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Foundations of Medicine > FOM: week 2 > Flashcards

FOM: week 2 Flashcards

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1
Q

What are the three regulatory steps in glycolysis?

A
  1. Glucose –> hexokinase –> Glucose-6-phosphate 2. Fructose-6-phosphate –> phosphofructokinase-1 –> Fructose -1,6-bisphosphate 3. phosphoenolpyruvate –> pyruvate kinase –> pyruvate
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2
Q

Out of the three regulatory steps in glycolysis, what is the most important step and why?

A

The rate limiting step of glycolysis is the conversion of Fructose-6-phosphate to Fructose-1,6-bisphosphate via PFK-1. It is the most important step because it is highly exergonic (large negative ∆G) and irreversible.

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3
Q

What are the PFK-1 allosteric activators and inhibitors?

A

Activators = AMP, Fructose-2,6-bisphosphate; Inhibitors = ATP Think about the pathway!

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4
Q

What is the overall net reaction for glycolysis?

A

glucose + 2 NAD + 2 ADP + 2 Pi –> 2 pyruvate + 2 NADH + H + 2 ATP

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5
Q

Under anaerobic conditions lactate is produced from pyruvate instead of entering the TCA cycle. What is the physiological signficance of this action?

A

Physiological significance: Lactic acidemia can occur if problems with TCA cycle, lack of O2, presence of ethanol, or poison persist. Lactic acidemia results in increased [lactate] and a decreased blood pH (<7.25)

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6
Q

Under anaerobic conditions lactate is produced from pyruvate instead of entering the TCA cycle. What is the energy yield of this action?

A

There is no net energy production from using lactate to produce glucose to then carry out glycolysis.

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7
Q

Under aerobic conditions glycolysis produces 2 ATP, 2 NADH, and 2 pyruvate molecules per molecule of glucose. What is the eventual energy yield of glycolysis, the TCA cycle, and oxidative phosphorylation in tissue?

A

32 ATP produced in liver, heart, and xxx; 30 ATP produced in skeletal muscle and the brain –> difference due to how NADH is transported into mitochondria (malate-aspartate vs. glycerol-3-phosphoglycerate methods, respectively)

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8
Q

Describe the biochemical basis for altered metabolism in cancer.

A

Cancer cells require a lot of glucose to proliferate. Thus fuel metabolism is increased in these cells . This can be identified by 18F-FdG imaging.

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9
Q

Describe the biochemical basis for altered metabolism in lactic acidosis.

A

Cause: Usually caused by lack of O2; cannot perform oxidative phosphorylation without O2!! Results in decreased blood pH and an increase in [lactate] in the blood.

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10
Q

Describe the biochemical basis for altered metabolism in Jamaican vomiting sickness.

A

Cause: eating unripe ackee fruit which contains hypoglycin which acts as an inhibitor of acyl-CoA dehydrogenase; this is harmful to short and medium chain FAs

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11
Q

Describe the biochemical basis for altered metabolism in Medium Chain Acyl-CoA dehydrogenase deficiency (MCAD).

A

Cause: due to an inborn error of metabolism which results in a faulty acyl-CoA-dehydrogenase enzyme found in 1st oxidation step of beta-oxidation; unable to metabolize medium chain FAs (10-14 carbons). Results in Reye syndrome, fasting hypoketotic hypoglycemia, hepatic encephalopathy, SIDS

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12
Q

Describe the biochemical basis for altered metabolism in Carnitine palmitoyl transferase-1 deficiency.

A

Cause: it is an autosomal recessive disorder of lipid metabolism and results in a CPT II enzyme; causes a build up of fatty acylcarnitine.

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13
Q

What are some diversion products from glycolysis?

A

glycogen, 2,3-bisphosphoglycerate, serine, alanine, pentose phosphate pathway - what are the mechanisms?

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14
Q

What are some diversion products from beta-oxidation?

A

ketone bodies - used for metabolism when glucose concentation is low. The brain uses ketone bodies as an energy source in addition to glucose.

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15
Q

What molecular names do ketone bodies have?

