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MSK Final Exams Sans Radiology/Anatomy > Biochemistry - FA, Ketone, Glucose > Flashcards

Biochemistry - FA, Ketone, Glucose Flashcards

1
Q

Structure of a Fatty Acid

A

aliphatic chain, carboxyl

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2
Q

Which carbon is the omega carbon?

A

Methyl Carbon on the end

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3
Q

Which carbon is carbon 1?

A

The carboxyl carbon

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4
Q

˜ 4 major functions of FA:

A

Fuel

Signal Transduction

Membrane Lipinds

Storage (TAG)

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5
Q

What are the four chain lengths categories and carbon number ranges for fatty acids?

A

˜ Chain length

>20C = very long chain (VLCFA)

12-20C = Long chain LCFA

6-12C = Medium chain MCFA

<6C = Small chain SCFA

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6
Q

Structure of Palmitate

A

16:0

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7
Q

Structure of Stearate

A

(18:0)

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8
Q

Structure of Oleate

A

18:1

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9
Q

Linoelate

A

18:2

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10
Q

What do we mean by “free” fatty acids?

A

They have not been esterified (i.e., have not ben bound to glycerides)

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11
Q

4 steps to LCFA metabolism and the enzymes required

A
  1. Dehydrogenation (oxidation) between C2 and C3 (alpha and Beta) - Done by Acyl CoA Dehydrogenase. Turns FADH to FADH2
  2. Hydration of double bond. Done by Enoyl CoA Hydratase
  3. Dehydrogenation (Oxidation) - Beta Hydroxyacyl CoA Dehydrogenase. Turns NAD+ to NADH2.
  4. Thiolytic Cleavage completed by Thiolase
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12
Q

What are adipocytes specialized for?

A

Adipocytes are specialized for storing TAGs or Triacylglycerides (fatty fat fat fat)

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13
Q

What are chylomicrons?

A

Specialized vesicles that transport TAGs fom the intestines to adipocytes

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14
Q

What does serum albumin do?

A

˜ Serum albumin carries FFA from adipocyte to tissues

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15
Q

Explain the steps of carnitine shuttling

A
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16
Q

How many Acetyl CoA’s, NADHs and FADH2s will we make for a fatty acid?

A

Acetyl CoAs is half

NADH and FADH2s are 1/2 - 1

Ex. With Palmitate, we have 16 carbons which means 8 acetyl CoAs will be made, but only 7 FADH2s and 7 NADHs (takes 7 beta oxidations)

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17
Q

How many ATPs will be generated from a fatty acid oxidation?

A

You get 1.5 for FADH2 and 2.5 for NADH.

Ex. With Palmitate, we have 16 carbons

This means 7 beta oxidations to complete it.

7*1.5 = 10.5 ATP

7*2.5 = 17.5 ATP

= Total of 28 ATP

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18
Q

What additional enzymes will we need to an unsaturated FA? What do they do?

A
  1. Enoyl CoA Isomerase - Turns our 3-4 double bond to a 2-3 double bond
  2. 2,4 dienoyl reductase - uses NADPH. After we have used Enoyl CoA isomerase to crank out a couple more Acetyl CoAs, we will end up wih a situation where we have a 4-5 and a 2-3 double bond. This enzyme consolidates them to a 3-4 double bond.

Te fina lstep is for another enoyl CoA isomerase to put that remaining double bond on the 2-3 spot to continue beta oxidation. See picture below if this is unclear.

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19
Q

What happens with fatty acid metabolism when we have an odd number of carbons?

A

We will produce a propionyl CoA, which is 3 carbons instead of 2

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20
Q

What do we do with propionyl CoA

A

We turn it to succinyl CoA

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21
Q

What does propionyl CoA Carboxylase need?

A

Vitamin B12

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22
Q

How do we check for Vitamin B12 deficiency?

A

We test for an intermediate in the reaction for propionyl CoA called methylmalonic acid.

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23
Q

How do we turn propionyl CoA to succinyl CoA?

A

The propionyl CoA would be carboxylated by propionyl CoA carboxylase which produces D-methylmalonyl CoA using up ATP and biotin to put a carboxyl group on the second carbon.

