Fatty acid synthesis and degradation Flashcards

1
Q

80% of Energy needs of mammalian heart and liver Are provided by

A

Fatty acids

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2
Q

fatty acids

What is beta oxidation

A

Repetitive four step process by which FA’s are converted into acetyl CoA

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3
Q

fatty acids

How is energy made from Beta Oxidation

A
  • Electrons removed from FA pass through ETC making ATP
  • Acetyl CoA produced from FA may be completely oxidizes to CO2 in TCA cycle
  • Acetyl CoA may also be converted to ketone bodies in liver and exported to the brain and other tissues when glucose is limiting
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4
Q

fatty acids

Advantages of triacylglycerol’s as storage fuels

A
  1. Highly reduced structures: two times the energy for the same way compared to carbohydrates or protein
  2. Triacylglycerol’s aggregate in the lipid droplets and so do not raise osmolality of cytosol
  3. They are inert chemically
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5
Q

fatty acids

What are the sources of fat

A

Dietary, lipid droplets in adipose tissue (triglycerides), fats synthesized from excess carbohydrates in liver

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6
Q

fatty acids

Provides more than half of energy to liver, heart and resting muscle and is virtually the sole source of energy and hibernating animals in migrating birds

A

Triglycerides

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7
Q

fatty acids

What are micelles

A
  • aggregate of surfactant molecules dispersed in a liquid colloid.
  • A typical micelle in aqueous solution forms an aggregate with the hydrophilic “head” regions in contact with surrounding solvent, sequestering the hydrophobic single-tail regions in the micelle centre.
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8
Q

fatty acids

What degrades triacylglycerol in diet

A

Intestinal lipases

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9
Q

fatty acids

How are chylomicrons made

A

Triacylglycerol’s are incorporated with cholesterol and a polypoproteins

Phopholipid surround them

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10
Q

fatty acids

What are the fates of fatty acids in diet

A

Maybe oxidized as fuel Or Reesterfied for storage

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11
Q

fatty acids

What does lipoprotein lipase do

A

Converts triacylglycerol to fatty acids and glycerol

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12
Q

fatty acids

What activates lipoprotein lipase

A

ApoC-II in Capillary

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13
Q

fatty acids

Acts as signal in uptake and metabolism of fatty acids

A

Apolypoprotein

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14
Q

fatty acids

Describe the composition of chylomicrons

A

80% is made up of triacylglycerol’s which are in the interior, there is also dietary cholesterol, and specific proteins such as apolipoprotein

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15
Q

fatty acids

Glucagon causes what

A
  1. Hormone binds receptor in adipocyte membrane
  2. Stimulates adenylil cyclase via G protein producing cyclic AMP
  3. PKA is activated, phosphorylates lipase and Perilipin on surface of lipid droplet
  4. lipase hydrolyzes triacylglycerols to free fatty acids
  5. fatty acids leave adipocyte, Bind serum albumin in blood , carried in blood; released
  6. Enter myocyte via fatty acid transporter; Can then be oxidized to CO2
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16
Q

fatty acids

What percentage of energy from triacylglycerol’s resides in their fatty acid chains

A

90%

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17
Q

fatty acids

Glycerol moiety contributes what percentage of energy from triacylglycerol

A

5%

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18
Q

fatty acids

What happens to glycerol after it’s released by lipase

A
  1. It is phosphorylated by glycerol kinase
  2. Glycerol three phosphate is oxidized to DHAP - via Glycerol 3 phosphate dehydrogenase
  3. DHA P is converted to glyceraldehyde 3 phosphate via Triose phosphate isomerase
  4. it is then oxidized via glycolysis
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19
Q

fatty acids

What happens when fatty acids enter myocytes

A

They are activated and transported into mitochondria

  1. Catalyzed by fatty acyl CoA synthetases and inorganic PPI 2.

Two steps –

  • Carboxylate ion displaces outer to phosphates of ATP to form a fatty acid adenylate; PPI is immediately hydrolyzed pulling the reaction forward
  • Thiol group of CoA carries out nucleophilic attack on enzyme
  • bound mixed anhydride displaces AMP and forms thioester thioester – CoA -Highly exergonic
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20
Q

fatty acids

What is the carnitine shuttle

A
  1. Rate limiting step of beta oxidation
  2. Most fatty acids with a chain length of 14 more can pass directly through the mitochondrial membrane
    - Convert to fatty acyl– CoA and React with carnitine to form fatty acyl–carnitine

