulation by hormones
106
Regulation by citrate
High citrate level activate the enzyme so it promotes fatty acid synthesis
107
Regulation by fatty acids
Fatty acids will inhibit acetyl CoA carboxylase since there’s already a lot of fatty acid in the body so don’t need more
108
Regulation by G3P
G3P will translocations the carbohydrate responsive element binding protein (ChREBP) to move from the cytoplasm to the nucleus
ChREBP will bind to the carbohydrate responsive element (ChoRE) and will initiative synthesis of acetyl CoA carboxylase
109
Regulation by hormone
Can be regulated by:
-Insulin: insulin will activate protein phosphates which will dephosphorylate ACC and activate it
-Glucagon: activates AMPK which phosphorylates ACC and inactive it
110
Fatty acid synthase
Fatty acid synthase is a dimer. Each part is make of 8 domains:
- 3 ketoacyl ACP-synthase (KS)
- Acetyl CoA ACP transacylase (AT)
- Malonyl CoA ACP transacylase (AT)
- Enoyl ACP reductase (ER)
- 3 ketoacyl ACP reductase (KR)
- 3 hroxyacyl ACP dehydratase (HD)
- Thiolesterase (TE)
- Acetyl binding protein (ACP)
111
Structural division
Each unit by itself has all the components to the synthesize a fatty acid but it can’t do it
112
Functional division
The dimers are divided in half so that both units share the binding domains. In this way, two fatty acids can be synthesized at the same time
113
Fatty acid synthesis
Divided into two main cycles
114
Cycle 1
- Acetyl CoA is moved to the ACP domain by AT and a CoA is removed
- The acetyl group is moved to the KS domain to empty out the ACP domain
- Malonyl CoA is moved to the ACP domain by MT
- The acetyl group and malonyl CoA condense together to release a carbon dioxide by KS
- The keto group is reduced to an alcohol by KR and NADPH is oxidized in the process
- A double bind is created between carbons 2 and 3 forming a water molecule by HD
- Double bone is reduce by the ER domain and NADPH is oxidized again
This forms a 4 carbon fatty acid called butyric acid
115
Summary of cycle 1
1 acetyl CoA+ 1 malonyl CoA+ 2NADPH -> 1 butyryl (4 carbon fatty acid)+ 2NADP+ + 2H+ + 1CO2+ 1H2O
116
Cycle 2
- Butyric acid is moved to the KS domain to allow a malonyl CoA to bind to the ACP domain
- The stems are repeated from malonyl CoA
In each successive cycle, two additional carbons are added and they come from malonyl CoA
117
Summary of making palmitic acid (16 carbons)
1 acetyl CoA+ 7malonyl CoA+ 14 NADPH-> palmitic acid+ 14 NADP+ + 14 H++ 6 H2O+ 7H2O
118
Cleaving palmitic acid
Thioesterase cleaves the fatty acid and uses one water molecule in the process
119
Elongating fatty acids
The fatty acids in our body can only make a fatty acid chain of up to 16 carbons long
Add additional carbons through elongate which adds malonyl CoA amino acids (so 2 carbons at a time)
This is in the endoplasmic reticulum
120
Desaturation fatty acids
Fatty acid synthase can’t produce unsaturated fatty acids. So this is done by desaturase
121
Monounsaturated fatty acids
Have only one double bond
Ex: oleic acid at carbon 9
122
Polyunsaturated fatty acids
Have more than one double bonds
Ex: a linoleic acid (omega 3, 3 double bonds), linoleic acid (omega 6, 2 double bonds)
123
Omega nomenclature
Start naming from the end opposite to the COOH group. Number based in first double bond that appears from that side
124
Problems with desaturase
Desaturase can only put double bonds from carbons 1 to 9 (ex: oleic acid) so double bonds after that can’t be synthesized like omega 3 and 6 so need to get them from diet
125
Arachidonic acid
Is a derivative of omega 6 and is synthesized by using the precursor double bonds in omega 6.
