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Biochem > Fatty Acid Synthesis > Flashcards

Fatty Acid Synthesis Flashcards

1
Q

When does synthesis of lipids occur?

Why?

A

FED STATE - high I/G after a meal

  • have an abundance of nutrients
  • also requires energy
  • conditions of excess caloric intake
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2
Q

(Most) biosynthetic reactions do not occur during the ________ state

A

Fasted

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3
Q

How are FA components of phospholipids?

A
  • Found in membranes

- Consist of 2 fatty acids + phosphate with polar head group on a glycerol backbone

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4
Q

How are FA components and properties of triglycerides?

A
  • 3 FA attached to glycerol backbone
  • Energy storage
  • Very hydrophobic
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5
Q

Functions of fatty acids (4)

A
  1. Components of phospholipids
  2. Components of triglycerides
  3. Second messengers
  4. Covalent modifications of proteins
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6
Q

How do FA covalently modify proteins?

A
  • Attaching a fatty acid to specific amino acid residue —> palmitate and myristate
  • Bring protein to a membrane and affect the protein’s activity
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7
Q

Major source of carbon for synthesis of lipids is _____________

Can also use?

A

Primarily excess dietary carbohydrates (glucose)

Can also use excess dietary protein

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8
Q

Primary tissue involved in synthesis of lipids

Also occurs in ?

A

Primary = liver

Also occurs in adipose tissue

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9
Q

Lipogenesis involves

A

Synthesis of fatty acids from glucose

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10
Q

Dietary carbohydrates —>

A

Dietary carbohydrates —> glucose —> acetyl CoA —> fatty acids —> triacylglycerols

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11
Q

Dietary proteins —>

A

Dietary proteins —> amino acids —> acetyl CoA —> fatty acids —> triacylglycerols

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12
Q

Insulin promotes conversion of acetyl CoA —>

A

Fatty acids

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13
Q

If take away insulin, what happens to acetyl CoA ?

A

Acetyl CoA builds up and goes to form ketone bodies

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14
Q

Untreated Type I diabetes

A

Overproduction of ketone bodies

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15
Q

Ketone bodies

A
  • Can be used for energy by anything but RBC
  • Occurs during periods of starvation
  • They are oxidized like fatty acids in the mitochondria
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16
Q

Early phase of low carb diet

A

Dec insulin -> any carbons go through acetyl CoA then make ketone bodies which are relied on for energy

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17
Q

5 Requirements for Fatty Acid Synthesis

A
  1. Acetyl CoA as starting substrate
  2. Reducing equivalents
  3. High I/G ratio (fed state)
  4. Energy
  5. Integration of 3 pathways
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18
Q

Acetyl CoA as starting substrate problem

A

It is not permeable to mitochondrial membrane and fatty acid synthesis occurs in the cytoplasm of liver cell

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19
Q

3 molecules that cannot cross mitochondrial membrane directly

A
  1. Acetyl CoA
  2. OAA
  3. NADH / NAD+
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20
Q

Reducing equivalents

A
  • Produce e- and H+

- Uses NADPH

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21
Q

NADPH is from:

A
  1. Pentose phosphate pathway

2. Malic enzyme

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22
Q

Why can NADH not be used as reducing equivalent in fatty acid synthesis?

A

NAD+ is needed to keep glycolysis going so that predominates there in the cytoplasm

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23
Q

Integration of what 3 pathways is required for fatty acid synthesis?

A
  1. Glycolysis
  2. TCA Cycle (citrate)
  3. Pentose Phosphate Pathway
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24
Q

Glucose can be oxidized in 2 ways:

A
  1. Glycolysis- produce pyruvate and NAD+ picks up electrons to give NADH
  2. Pentose phosphate pathway- produce a 5-C sugar and NADP+ picks up electrons to give NADPH
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25
Q

Both ways to oxidize glucose occurs during?

Which predominates?

A

During the fed state.