A

Acetoacetone and beta-hydroxybutyrate

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16
Q

What significance does 2,3-bisphosphoglycerate have in the body?

A

2,3-BGP is involved in binding to Hb which causes oxygen to be released. Levels of 2,3-BGP are increased in people living in high altitudes and smokers (people living with a lack of oxygen).

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17
Q

What are the key regulatory steps in beta-oxidation?

A

Carnitine-palmitoyl transferase 1 (CPT I)

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18
Q

What is the allosteric inhibitor of CPT I?

A

Malonyl CoA – production is regulated by insulin and AMP

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19
Q

What is the energy production from beta-oxidation?

A

The amount of energy produced depends on the length of the fatty acid metabolized.

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20
Q

How does odd chain length fatty acid catabolism occurs?

A

β-oxidation occurs normally until the chain is five carbons long. Then, thiolase makes one molecule of acetyl CoA, and one propionyl CoA.

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21
Q

How does branched chain fatty acid catabolism occurs?

A

First, the α-carbon is oxidized to CO2; then β-oxidation occurs be alternatively releasing propionyl CoA and acetyl CoA. They are broken down in peioxisomes - similar to very long chain fatty acids.

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23
Q

How does peroxisomal oxidation in fatty acid catabolism occur?

A

The first step in the reaction donates electrons to molecular oxygen rather than FAD and instead of producing energy, the first step produces H2O2. Beta-oxidation continues until the chains are reduced to 4-6 carbons. These shorter chains are then transferred to the mitochondria (via carnitine transport) for further beta-oxidation.

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24
Q

How does very long chain fatty acid catabolism occur?

A

β-oxidation continues until the chains are reduced to 4 to 6 carbons. The short fatty acids then are transferred to the mitochondria for complete β-oxidation. o Acetyl CoA and short chain fatty acids produced by peroxisomal degradation of very long chain

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25
Q

How does ω-oxidation fatty acid catabolism occur?

A

Cytochrome P450 enzymes can oxidize the ω terminal carbon to a carboxyl, producing a dicarboxyl fatty acid. Both ends terminate in carboxyls. The dicarboxyls are then broken down to medium chain length dicarboxyls and may be used by other tissues or excr