The next step simply involves changing the stereochemistry by methylmalonyl CoA epimerase, producing L-methylmalonyl CoA

Then, vitamin B12 switches the carbonyl attached to the CoA with the neighboring hydrogen. This is catalyzed by methylmalonyl CoA mutase to produce Succinyl CoA

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24
Q

What can we do with succinyl CoA?

A

Replenish TCA cycle

Provide carbons for gluconeogenesis

Can be oxidized to CO2 and H2O

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25
Q

Compare MCFA beta oxidation to regular FFA metabolism

A

Basically the same except

  1. Don’t use carnitine, we just use a non-carboxylate transporter
  2. We use MCFA Acyl CoA Synthetase
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26
Q

What else can digest MCFAs besides the route similar to regular FFAs?

A

Enzymes for similar chain length substrates (like benzoates and salicylates) can also catabolize MCFAs

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27
Q

What do we need in order to digest VLCFA?

A

Peroxisomes

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28
Q

Why doe we need peroxisomes to digest VLCFAs and what else can the peroxisomes do for us for FA metabolism?

A
  1. VLCFA – must trim before entering mitoch.
  2. Branched FA (α oxidation = add OH to α carb). Just like beta ox. Except 1st step is FAD oxidase
  3. Long chain branched FA cannot undergo 3rd step of beta ox → requires peroxisomal α hydroxylase to remove C1 and convert C2 to COOH
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29
Q

What is Zellweger syndrome and what does it result in biochemically?

What are the symptoms?

A

Zellweger syndrome – defect in peroxisomal biogenesis

Accumulation of VLCFA in tissues, affecting liver and brain

Elevated C26:0 and 26:1 FAs in plasma

Symptoms: neural + optic abnormalities

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30
Q

What is Refsum disease and what does it result in biochemically?

What are the symptoms? Treatments?

A

Refsum disease – α hydroxylase deficiency

Rare autosomal recessive condition

High [Phytanic acid] (from plants) in tissues

Symptoms: neural

Tx: dietary restriction (vegetables)

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31
Q

As far as fatty acid metabolism goes, what occurs in the smooth ER? What else can the Smooth ER help us with besides the oxidation of fatty acids?

A

Omega oxidation. Mixed function oxidases perform “oxygen insertion reaction” using CYP450

Also does metabolism of normal FA when β-ox is defective (removes 1C at a time). Products are C6-8 dicarboxylic acids for excretion

Smooth ER can also metabolize hydrophobic xenobiotics

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32
Q

There are 3 things that regulate Fatty Acid Oxidation. What are they?

A
  1. NAD/NADH ratio = high = cell needs energy = Increase in FFAs
  2. Compartmentalization - Oxidation occurs in the mitochondrial matrix and synthesis in the cytosol.
  3. Direct inhibition of FAO by Malonyl CoA, which inhibits carnitine transport by blocking CPT (CAT) I
33
Q

What are these three structures?

A

Top: acetone

Middle: acetoacetic acid

Bottom: b-hydroxybutyric acid

34
Q

What two important ketones should we know and why?

A

b-hydroxybutyric acid and acetoacetic acid are the main ketone body fuels for the brain

35
Q

Why do we even do ketogenesis?

A

Form of energy for the BBB and when we are fasting ti prevents us from using muscle protein

36
Q

What is the process we use to get ketones for the brain?

A

Remember thiolase from fatty acid oxidation? We used it to generate acetyl CoA in the last step. We can do the reverse reaction with thiolase as well

  1. Use thiolase to make Acetoacetyl CoA from 2 Acetyl CoAs and an acyl CoA (we lose CoA in this reaction)
  2. Use HMG CoA synthase to turn your new acetylacyl CoA to an HMG-CoA.
  3. Use Use HMG CoA Lyase to cleave an acetyl-CoA from your HMG-CoA to make acetoacetate
37
Q

After the liver has gone through ketogenesis, does it always just release acetoacetate?

A

No. It can do one of three things

  1. Release acetoacetate
  2. Turn Acetoacetate to Acetone and CO2 via non-enzymatic decarboxylation
  3. Turn Acetoacetate to D-B-hydroxybutyrate via D-B-Hydroxybutyrate dehydrogenase, turning NADH to NAD+ in the process.
38
Q

Does the liver use the ketones it produces for energy? Why?

A

No it does not, because it does not have Succinyl CoA transferase.

39
Q

What increases/decrease ketogenesis activity?