Which pathway predominates depends on the respective Kms on the enzymes in each pathway:
Lower Km = higher affinity so gets glucose first

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26
Q

Overall Reaction

A

8 acetyl CoA + 7 ATP (activation step) + 8 ATP (citrate lyase step) + 14 NADPH —> Palmitate + 14 NADP+ + 8 CoA + 6 H2O + 15 ADP + 7 Pi

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27
Q

Fatty acids are built from

A

2-C units (acetyl CoA)

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28
Q

Starting point for all fatty acids =

A

16-C saturated fatty acid

Called palmitate

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29
Q

____ acetyl CoA total are required

A

8

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30
Q

Activation step

A
  • Consumes 7 ATP total
  • Needs to occur for every acetyl CoA molecule except the first one
  • Acetate units are activated for transfer by conversion to malonyl-CoA (3-C)
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31
Q

Malonyl- CoA serves as __________

A

“ Active 2-C donor “

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32
Q

What drives chain growth?

A
  1. Decarboxylation of malonyl Co-A

2. Reducing power of NADPH

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33
Q

How many glucose are required for 1 palmitate (16-C)?

A

4 glucose

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34
Q

Problem once pyruvate gets into mitochondria?

A
  1. Need to keep TCA cycle going but OAA is very limiting..
    Reaction that produces OAA is not favorable and only reason TCA cycle goes forward is because whatever OAA is made is immediately bound to citrate synthase to make a binding site for acetyl CoA and form citrate
  2. Also need to produce enough citrate for it to exit mitochondria
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35
Q

How is the glucose conversion to Acetyl Co-A problem solved?

A

2 enzymes:

Pyruvate carboxylase

Pyruvate Decarboxylation

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36
Q

Pyruvate carboxylase

A

Converts pyruvate —> 4-C OAA

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37
Q

Acetyl CoA _________ modifies pyruvate carboxylase

A

Positively allosteric

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38
Q

Pyruvate dehydrogenase

A

Converts pyruvate —> Acetyl CoA

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39
Q

Acetyl CoA _________ modifies pyruvate dehydrogenase

What else regulates PDC?

A

Negative allosteric

Insulin activates via dephosphorylation

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40
Q

Support pyruvate dehydrogenase is the lower Km enzyme….

A

Acetyl CoA will be in slight excess —> if it builds up, PDC slows down —> any pyruvate entering mitochondria is diverted to pyruvate carboxylase and also acetyl CoA positively modifies the pyruvate carboxylase —> make enough OAA to condense with acetyl CoA to form citrate that can exit the mitochondira

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41
Q

ATP-Citrate Lyase reaction

A

Citrate + ATP + CoA-SH + H2O —> Acetyl CoA + ADP + Pi + OAA

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42
Q

Acetyl CoA is made in the __________ but __________

A

Made in the mitochondria but is not permeable to the mitochondrial membrane

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43
Q

Acetyl CoA is transferred out of the _______ into the ________ as ________

A

Out of the mitochondria into the cytoplasm as citrate

44
Q

Enzyme that catalyzes the split of citrate back into acetyl CoA and OAA

A

ATP- citrate lyase

45
Q

Even though you hydrolyze an ATP for every citrate that exits the mitochondria and used in cytoplasm for FA synthesis there are 2 benefits:

A
  1. Make NAD+ for glycolysis

2. Make NADPH for FA synthesis (in addition to pentose phosphate pathway)

46
Q

What happens to the acetyl CoA from ATP-citrate lyase reaction?

A

Goes towards fatty acid synthesis

47
Q

What happens to the OAA from ATP-citrate lyase reaction?

A

Must return to the mitochondria for TCA cycle to continue

BUT it is impermeable to the membrane

48
Q

2 enzymes involved in getting OAA back into the mitochondria (as pyruvate)

A
  1. Cytoplasmic malate dehydrogenase

2. Malic enzyme

49
Q

Cytoplasmic malate dehydrogenase reaction

A

OAA + ADP + NADH —> Malate + NAD+

  • Favorable
  • NAD+ can go to glycolysis
50
Q

Malic enzyme reaction

A

Malate + NADP+ —> pyruvate + NADPH

  • Pyruvate enters mitochondria
  • NADPH goes toward FA synthesis
51
Q

Rate-Limiting Step of Fatty Acid Synthesis

A
  • The activation step

Acetyl CoA + ATP + HCO3- —> Malonyl CoA + ADP + Pi + H+

Enzyme: Acetyl CoA Carboxylase (ACC)

52
Q

Substrate for fatty acid synthesis

A

Acetyl CoA (cytoplasm)

53
Q

Acetyl CoA Carboxylase (ACC)

Type of reaction?