Enzyme: carnitine Acyltranferase I

  • pass through mitochondrial Outer membrane via pores and enters matrix via acyl– carnitine/carnitine transporter of inner mitochondrial membrane
  • Fatty acyl group is then transferred from carnitine to CoA in mitochondrial matrix

Enzyme: Carnitine Acyltranferase II

-Carnitine exist to cytosol to repeat cycle

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21
Q

fatty acids

What are the three stages of fatty acid oxidation

A
  1. Fatty acid undergoes oxidative removal of successive to carbon units in form of acetyl CoA (beta – oxidation)
  2. Acetyl groups are oxidized to CO2 via TCA cycle
  3. Electrons from oxidations of stage one and 2 pass to electron transport chain making ATP by Oxidative phosphorylation
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22
Q

fatty acids

What are the four basic steps of beta oxidation of saturated fatty acids

A
  1. Dehydrogenation of fatty acyl CoA produces a double bond between C2 and C3, yielding trans – enoyl CoA

FAD is electron acceptor; electron from reaction enters electron transfer chain -

Enzyme: aCYL – CoA Dehydrogenase

  1. Hydration to form beta hydroxy acyl- CoA -

Enzyme: Enoyl – CoA hydratase

  1. Dehydrogenation to form beta ketoacyl – CoA; NAD plus is electron acceptor; NADH formed donates its electron to NADH dehydrogenase of respiratory chain; ATP formed as an electron Passed to O2
    - Enzyme: beta hydroxyacyl- CoA Dehydrogenase
  2. Thiolysis : cleave carboxy – terminal 2 – C fragment of fatty acid as acetyl – CoA and CoA Thioester from original fatty acid.
    - Enzyme:acyl CoA Acetyltransferase (thiolase)
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23
Q

fatty acids

What are the products of palmitate oxidation

A
  • 8 acetyl CoA

10 ATP per acetyl CoA = 80 ATP

  • 7 FADH2 = 1.5 ATP
  • 7 NADH = 2.5 ATP
  • 7 H+
  • 4 ATP formed per beta oxidation (1 NADH and 1 FADH2)
  • 7*4 ATP/pass = 28 ATP
  • Total= 28+ 80 = 108 ATP
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24
Q

fatty acids

Regulation of beta oxidation

A
  • Carnitine shuttle is rate limiting step
  • malonyl-CoA- first intermediate from FA synthesis inhibits carnotine acyl transferase
  • High [NADH/NAD+] ratios: inhibit beta- hydroxyacyl dehydrogenase
  • high Acetyl CoA: conc. inhibits thiolase
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25
Q

fatty acids

How does blood glucose affect fatty acid synthesis ?

A
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26
Q

fatty acids

How do blood glucose levels affect fatty acid breakdown

A
  1. High carb meal: raises blood glucose levels; insulin release; insulin-dependent phosphatase dephosphorylates ACC, activating it; ACC catalyzes formation of malonyl-CoA, which inhibits carnitine acyltransferase, preventing fatty acid entry into matrix.
    2)   Blood glucose level drops between meals: glucagon release activates PKA; phosphorylates and inactivates ACC; low malonyl-CoA; FA enter matrix and become major fuel
27
Q

fatty acids

What enzymes are involved in regulation of fatty acid breakdown and synthesis? How do they do it?

A

Coordination of fatty acid metabolism by two enzymes:

a) acetyl CoA carboxylase (ACC; 1st enzyme in synthesis) - its product (malonyl CoA) inhibits carnitine acyltransferase
b) carnitine acyltransferase (limits FA transport through mitochondrial matrix for β-oxidation)

28
Q

fatty acids

Acetyl-CoA produced in beta oxidation can:

A
  • Enter TCA cycle
  • undergo conversion to “ketone bodies” -acetone, acetate, D-β-hydroxybutyrate
29
Q

fatty acids

What happens to ketone bodies after they are formed

A
  • Acetone is exhaled
  • -Acetoacetate and D-β-hydroxybutyrate aretransported by blood to extrahepatic tissues, where they are converted to acetyl CoA and oxidized in TCA
30
Q

fatty acids

Describe the reaction that produces ketone bodies ( substrates, products, enzymes)

A
31
Q

fatty acids

How does the brain use D-beta hydroxybuterate?