A

Epinephrine and Glucagon increase ketogenesis.

Insulin decreases ketogenesis

40
Q

How does our body respond to fasting with hormones and biochemical processes? Give a general overview of the body’s response.

A

When we fast, due to the low levels of glucose in the blood, we increase glucagon and decrease insulin.

We then begin fatty acid oxidation to break down fats for fuel, mainly in the liver. Starting about 3 hours after our last meal and going for the first day or so, we just keep doing fatty acid oxidation to generate Acetyl CoAs for storage, to eventually do the Kreb’s Cycle where we will generate electron carriers to enter the ETC to generate ATP.

41
Q

How does our body respond to fasting with hormones and biochemical processes? Give a general overview of the body’s response after it has been fasting for a couple of days and has a lot of Acetyl CoA’s floating around from all of the fat you have been metabolizing.

A

After the first 2-3 days of churning out Acetyl CoAs from fatty acid metabolism, the body starts to realize that it has more than enough Acetyl-CoA to maintain ATP levels, but there is no direct shutoff for Acetyl CoA (i.e., high Acetyl CoA levels does not stop Fatty Acid oxidation).

However, we can slow down the process. An increase in ATP stimulates the ETC to slow down, which causes a buildup of NADH which is not going through the ETC to donate protons. NADH, a big regulator of the kreb’s cycle, slows the Kreb’s Cycle down.

Well now the Acetyl-CoA doesn’t want to enter the Kreb’s cycle, so it gets shunted to developing Ketones, which is why we start to generate ketones in the body after a few days.

42
Q

During fasting after a few days when we have begun to generate ketones due to our buildup in Acetyl-CoA, what happens to the ketones? What is so beneficial about entering ketone generation, why not just do gluconeogenesis like in the first couple of days?

A

They diffuse from the liver to the blood and enter peripheral tissues to revert back to Acetyl CoA to go through the Kreb’s Cycle.

Ketone production puts less pressure on the body to do gluconeogenesis. This is great because by decreasing gluconeogenesis, you are saving your muscle protein from being turned into glucose for the body

43
Q
A
44
Q

What steps do peripheral tissues take to generate Acetyl CoA from ketones they receive from the liver?

A
  1. The tissues will typically receive Hydroxybutyrate or Acetoacetate. If it receives hydroxy butyrate, it will need to use Hydroxybutyrate dehydrogenase to to turn the hydroxybutyrate to acetoacetate, turning NAD+ to NADH along the way.
  2. Following the production of acetoacetate, Sucinyl CoA acetoacetate CoA transferase turns the acetoacetate to an acetoacetyl CoA, turning Succinyl CoA to Succinate along the way.
  3. The final step is to use thiolase to break up the acetoacetyl CoA into 2 Acetyl CoAs, utilizing help with an additional CoA to do the reaction.
45
Q

Ketone bodies reduce glucose demand by howm uch?

A

75%

46
Q

What are the five phases of starvation and when are we in them?

A
  1. Absorptive phase (Fed) (Up to four hours after eating)
  2. Post Absorptive phase (Easrly Fasted) (4 - 16 hours after eating)
  3. Early Starvation (16 hours to full day after a meal)
  4. Intermediate Starvation (2 - 24 days after meal)
  5. Prolonged Starvation (25+ days of no food)
47
Q

At what point are the kidneys recruited to help with gluconeogenesis?

A

Phase 4 starvation and forward, which is 1 - 2 days after a meal and beyond.

48
Q

What is the first organ to steop using glucose during fasting? Who stops next?

A

Liver stops first after 4 hours, at which time muscle and adipose tissue slow down.

After a day or two, the only organs using glucose still are the RBCs, renal medulla, and the brain, which diminishes its glucose use after 24-25 days when it starts to use ketones more and more.

49
Q

At what point does the liver kick start its gluconeogenesis enzymes?

A

After the first four hours post meal.

50
Q

What cells make insulin? What about Glucagon? When are these cells most active?

A

Insulin is made by beta cells in the pancreas, active under high glucose conditions

Glucagon is made by alpha cells in the pancreas when there is low blood sugar.

51
Q

What does glucagon do to glucose? What is done to glucose in tissues?

A

Glucagon turns glycogen to glucose, which then is broken up into CO2 and water and energy

52
Q

What inhibits/activates glycogenolysis?