Double bond created at carbon 6. Add elongase so changes position. Double bond at carbon 5
So double bonds at 5, 8, 11, 14 and is a 20 carbon lipid
126
DHA
Derivative if omega 3
Put double bond at carbon 6. Add elongase. Add double bond at carbon 5. Add elongase. Add double bond at carbon 4
So have 5 double bonds: 4, 7, 10, 13, 16, 19 and is 22 carbon lipid
127
Triacylglycerides
Three fatty acids bound to a glycerol molecule through an Easter reaction (OH of glycerol and COOH of fatty acid)
Done in 3 steps:
- Activating glycerol
- Activating fatty acid
- Making triacylglycerol
128
Activating glycerol
In liver and adipose, dihydroxyacetone phosphate (DHAP) from glycolysis is converted into activates glycerol (G3P) by glycerol-3 phosphate dehydrogenase
Only in the liver is there glycerol kinase which changes glycerol to G3P
129
Activating fatty acid
Done by adding an acetyl CoA to the COOH end of the fatty acid carried out by fatty acyl CoA synthase
130
Traicylglyecerol synthesis
Glycerol 3 phosphate acyl transverse adds a fatty acid to form lysophosphitic acid (monoacyl glycerol 3 phosphate)
Lysophophitic acid gets another fatty acid by monoacyl glycerol 3 phosphate acyl tranferase to form phosphatic acid (diacyl glycerol 3 phosphate)
Phophatidic phosphate seems cleaves the phosphate to just have diacyl glycerol
Diacyl glycerol acyl transferase adds the last fatty acid to form triacylglyceride
131
Lipolysis takes place...
When there is low glucose
132
Lipogenesis takes place when...
There is high glucose
133
Adipose triglyceride lipase
Breaks down the triglyceride into diglycerides and releases one fatty acid
134
Hormone sensitive lipase
Breaks down diglycerides into monoglycerides and releases one fatty acid
135
Monoglyceride lipase
Breaks down the monoglyceride into fatty acid and glycerol
136
Regulation of hormone sensitive lipase by glucagon
Glucagon or epinephrine binds to its receptor and activated adenykate cyclase which activates cAMP
cAMP activates protein kinase A which phosphorylates hormone sensitive lipase and activates it
137
Regulation of hormone sensitive lipase by insulin
When there’s high glucose, insulin will activate a phosphates which will inactivate hormone sensitive lipase
138
Perilippin
Coat protein present on lipid droplets in adipose
Changes the confirmation of lipid droplets and exposes triglycerides for lipolysis
139
Regulation of perilipin
When glucose levels are low, glucagon will bind to its receptor and activate adenylate cyclase and form cAMP
cAMP will activate protein kinase A which will activate the protein
140
Transport of glycerol
After degradation of triglycerides in adipose, glycerol is transported to the liver
141
Transporting fatty acids
Transported to muscles and enters the cytoplasm of muscle cells and enters the mitochondria for oxidation
142
Albumin
Carrier protein of fatty acids
143
Activating fatty acids
Fatty acids are activated in the cytoplasm by adding an acetyl CoA by fatty acyl CoA synthase to form fatty acyl CoA
Uses 1 ATP in the process
By activating the fatty acid, it can easily diffuse into the outer mitochondrial membrane but not the inner mitochondrial membrane
144
Transporting fatty acyl CoA into the matrix
Can’t enter matrix because of CoA so use the carnitine shuttle
145
Carnitine shuttle
Done in 3 steps:
- Carnitine palmitoyl transferase 1 removes the CoA and adds a Carnitine
- Carnitine acylcarnitine translocase transfers the complex into the matrix and in exchange, a carnitine is shuttled to the mitochondrial space
- Carnitine palmitoyl transferase 2 removes the carnitine and puts the CoA. This step uses an ATP in the process
146
Regulating carnitine cycle
High levels of malonyl CoA inhibit the carnitine shuttle
147
B oxidation
Removing the carbons from the 2-3 group which is known as the B carbon from the COOH side
Involves cleaving 2 carbons at a time and completed in 4 reactions
- Oxidizing reaction generating FADH2 by acyl CoA dehydrogenase
- Hydration reaction catalyze by enoyl CoA hydratase
- Oxidation reaction generating NADH by 3-OH-acyl CoA dehydrogenase
- Cleavage by B-ketoacyl CoA thiolase
148
Each B oxidation cycle for even number of carbons generates
1 acetyl Co A, 1 NADH, and 1 FADH2
In the last cycle, 2 acetyl CoA are generated
149
Each acetyl CoA gives...