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26
How are ketone bodies regulated?
increased levels of β-oxidation result in abundant NADH and acetyl CoA which drives the TCA cycle backwards: oxaloacetate to malate to gluconeogenesis. Reduction of oxaloacetate diverts acetyl CoA into ketone body synthesis rather than TCA cycle.
27
What is the clinical significance of ketoacidosis?
Ketoacidosis is caused by the depression of blood pH due to excessive ketone body production which is caused by starvation or diabetes. Ketone body synthesis is often compensation for hypoglycemia – whereas absence of elevated ketone bodies in hypoglycem
28
Due to oxidative stress, the incomplete reduction of O2 can form free radicals. How is this mechanism carried out?
Superoxide forms from an addition of one electron to O2. Superoxide then becomes H2O2 through addition of another electron and H+ which splits and becomes water and a hydroxyl radical (OH.) The presence of H2O2 in cells can be very detrimental!
29
What are the diverted products of the TCA cycle and what action are they involved in?
Oxaloacetate - amino acid biosynthesis; citrate - fatty acid biosynthesis; a-ketoglutartate - glutamate --> GABA; succinyl CoA - heme biosynthesis; malate - gluconeogenesis --> glucose
30
What intermediates enter the TCA cycle?
acetyl CoA, oxaloacetate (pyruvate --> pyruvate carboxylase --> oxaloacetate; alanine/serine --> pyruvate --> oxaloacetate); glutamate --> a-ketoglutarate; valine/isoleucine --> propionyl CoA --> succinyl CoA; aspartate --> malate
31
Describe the biochemical basis for PDH deficiency.
PDH links glycolysis to the TCA cycle. Defects can lead to serious neurological conditions because ketone bodies cannot be produced from fatty acids - the brain only uses ketone bodies.
32
What activates and inhibits PDH?
Activates = PDH kinase (phosphorylates PDH which inactivates it); inhibits = PDH phosphatase (activates PDH)
33
What activates and inhibits PDH kinase?
Activate = acetyl CoA, NADH; inhibits pyruvate, ADP
34
What activates PDH phosphatase?
Ca2+
35
Draw out glycolysis! Make sure to label major regulatory steps, points of diversion, and what those divergent molecules are involved in.
good job!
36
What are the ΔG of the major enzymes in glycolysis?
Correct-a-mundo
37
What phospholipids are on the cytosolic leaflet and on the external leaflet?
External = phosphatidylcholine, sphingomyelin, and glycolipids; Cytosolic = phosphatidylserine, phosphatidylethanolamine
38
Draw the electron transport chain and make sure to include all redox factors including the proton pumps.
Sweet!
39
What causes oxidative stress within mitochondria?
the formation of superoxide from O2 creates H2O2 which is harmful to the cell!
40
What are the sources of acquiring acetyl CoA from the cell?
FA palitate, acetoacetate (ketone body), glucose (sugar) → pyruvate ← alanine, and ethanol all produce acetyl CoA
41
What other intermediates of the TCA cycle are synthesized from other reactions?
Pyruvate → (pyruvate carboxylase) → oxaloacetate, alanine/serine → pyruvate → oxaloacetate, glutamate → a-ketoglutarate, valine/isoleucine → propionyl CoA → succinyl CoA, aspartate → malate
42
Describe the substrate, enzymatic steps, required cofactors, and products of saturated fatty acid biosynthesis.
Remember steps: 1. bond cleavage 2. reduction 3. dehydration 4. reduction
43
Compare and contrast fatty acid synthesis with beta-oxidation. What regulatory step do these two pathways share?
Regulatory step = acetyl CoA → (acetyl CoA carboxylase) → malonyl CoA
44
Draw out fatty acid synthesis.
super fantastic!
45
Draw out beta-oxidation.
look at your drawing skills! v. nice! :)
46
Why can humans not synthesize certain unsaturated fatty acids?
Due to the necessity of having a handle on the fatty acid for the enzyme to grab it, the carbons to be unsaturated must be at least 9 carbons away from the ω carbon (the last carbon).
47
What unsaturated fatty acids are required in our diets?
linoleic and linolenic acids
48
What do lenoleic and linolenic acids serve as a precursor for?
Arachidonic acid – needed to synthesize prostaglandins
49
How does the body produce arachidonic acid from linolenic acid?
The body uses fatty acyl CoA desaturase to create two more degrees of unsaturation in linolenic acid. This requires energy from NADH oxidation. Linolenic acid also needs to add two more carbons to the chain which is accomplished through fatty acid synthesis by adding two carbons from malonyl CoA. This is carried out in the ER!
50
What type of fatty acid has a lower melting point and why?
Unsaturated fatty acids have a lower melting point due to the kinks in their fatty acid tails. These kinks result in a reduction of intermolecular interactions between tails.
51
How are triacylglycerols packaged and transported in the cell? It might help to draw out the pathway.