A

Catalyzes the carboxylation of acetyl CoA (2-C) to form malonyl CoA (3-C)

  • Irreversible
54
Q

ACC requires ?

A

Biotin is a coenzyme

55
Q

2-steps of ACC reaction

A
  1. Biotin accepts HCO3-

3. Add C from HCO3- to form malonyl CoA “active 2-C donor”

56
Q

How is Acetyl CoA Carboxylase is regulated?

A

Hormonally AND allosterically

57
Q

Hormonal regulation of ACC

A

Dephosphorylated and active in FED state

Phosphorylated and inactive in FASTED state

58
Q

Mechanism of ACC being dephosphorylated and active in fed state

A

Insulin signaling activates protein phosphatase 2A which activates ACC

59
Q

Mechanism of ACC being phosphorylated and inactive in fed state

A

Glucagon signaling activates AMP-dependent protein kinase (AMPK) which inactivates ACC by directly phosphorylating it

60
Q

AMPK activated by? Inhibited by?

A

Activated by AMP

Inhibited by ATP

So during times of low energy charge (glucagon predominates during fasted state), AMPK is activated and goes to inactivate ACC by phosphorylating it

61
Q

ACC is normally a _____ —> ends up _________ to become active

A

Normally a dimer —> polymerizes to become active

Active as a polymer.

62
Q

Positive allosteric modifier of Acetyl CoA Carboxylase

How?

A

Citrate

Activates ACC by facilitating the polymerization of the inactive dimer.

63
Q

Negative allosteric modifier of Acetyl CoA Carboxylase

How?

A

Palmitoyl CoA

Palmitoyl CoA is generated at end of synthesis of FA —> when it builds up it causes depolymerization

64
Q

Citrate’s effect on phosphorylated ACC

Importance:

A

Can take phosphorylated ACC —> add citrate to it —> restore part of ACC’s activity

  • Advantage for efficiency/conservation in terms of using carbon skeletons because hormonal control is still slower than changes in metabolite flux
  • Metabolite flux changes rapidly - concentrations matter
65
Q

What enzyme extends the fatty acid chain?

A

Fatty acid synthase

66
Q

The intermediates are ______ as a ______ to either ____ or _____ during the entire biosynthesis

A

Covalently bonded as a thioester bond to either ACP or condensing enzyme

67
Q

3 reaction types in fatty acid extending chain

A
  1. Condensation
  2. Reduction
  3. Dehydration
68
Q

Condensation

A

Put 2 molecules together

69
Q

Reduction

A

Requires NADPH

70
Q

Dehydration

A

Get rid of all double bonds to make saturated fatty acid

71
Q

4 important structural domains of fatty acid synthase

A
  1. Condensing domain
  2. Modification domain
  3. Thioesterase (TE)
  4. Acyl carrier protein
72
Q

Modification domain

A

Where reduction and dehydration reactions occur

73
Q

Thioesterase

A

Split fatty acid chain and release it from complex

74
Q

Acyl carrier protein (ACP)

A

Has an SH group to form thioester bond to link intermediates to ACP with growing chain throughout entire biosynthesis

75
Q

2 important steps to occur before elongation

A
  1. Priming reaction

2. Condensation

76
Q

Priming reaction

A

Acetyl CoA + ACP —> Acetyl-ACP + CoA

Malonyl CoA + ACP —> Malonyl-ACP + CoA

77
Q

Explain what happens during priming reaction.

Enzyme?

A

First load acetyl CoA and then load malonyl CoA onto the acyl carrier protein.

Enzyme: Malonylacetyl transferase (MAT)

78
Q

Important prosthetic group on ACP

A
  • from vitamin phosphopantetheine
  • identical to portion of CoA
  • SH group is point of attachment
79
Q

ACP does what?