A

Inhibited by PP-1, activated by Epinephrine/Glucagon (GPCR)

53
Q

What activates glycogen enzymes?

A

Protein Kinase A

54
Q

What is the stepwise mechanism of turning glycogen to glucose?

A

Glycogen Phosphorylase cleaves glycogen to produce glucose 1-P, which is then acted on by PGM to make Glucose-6-P. Then G6Pase converts Glucose-6-P to glucose.

55
Q

What is the pathway of turning glucose back to glycogen?

A

Glucokinase in the liver turns glucose to glucose-6-P. PGM turn G6P to G1P, and then UDGPG and Glycogen Synthase turn G1P to glycogen.

56
Q

What types of autosomal recessive glycogen conditions do we need to know and what disease falls into each type?

A

Type 1 - Von Gierke’s

Type 2 - Pompe

Type 3 - Cori

Type 5 - McArdle’s

Acronym - Very Poor Carb Metabolism (VPCM)

57
Q

What causes Von Gierke’s? What happens biochemically because of it and how does it present?

A

Type 1 (Von Gierkes) = G6Pase deficiency

Glycogen build up in tissue (e.g. hepatomegaly)

58
Q

What causes Pompe? What happens biochemically because of it and how does it present?

A

Type 2 (Pompe) = α1,4-glucosidase (acid maltase)

Systemic energy deficiency = fatal

“Pompe trashes the Pump” (cardiomegaly)

59
Q

What causes Cori? What happens biochemically because of it and how does it present?

A

Type 3 (Cori) = α1,6-glucosidase breaks alpha1-6 linkages that branch glycogen molecules to other ones. Deficiency or problem causes branching of glycogen stores in heart, liver, and skeletal muscle. Causes a variety of issues. Liver pathology usually ends in teen years, patients need protein diets to do gluconeogenesis.

60
Q

What causes McArdle’s? What happens biochemically because of it and how does it present?

A

Type 5 (McArdles) = Muscle glycogen phosphorylase issue

Excess muscle glycogen, painful cramps, rhabdo

61
Q

What are the oxidative processes of the Pentose Phosphate pathway?

A
  1. Glucose-6-Phosphate turns to 6-Phosphogluconolactone via Glucose-6-phosphate dehydrogenase, turning NADP+ to NADPH.
  2. 6-Phosphogluconolactone is turned to 6-Phosphogluconate via gluconolactonase, using water up in the process
  3. 6-Phosphogluconate is turned into Ribulose-5-phosphate by 6-phosphogluconate dehydrogenase, turning NADP* to NADPH and releasing CO2 in the process.
  4. The nthe non-oxidative reactions begin.
62
Q

What enzyme in the nonoxidative mechanisms turns Ribulose-5-Phosphate into Ribose-5-Phosphate? What else can happen to Ribulose-5-Phosphate?

A

Ribulose-5-Phosphate isomerase turns Ribulose-5-Phosphate into Ribose-5-Phosphate..

At the same time, Ribulose-5-Phosphate can turn turn into Xylulose-5-Phosphate via Ribulose-5-Phosphate epimerase

63
Q

Once we have turned some Ribulose-5-Phosphate into Xylulose-5-Phosphate and Ribose-5-Phosphate, what happens next? Finish themechanism for non-oxidative pentose phosphate generation.

A

A Transketolase turns Xylulose-5-Phosphate and Ribose-5-Phosphate into Sedaheptulose-7-Phosphate and glyceraldehyde-3-Phosphate

A Transaldolase then turns the S7P and G3P into Erythrose-4-Phosphate and Fructose-6-Phosphate.

Lastly, and this is a little goofy, since Fructose-6-Phosphate is fine how it is, we can use Erythrose-4-Phosphate and some early product, Xylulose-5-Phosphate, to make G3P and more Fructose-6-Phosphate via a Transketolase. The G3P can then be used in the cycle as stated above.

64
Q

What is our end results from the PP pathway? What is so great about these products?

A

End Result: NADPH for reductions, Pentoses for nucleotide synthesis.

NADPH is useful for reductions because it has a higher ratio than NADH/NAD because it is not used in the ETC

65
Q

What does Transketolase require?

A

TTP

66
Q

How does G6PDH affect males and females differently? Where do we see this condition the most?