glycerol 3-phosphate (glycerol) is used as the backbone and two free FAs are added to create phosphatidic acid → diacylglyercol once inorganic phosphate leaves. Another free FA is added to create TAG. In the liver, TAG is processed to become VLDL which is secreted into the blood and once it reaches it's cell of choice (muscle cell, adipocyte, etc.) lipoprotein lipase (LPL) cleaves the FAs free where they enter the cell of choice and become oxidized (muscle) for energy or are stored as TAGs (adipocyte).
52
How are glycerophospholipids synthesized in the cell?
Glycerolphospholipids are synthesized similarly to TAGs by using phosphatidic acid → DAG. What is added in the enzyme determines which product will result. i.e. phosphatidylcholine: DAG – (CDP-choline) → phosphatidylcholine, etc.
53
What is cardiolipin and where is it found in the cell?
Cardiolipin is a member of the glycerolphospholipids and is found in the inner mitochondrial membrane and causes this membrane to be very difficult to pass through.
54
How are ether phospholipids synthesized?
Ether phospholipids are synthesized similarly to glycerolphospholipids but have an ether linkage at carbon 1 of the glycerol backbone. i.e. ethanolamine plasmalogen (component of myelin sheath) has an ether linkage at carbon1, an ester linkage at carbon 2, and a phosphate linkage at carbon 3 –head group!
55
How are sphingolipids synthesized?
Sphingolipids use ceramide as a backbone instead of glycerol. Ceramide is derived from serine and palmitoyl CoA.
56
What are some uses of sphingolipids in the cell?
The most important sphingolipid is sphingomyelin which is present in the myelin sheaths of nerve fibers. Sphingomyelin is also used as a lung surfactant and an indicator of gestational progress in a ratio of sphingomyelin to phosphatidylcholine.
57
How does leptin function with fatty acid metabolism?
Leptin acts as a satiety hormone and increases as TAG levels increase in the cell. Leptin works through the JAK/STAT pathway receptors in the hypothalamus which releases anorexigenic factors that depress appetite.
58
How does adiponectin work in conjunction with fatty acid metabolism?
Adiponectin works in complement with leptin and signals through the AMP-PK and PPAR pathways which lead to suppression of FA synthesis and increases FA oxidation. Adiponectin also acts to inhibit acetyl CoA carboxylase (ACC).
59
Which monolayer are the major types of membrane lipids located on?
Non-cytosolic = phosphatidylcholine, sphingomyelin, glycoproteins; cytosolic = phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol
60
What is a glycocalyx?
The glycocalyx is a thick carbohydrate layer around the cell which consists of membrane proteins that possess covalently bound sugar groups. These sugar groups are attached to the non-cytosolic leaflet of the cell membrane and provides the cell with protection, identification, and adhesion properties. These are all functions that are essential to have on the outer monolayer.
61
Draw the urea cycle. What's it's function in the fasted state?
Function = to eliminate excess nitrogen that the body does not need
62
What are the sources of nitrogen for urea?
Sources = protein from the 'other' cells, such as muscle, that were created in the fed state. The proteins are degraded once glucagon, cortisol, epi, and norepi are in circulation. Glutamate and Alanine (+ other AAs) are transported in the blood to tissues as nitrogen sources.
63
How are the sources of nitrogen transported to the liver?
After obtaining the free amino acids from proteins in the tissues, the free amino acids are transported to the liver via circulation (blood).
64
What are the three ways the urea cycle is regulated?
1. Carbamoyl phosphate synthetase -1 (CPS-1): allosterically regulated by NAG (arginine, glutamate, acetyl CoA – via NAG synthase) 2. Arginine: when builds up it a) increases the synthesis of NAG which activates CPS-1, and b) it increases arginase activity 3. Transcriptional regulation i.e. glutamine regulates the enzyme transcription of argininosuccinate synthase a. Transcriptional changes occur due to long term adaptations caused by excess protein breakdown: high protein diet, starvation
65
Where does the free nitrogen come from to start the urea cycle?
from deamination of AAs: Thr, Ser, His, Glu, Asp, Gln; or from purine nucleotide metabolism
66
What are the three enzymes that can fix free nitrogen?
1. Glutamate dehydrogenase (GDH): reversible reaction, uses either NAD(P)H/NAD(P)+ 2. Carbamoyl phosphate synthetase-1 (CPS-1) 3. Glutamine synthetase
67
What is the function and significance of: glutamate with respect to nitrogen elimination through the urea cycle?
Glutamate is used as a form of free nitrogen that can be transported via circulation to liver for the urea cycle.
68
What is the function and significance of: aspartate with respect to nitrogen elimination through the urea cycle?
Asp is used in the urea cycle and donates nitrogen in the argininosuccinate synthetase step.
69