A

D-β-hydroxybutyrate is converted in 3 steps to acetyl CoA:

1) oxidized to acetoacetate
2) activated w/ CoA donated from succinyl CoA
3) Split by thiolase

32
Q

fatty acids

What happens in conditions that promote gluconeogenesis ( such as untreated DM)

A
  • Oxaloacetate is drawn away from TCA
  • Conversion from Acetyl CoA to oxaloacetate increased
  • released CoA allows continued beta oxidation of fatty acids with only minimal oxidation of acetyl CoA
33
Q

fatty acids

DM and starvation lead to:

what blood states?

what is overproduced?

A
  • Overproduction of ketone bodies
  • ketosis
  • acidosis
34
Q

fatty acids

What happens to the TCA cycle in starvation?

What does this lead to?

A

During starvation, gluconeogenesis depletes TCA intermediates, diverting acetyl-CoA to ketone body formation

35
Q

fatty acids

What happens in untreated DM

A

when insulin level is insufficient, extrahepatic tissues can’t take up glucose from blood; levels of malonyl-CoA fall; inhibition of carnitine acyltransferase is relieved; FA enter mitochondria to be converted to acetyl CoA, but can’t pass through TCA because intermediates have been drawn off for gluconeogenesis; accumulation of acetyl CoA cause formation of ketone bodies; lowers blood pH (acidosis) -can lead to coma and death

36
Q

fatty acids

what are the differences between fatty acid synthesis and breakdown.

A

Fatty acid biosynthesis and breakdown occur by different pathways, different enzymes, takes place in different parts of the cell

37
Q

fatty acids

What is the first step in fatty acid synthesis?

A

Acetyl CoA and bicarbonate react to form malonyl CoA via Acetyl CoA carboxylase. Biotin is cofactor - carried by biotin carrier protein - important intermediate - rate limiting step

38
Q

fatty acids

Describe ACC’s structure and function

How many functional regions?

what are the names of the subunits?

what does each do?

A

3 functional regions:

1)   Biotin carrier protein.
2)   Biotin carboxylase: activates CO 2 by attaching it to a nitrogen in the biotin ring; uses ATP .
3) Transcarboxylase: transfers activated CO2 CoA, forming malonyl-CoA (long flexible biotin arm carries activated CO2 from biotin carboxylase region to transcarboxylase active site)

39
Q

fatty acids

What is the repetitive 4 step process in FA synthesis

A

Enzyme System: Fatty Acid Synthase

1)   Condensation of an activated acyl group and 2 C from malonyl-CoA, w/ elimination of CO2 (extends acyl chain by 2C) The β-keto product from condensation is reduced in next 3 steps:
2) β-keto group is reduced to alcohol.
3) Elimination of H20 creates a double bond.
4) Double bond is reduced to form the corresponding saturated fatty acyl group.

40
Q

fatty acids

What is the reducing agent in fatty acid synthesis

A

NADPH

41
Q

fatty acids

How are fatty acids elongated to form palminate

A

1)   The fatty acyl chain grows by 2-carbon units donated by activated malonate, with loss of CO2 at each step
2)   After each 2-carbon addition, reductions convert the growing chain into a saturated fatty acid of 4, then 6, then 8, and so on. The final product is palmitate (C16)

42
Q

fatty acids

Where does FA synthesis occur in the cell? Why?

A

Cytosol:

  • In most higher eukaryotes, fatty acid synthase complex is in cytosol, together w/ biosynthetic enzymes for nucleotides, amino acids, and glucose
  • location segregates synthetic processes from degradative processes NADPH = for anabolic rxns NAD+ = for catabolic rxns Fatty acid synthesis occurs in compartment where NADPH is available for reductive synthesis (high [NADPH/NADP+] ratio)
43
Q

fatty acids

Name and describe the alloesteric and covalent modifications that regulate FA synthesis.

A

Rxn catalyzed by acetyl- CoA carboxylase is the rate-limiting step in the biosynthesis of fatty acids

  • important site of regulation
    1) Palmitoyl-CoA = feedback inhibitor of enzyme
    2) Citrate = allosteric activator of enzyme
    3) Also regulated by covalent modification: phosphorylation triggered by hormones glucagon and epinephrine inactivates enzyme; slows fatty acid synthesis
44
Q

fatty acids

How does the shuttle for transfer of acetyl groups from mitochondria to cytosol work?