3 NADH, 1 FADH2, 1 GTP which go to the electron transport chain to make 12 ATP
150
1 NADH
3 ATP
151
1 FADH2 gives
2 ATP
152
Breaking down odd number of fatty acid chain
Humans can’t do it but bacteria can
Reaction is the same except in the last cycle, 1 acetyl CoA and 1 propional CoA are produced
153
Propinoly CoA
Is converted to succinyl CoA which is a TCA cycle intermediate and uses one ATP in the process.
Can generate 1 NADH, 1 FADH2, AND 1 GTP so gives off 6 ATP
154
Cholesterol
27 carbon compound that has an 8 carbon chain attached to at at carbon 17. Made up of 4 rings
155
Cholesterol synthesis
Divided into 3 stages:
- Acetyl CoA synthesis
- Mevalonate synthesis
- Cholesterol synthesis
156
Mevalonate synthesis
- 2 acetyl CoAs come to form acetoacetyl CoA by thiolase
- Another acetyl CoA is added forming HMG CoA by HMG CoA synthase
- HMG CoA is converted to mevalonate by HMG CoA reductase. Uses 2 NADPH in the process
157
Statin
Inhibits HMG CoA reductase
158
Regulating HMG CoA reductase by cholesterol
SREBP-2 binds to its cleaving activating protein (SCAB) in the ER and moves to the Golgi where it cleaves SREBP-2 and produces a DNA binding protein of SREBP-2 (DBD)
DBD goes to the nucleus and binds to the SRE and initiates transcription of HMG CoA reductase
Process happens when the cell is low on cholesterol
When cholesterol levels are high, INSIG binds to SREBP-2 so it doesn’t leave the ER
159
Regulating HMG CoA reductase degradation by cholesterol
HMG CoA will bind to INSIG when there are high amounts in the body. This will allow the complex to leave the ER and enter the cytoplasm where uniquitin will attach and take it to a proteosome complex to degrade it
160
Regulating HMG CoA reductase by insulin
Insulin will activate a phosphates which will activate HMG CoA reductase
161
Regulating HMG CoA reductase by glucagon
Glucagon will activate AMPK and phosphorylates HMG CoA reductase which inactivated it
162
Forming cholesterol
- Kinases convert mevalonate into 5-pyrophosphomevalonate by adding 2 Ps
- Decarboxylase changes 5 pyrophosphomevalonate into isopentyl pyrophosphate (IPP)
- Isomerase will change IPP into DPP
- Transferase adds an IPP to DPP to form GPP
- Tranferase adds IPP to GPP to form FPP
- Sqalene synthase adds 2 FPPs together to form squalene
- Squalene monoxygenase converts squalene into lanosterol
- Lanisterol is converted to cholesterol by 19 more reactions
163
Cholesterol esterification
A fatty acid is added to cholesterol by acyl CoA cholesterol transferase
164
Transporting cholesterol
Needs to be transported by a carrier protein because it’s so hydrophobic
165
Cholesterol uses
Can’t be used for energy purposes
Instead used for steroid synthesis such as:
- Androgens
- Testosterone
- Progestrone
- Estrogen
166
Cholesterol ester uses
Maintains integrity+fluidity in lipid bilateral
167
Forming bile salts
Cholesterol is converted to 7 alpha hydroxycholesterol by 7 alpha hydroxylase (rate-limiting step)
Undergoes a lot of reactions to form bile acids:
- Cholic acid
- Chenodeoxycholic acid
168
Glycocholic acids
Formed by glycine and cholic acid
169
Taurocenodeoxycholic acid
Formed by taurine and chenodeoxycholic acid
170
Recycling bile salts
When bile salts are given to the intestine, 95% of them will be recycled back to the liver
Intestinal bacteria change primary bile acids to secondary bile acids
Primary/secondary bile acids/salts are all reabsorbed by iliac mucosal cells back to the liver to be used again
171
Essential fatty acids
Aren’t synthesized in the body and are essential for growth and development
Deficiency of essential fatty acids leads to rash, decreased growth, susceptibility to infection
Ex: omega 3 and 6
172
Arachidonic acid
Important for cell signaling, making eicosanoids (prostaglandins and leukotriens)
173
DHA
Structural component in the brain, cerebral cortex, and retina
174
Modifications of DHA
When the 5 double bond is added and elongase is added need to add two carbons since lack of desaturase 4 in the body