What is the function and significance of: glutamine with respect to nitrogen elimination through the urea cycle?
Glutamine is converted to glutamate which is used as a source of nitrogen for the urea cycle.
70
What is the function and significance of: alanine with respect to nitrogen elimination through the urea cycle?
Alanine comes from pyruvate and is transported to the liver via circulation. Alanine is broken down and used in the urea cycle (nitrogen) and in gluconeogenesis (carbon).
71
What is the function and significance of: ornithine with respect to nitrogen elimination through the urea cycle?
Ornithine is a mediator between mitochondira and the cytosol in the urea cycle. It is a component of the ornithine-citrulline anitporter.
72
Draw out urea cycle again and predict what different inherited pathologies would result due to the seven enzyme defects. Especially think about the conversion of carbamoyl phosphate's other synthetic use.
Carbamoyl phosphate is also used in pyrimidine synthesis which results in significant elevation of urinary orotic acid if ornithine transcarbamoylase (OTC) is not functioning.
73
What causes HHH syndrome and what do the three H's stand for?
HHH syndrome is caused by a defect in the ornithine-citrulline antiporter. The H's stand for: hyperammoniaemia, homocitrullinaemia, and hyperornithaemia. This means that there is an excess of ammonia, citrulline, and ornithine in the blood. Look at urea cycle to understand molecularly.
74
Kwarshiorkor disease is caused by?
A negative nitrogen balance which is usually due to malnutrition. More nitrogen is being excreted than is in the body to begin with.
75
What are the symptoms of hyperammonaemia?
refusal to eat/protein aversion, seizures, irritability, lethargy, ataxia, tremors, FTT
76
Why do seizures and tremors result from hyperammonaemia?
Free ammonia in the body acts adversely on neuronal tissue and can cause damage and detrimental effects.
77
How can someone measure free ammonia?
Obtain a patient's blood sample and test it with recombinant GDH, a-KG, and NADPH. NADPH absorbs UV light, thus absorption decreases as NADPH is oxidized. Decrease in absorbance is proportional to [NH4+] in blood.
78
What is BUN and how is it used?
BUN stands for Blood Urea Nitrogen. To perform this diagnostic test, a sample of patient's blood is incubated with bacterial urease and then the GDH reaction from free ammonia measurement is carried out.
79
How is insulin synthesized from preproinsulin?
preproinsulin --> proinsulin -- (C-peptide) --> insulin
80
What causes insulin to be released from the beta-cells in the pancreas?
Once glucose enters the beta-cell via a GLUT2 transporter it is metabolized to produce ATP which closes K+ channels causing a depolarization of the cell membrane. This depolarization results in Ca2+ entering the cell that then interacts with the insulin vesicle thus causing it to release its contents into the blood stream.
81
How does insulin act on the insulin receptor?
Insulin binds on the tyrosine kinase dimer which phosphorylates the receptor as well as Insulin Receptor substrate -1 (IRS-1). The phosphorylated tyrosines amek docking sites for Grb2 protein, phopholipase PLC gamma, and PI3K. Grb2 activates the MAPK cascade which modulates gene expression via transcription regulation. PI3K phosphorylates phosphatidylinositol to make PI-3,4,5-P which activates PDK kinase. PDK1 phosphorylates and activates PKB which phosphorylates both glycogen synthase kinase (inactivates) and protein phosphatase 1 (activates).
82
How is glucagon synthesized?
Glucagon is a protein that comes from transcription of the glucagon gene and translation of the proglucagon protein (160 AAs). Proteolytic processing creates glucagon (29 AAs).
83
How is glucagon released into circulation?
In the fed state, glucagon is retained within its vesicle due to the presence of glucose and insulin receptor signals. When the cell is absent of glucose and insulin, glucagon is able to be released from the alpha-cell.
84
What is the pathway of amino acids in the fed state?
Ingestion - stomach where broken down by pepsin - further digestion in intestines by pancreatic enzymes - transported across intestinal cell via AA-Na+ symporter - AA leaves via facilitated transport to the portal vein - off to liver where it can be processed in many ways (TAGs, proteins, glycogen) or it can go to other cells where protein is made and stored.
85
How does glucagon regulate pyruvate kinase?
Glucagon acts on a G-PCR which creates cAMP from adenylyl cyclase. cAMP then binds to a regulatory protein which causes the catalytic subunits to dissociate and phosphorylate pyruvate kinase rendering it inactive and it phosphorylates glycogen phosphorylase kinase which results in the breakdown of glycogen stores to glucose-6-phosphate.
86
What are the three main amino acid metabolism cofactors?
PLP, FH4, BH4-

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