A

Shuttles intermediates (similar to what lipoamide arm does)

80
Q

Condensation reaction

A

Acetyl-ACP + Malonyl-ACP —> acetoacetyl-ACP + ACP+ CO2

81
Q

Process of condensation reaction

A

Acetyl CoA binds to carrier protein —> moves over to condensing enzyme freeing up its site on the carrier protein —> ACP binds malonyl CoA —> condensing enzyme catalyzes a decarboxylation —> CO2 that was added by acetyl CoA carboxylase comes off —> 2 carbons that originated from acetyl CoA will end up where the CO2 was lost from (at the bottom-defining the omega end of the fatty acid)

82
Q

Decarboxylation reaction purpose

A

It is favorable — makes the condensation favorable by providing the energy for it

83
Q

Synthesize fatty acid from _____ end to ______ end

A

Omega end to Carboxy terminus end

84
Q

Growing end of the fatty acid is on the

A

Acyl carrier protein

85
Q

Elongation involves a step wise reduction of ________ to __________

A

Keto group at C-3 to a methylene group (CH2)

86
Q

Acetyl CoA goes in as acetyl CoA when?

A

ONLY THE FIRST ONE that makes up the omega end

87
Q

The liver being the primary site of FAS also explains why

A

Glycolysis increases in the fed state in the liver

88
Q

ATP in the fed state

A

Make a lot of it but it is rapidly consumed.

As always, cell tries to maintain ATP levels so energy charge is around 0.85

89
Q

Biosynthetic reactions occur when

A

You have plenty of carbon sources coming in from diet so that you can use some of them for energy and put the others into storage (which also requires energy to do).

90
Q

Order of reaction type in FAS

A

Condensation —> reduction —> dehydration —> reduction

91
Q

Products formed (in order) during fatty acid synthesis

A

Acetyl-ACP —> malonyl ACP —> acetoacetyl ACP —> 3-hydroxbutyryl ACP —> crotonyl ACP —> butyryl ACP —> butyryl ACP then condenses with malonyl ACP to begin another round

92
Q

Introduction of double bonds occurs in

A

The endoplasmic reticulum

93
Q

Mammals cannot add double bond beyond?

A

C-9

94
Q

2 essential fatty acids

A

Linoleate (omega-6)

Linolenate (omega-3)

95
Q

Linoleate (omega-6) structure and use?

A

18:2 ; double bond at carbon 9 and 12

Used to synthesize arachidonic acid (20:4)

96
Q

Arachidonic acid use

A

Precursor for prostaglandins, leukotrienes, thromboxanes

97
Q

Aspirin does what?

A

Inhibits synthesis of prostaglandins by occupying site on prostaglandin synthase which prevents arachidonic acid from getting access to active site

98
Q

Lineolenate (omega-3) structure

A

18:3

Double bonds at carbon 9,12,15

99
Q

Pentose Phosphate Pathway has?

A

2 branches- oxidative and nonoxidative

100
Q

Oxidative branch of pentose phosphate pathway chemistry

Reaction?

A

Going from 6 carbons to 5 carbons

  • Oxidation / reduction
  • Occurs in 3 steps

Glucose-6-Phosphate + 2 NADP+ —> ribulose-5-phosphate + 2 NADPH + CO2

101
Q

Step 1 of oxidative branch of pentose phosphate pathway

Enzyme?

A

OXIDATION
Glucose-6-phosphate + NADP+ —> 6-phosphoglucono-delta-lactone + NADPH

  • OH group becomes C=O
  • NADP+ picks up electrons to form NADPH
  • Rate limiting step!

Enzyme: glucose-6-phosphate dehydrogenase

102
Q

Step 2 of oxidative branch of pentose phosphate pathway

A

6-phosphoglucono-delta-lactone + H2O —> 6-phosphogluconate + H+

  • Goes from closed structure to open structure
  • C=O —> CO2 with resonance
103
Q

Step 3 of oxidative branch of pentose phosphate pathway

Enzyme:

A

DECARBOXYLATION

6-phosphogluconate + NADP+ —> Ribulose-5-phosphate +NADPH + CO2

Enzyme: 6-phosphogluconate dehydrogenase

104
Q

Non oxidative branch of pentose phosphate pathway primary function

A

Produce 5-C sugars (ribulose-5-phosphate) for nucleotide biosynthesis

  • where ribose and deoxyribose come from
105
Q

Which branch of pentose phosphate pathway is favored?

A

Depends on needs of cell

Biochem (15 decks)

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