A

1) Mitochondrial OM is freely permeable to all compounds
2) Pyruvate derived from aa catabolism in matrix or glucose by glycolysis in the cytosol is converted to acetyl CoA in matrix
- Acetyl groups pass out of mito as citrate; in cytosol, they are delivered as acetyl-CoA for fatty acid synthesis Oxaloacetate is reduced to malate, which returns to mito matrix and is converted to oxaloacetate

45
Q

fatty acids

What is osmolality

A

: the concentration of an osmotic solution measured in osmols or milliosmols per 1000 grams of solvent

46
Q

fatty acids

What is an osmole

A

An osmole is a unit of measurement that describes the number of moles of a compound that contribute to the osmotic pressure of a chemical solution.

47
Q

how many active sites does fatty acid synthase have?

A

7

48
Q

what happehe first step of ketone body formation?

A

2 acetyl CoA’s react to form acetoacetyl-CoA

Enzyme: thiolase AKA acetyl-Coenzyme A acetyltransferases (ACAT)

released: CoA-SH

49
Q

what is the first step in tryglyceride synthesis

A

combine one glycerol-3-phosphate and FA-CoA ester to make lysophosphatidic acid

Enzyme: Glycerol-3-Phosphate acyltransferase

50
Q

what is the solubility of ketone bodies?

A

they are water soluble

51
Q

acetoacetyl-CoA is converted to what in ketone formation? (2nd rxn)

A

acetoacetyl-CoA is reacted with another acetyl CoA to form beta- hydroxy- beta- methylglutaryl-CoA (HMG-CoA)

enzyme: HMG-CoA synthase

releasing CoA-SH

52
Q

what happens in third step of ketone body formation

A

HMG-CoA is converted to acetoacetate

Enzyme: HMG-CoA lysase

acetyl CoA released

53
Q

what are the 2 rxns that occur after formation of acetyoacetate?

A

acetoacetate can either be converted to acetone via acetoacetate decarboxylase; releasing CO2

or it can be converted to D-Beta- hydroxybutyrate by D-Beta- hydroxybutyrate dehydrogenase

uses NADH + H+

54
Q

what is the 1st rxn in the breakdown of D-beta-hydroxybutarate for fuel

A

D-beta-hydroxybutarate with NAD+ to make acetoacetate and NADH

enzyme: D-beta-hydroxybutarate dehydrogenase

55
Q

what is acetoacetate converted to when being broken down for fuel? (2nd step when using D-Beta hydroxybutyrate)

A

acetoacetate reacted with succinyl CoA to make acetoacetyl-CoA ; releasing Succinate

enzyme: beta-ketoacyl-CoA tranferase

56
Q

Acetoacetyl CoA is converted to what when making fuel (3rd step when breaking down D-beta- hydroxybutyrate for fuel)

A

Acetoacetyl CoA is reacted with CoA-SH to yield 2 acetyl CoA molecules

enzyme: thiolase AKA acetyl-Coenzyme A acetyltransferases (ACAT)

57
Q

What are the 2 variants of the fatty acid synthase “system”?

what organisms are they found in?

A

Fatty Acid Synthaze I: found in vertatbrates and fungi

Fatty Acid Synthase II: found in plants and bacteria

58
Q

how many polypeptides in FAS? How many active sites?

what is the molecular weight?

What happens when all active sites of one subunit are inactivated by mutation?

A

One single multifunctional polypeptide

7 active sites on 7 different domains

Mr 240,000 ( Mammalian is Homodimer: 480,000)

in case of mutation: FA synthesis is only moderately reduced

59
Q

What are the point of attachment on the fatty acyl synthetase

A

one is a Cys group on beta-ketoacyl-ACP synthase; KS)

Other is the -SH group of acyl carrier protein in a separate domain of the same polypeptide

60
Q

what are teh energetics of thioester hydrolysis?

what does this energy help power

A

they are highly exergonic

powers 1st and 5th steps: condensation and tranlocation of butyryl group of Cys on beta-ketoacyl-ACP synthase (KS)

61
Q

what is lysophosphatidic acid converted to during Tryglycerol synthesis?

A

Lysophosphatidic acid is reacted with Acyl-CoA and converted to phosphatidic acid

Enzyme: acylglyceroophosphate acyltransferase (AGPAT)

62
Q

Phosphatidic acid makes what during TAG Synthesis?

A

Phospahtidic acid makes diacylglycerol

Enzyme: phosphatidic acid phosphohydrolase (PAP)

63
Q

diacylglycerol is reacted to make what in TAG synthesis?

A

Diacylglycerol is reacted with FA-CoA to make triacylglycerol

Enzyme: Diacylglycerol Acyltransferase (DGAT)