A

Affects males (X-linked) of African, Mediterranean origin (malaria endemic areas)

~11% of African American males affected

Heterozygous females are protected against malaria

Affected males have 10% normal enzyme activity, sufficient to handle oxidative stress

67
Q

What stimulates the symptoms of G6PDH deficiency and what happens in the body? What cellular changes do we see?

A

Symptoms w/free radicals (e.g. antimalarial -> “quines”)

RBCs most susceptible b/c they can’t repair ox damage by replacement of lipids, proteins

Heinz bodies – particles of denatured protein adhere to membrane, stain w/basic dye

When engulfed by macrophage → Bite cells

68
Q

Outline the biochemical issues that arise with G6PDH deficiency

A

Low Glucose 6-Phosphate dehydrogenase leads to a drop in NADPH/NADP+ which drops GSH/GSSG lratio (meaning more GSSG which leads to heinz bodies), This causes a drop in peroxidase activity which means we have lower protection against oxidative damage.

69
Q

What are our sources of fructose? What are side effects associated with them?

A

Source of fructose = Sucrose (Glucose+Fructose) or other means such as high fructose corn syrup (HFCS)

HFCS induces FGF21 → Metabolic syndrome

70
Q

What are the steps to breaking down Fructose?

A

Fructose is turned to F1P via Fructokinase and then to DHAP + Glyceraldehyde via Aldolase.

71
Q

What diseases are associated with the fructose metabolism pathway?

A

They involve the enzymes:

First enzyme = Fructokinase. Deficiency = Essential Fructosuria a benign condition where fructose is excreted in urine, no F1P

Second Enzyme = Aldolase (B in liver, A in other). Deficiency = Fructose Intolerance, leading to a build up of F1P → Depletes ATP/Pi. Treated with fructose restriction

72
Q

What are our sources of Galactose?

A

Source of galactose = Lactose (Gal + Gluc)

73
Q

Describe the breakdown of Galactose.

A

Galactose is turned to G1P by Galactokinase and then to G6P by GUT, which requires UDP-Glucose (regenerated by UDP-Glucose Epimerase)

74
Q

Discuss Galemia and what causes it, along with symptoms

A

Galemia is caused by a deficiency in the enzymes of galactose metabolism. Non-classically it can be the first enzyme, Galactokinase, but more commonly is a defect in GUT, the second enzyme. Issues with these enzymes causes a buildup of Galactitol, which is worse with GUT problems. Symptoms include cataracts, and mental deficiencies as well as liver complications.

75
Q

What, in general, is the Polyol pathway and what enzymes does it use?

What issues do we see with this pathway.

A

We can store sugars in other forms, particularly in the eyes.

The mechanism is just taking a sugar, converting it to Sorbitol, and then to some other sugar, an example being Glucose to Sorbitol to Fructose.

Turning sugar to sorbitol requires Aldol reductase, which uses NADPH.

Turning Sorbitol to a sugar takes Sorbitol Dehydrogenase which uses NADH.

The only issue with this pathway is a buildup of ocular pressure.

76
Q

After a meal, insulin levels go up. Why? What does insulin do specifically?

A

Insulin: increases after a meal, stimulates the synthesis of glycogen

· cAMP => AMP by phosphodiesterase

· Inactivates protein kinase A

· Causes activation of phophatases that inactivate enzymes

77
Q

What do Glucagon and Epinephrine do specifically in the body?

A

Glucagon and Epinephrine: acts on liver cells (Epi on both liver and muscle) to stimulate glycogen degradation

· Via g-proteins, activate adenylyl cyclase to convert ATP to cAMP

· cAMP binds to regulatory subunits releasing catalytic subunits

78
Q

What does cAMP do for us?

A

o cAMP allows for the amplification of the hormonal signal (insulin or glucagon)

79
Q

· List the sequence of events from the binding of hormones by their receptors to the phosphorylation of glycogen synthase and phosphorylase.

A

o Hormone binds and acts on adenylyl cyclase; cause an effect on cAMP

o Change in cAMP effects protein kinase A

o Protein kinase A effects phosphorylase kinase

o Phosphorylase kinase determines action of glycogen phosphorylase or glycogen synthase

MSK Final Exams Sans Radiology/Anatomy (3 decks)

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