Desaturase 6 is then added and then decrease 2 carbons
175
Desaturates in the body
- 4
- 5
- 6
- 9
176
Mead acid
Made from oleic acid. Desaturase 6 is added and then elongated and then desaturase 5 is added
Mead acid is high when omega 3 and omega 6 is low
177
Omega 3 derivatives
Plays a role in:
- Blood coagulation
- Inflammation
- Regulating blood vessel contractiliy
- Helps in brain and retina function
178
Lipoprotein
Pack lipids into vesicles
Inner core is hydrophobic and has triglycerides and cholesterol esters
Outer core has apolipoproteins, phospholipids, and free cholesterol
179
Types of lipoproteins
- Chylomicrons (highest TAGs)
- VLDL
- LDL (highest cholesterol)
- HDL (most dense)
180
Apolipoproteins
Structural component of lipoproteins
Function:
- Provide recognition sites: Apo E and Apo A
- Activating enzymes: Apo CII
- Specific to lipoproteins: Apo A, ApoB10, Apo B48
- Exchangeable between lipoproteins: Apo E and ApoCII
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Chylomicrons
Transport TAGs from intestinal mucosal cells to peripheral tissue to liver
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Chylomicrons synthesis
Dietary lipids are absorbed by intestinal mucosal cells and are converted in TAGs, cholesterol esters, and phospholipids
Attached to Apo B48 to form Chylomicrons. Process is mediated by microsomal triacylglycerol transfer protein (MTP)
Released into circulation
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Chylomicrons transport and metabolism
In circulation, HDL gives Apo E and Apo CII
Apo CII activates lipoprotein lipase and breaks down TAGs. When finished, Apo CII leaves
By this time, Chylomicrons is very small and is called remnant so goes to liver
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Chylomicron in liver
Bind through ApoE on specific receptors. When enters the cell, lysosome degrades the remnant and releases it content
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Lipoprotein lipase regulation
When there is high dietary fat, insulin senses it and starts creating LPL and releases it into the circulation
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VLDL metabolism
Goes from liver to peripheral tissue.
Apo B100 binds and liver releases it into circulation. Recieves Apo E and Apo CII
LPL degrades TAGs and Apo CII goes back to HDL
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Making LDL
In the circulation, some TAGs go from VLDL to HDL and HDL gives cholesterol esters and this forms LDL
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LDL metabolism
Apo B100 of LDL binds with LDL receptor in periphery and Clathrin forms a coat bringing it in
Clathrin then degrades and an endosome forms over the LDL
Endosomal ATPase separates LDL from receptors and receptors go back to cell surface
LDL is hydrolyzed by lysosomal acid hydrolase
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LDL cholesterol and effects in homeostasis
- High cholesterol means stop making more cholesterol
- High cholesterol reduces LDL receptors
- High cholesterol will be esterified and stored for later
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HDL
Goes from peripheral tissue to liver
Bound to Apo A, Apo CII and Apo E and phospitidylcholine
Takes up free cholesterol through ATP-binding cassette protein 1. Free cholesterol is esterified by lecithin cholesterol acyltransferase by taking fatty acid from phosphatidylcholine. Activated by Apo A
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HDL2
As cholesterol esters accumulate, becomes HDL 2
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HDL3
Cholesterol ester poor HDL
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HDL2 metabolism
Binds with scavenger receptor class B type 1 receptors on the liver and gives cholesterol
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Cholesterol ester transfer protein
Transfers some cholesterol esters from HDL to VLDL
