Fatty Acid Synthesis Flashcards Preview

MCB 2000 > Fatty Acid Synthesis > Flashcards

Flashcards in Fatty Acid Synthesis Deck (105):
1

When does synthesis of lipids occur?

Why?

FED STATE - high I/G after a meal

- have an abundance of nutrients
- also requires energy
- conditions of excess caloric intake

2

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

Fasted

3

How are FA components of phospholipids?

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

4

How are FA components and properties of triglycerides?

- 3 FA attached to glycerol backbone
- Energy storage
- Very hydrophobic

5

Functions of fatty acids (4)

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

6

How do FA covalently modify proteins?

- Attaching a fatty acid to specific amino acid residue —> palmitate and myristate

- Bring protein to a membrane and affect the protein’s activity

7

Major source of carbon for synthesis of lipids is _____________

Can also use?

Primarily excess dietary carbohydrates (glucose)

Can also use excess dietary protein

8

Primary tissue involved in synthesis of lipids

Also occurs in ?

Primary = liver

Also occurs in adipose tissue

9

Lipogenesis involves

Synthesis of fatty acids from glucose

10

Dietary carbohydrates —>

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

11

Dietary proteins —>

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

12

Insulin promotes conversion of acetyl CoA —>

Fatty acids

13

If take away insulin, what happens to acetyl CoA ?

Acetyl CoA builds up and goes to form ketone bodies

14

Untreated Type I diabetes

Overproduction of ketone bodies

15

Ketone bodies

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

16

Early phase of low carb diet

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

17

5 Requirements for Fatty Acid Synthesis

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

18

Acetyl CoA as starting substrate problem

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

19

3 molecules that cannot cross mitochondrial membrane directly

1. Acetyl CoA
2. OAA
3. NADH / NAD+

20

Reducing equivalents

- Produce e- and H+

- Uses NADPH

21

NADPH is from:

1. Pentose phosphate pathway
2. Malic enzyme

22

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

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

23

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

1. Glycolysis

2. TCA Cycle (citrate)

3. Pentose Phosphate Pathway

24

Glucose can be oxidized in 2 ways:

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

25

Both ways to oxidize glucose occurs during?

Which predominates?

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

26

Overall Reaction

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

27

Fatty acids are built from

2-C units (acetyl CoA)

28

Starting point for all fatty acids =

16-C saturated fatty acid

Called palmitate

29

____ acetyl CoA total are required

8

30

Activation step

- 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)

31

Malonyl- CoA serves as __________

“ Active 2-C donor “

32

What drives chain growth?

1. Decarboxylation of malonyl Co-A

2. Reducing power of NADPH

33

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

4 glucose

34

Problem once pyruvate gets into mitochondria?

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

35

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

2 enzymes:

Pyruvate carboxylase

Pyruvate Decarboxylation

36

Pyruvate carboxylase

Converts pyruvate —> 4-C OAA

37

Acetyl CoA _________ modifies pyruvate carboxylase

Positively allosteric

38

Pyruvate dehydrogenase

Converts pyruvate —> Acetyl CoA

39

Acetyl CoA _________ modifies pyruvate dehydrogenase

What else regulates PDC?

Negative allosteric

Insulin activates via dephosphorylation

40

Support pyruvate dehydrogenase is the lower Km enzyme....

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

41

ATP-Citrate Lyase reaction

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

42

Acetyl CoA is made in the __________ but __________

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

43

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

Out of the mitochondria into the cytoplasm as citrate

44

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

ATP- citrate lyase

45

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

1. Make NAD+ for glycolysis
2. Make NADPH for FA synthesis (in addition to pentose phosphate pathway)

46

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

Goes towards fatty acid synthesis

47

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

Must return to the mitochondria for TCA cycle to continue

BUT it is impermeable to the membrane

48

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

1. Cytoplasmic malate dehydrogenase

2. Malic enzyme

49

Cytoplasmic malate dehydrogenase reaction

OAA + ADP + NADH —> Malate + NAD+

- Favorable
- NAD+ can go to glycolysis

50

Malic enzyme reaction

Malate + NADP+ —> pyruvate + NADPH

- Pyruvate enters mitochondria
- NADPH goes toward FA synthesis

51

Rate-Limiting Step of Fatty Acid Synthesis

- The activation step

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

Enzyme: Acetyl CoA Carboxylase (ACC)

52

Substrate for fatty acid synthesis

Acetyl CoA (cytoplasm)

53

Acetyl CoA Carboxylase (ACC)

Type of reaction?

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

* Irreversible

54

ACC requires ?

Biotin is a coenzyme

55

2-steps of ACC reaction

1. Biotin accepts HCO3-

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

56

How is Acetyl CoA Carboxylase is regulated?

Hormonally AND allosterically

57

Hormonal regulation of ACC

Dephosphorylated and active in FED state

Phosphorylated and inactive in FASTED state

58

Mechanism of ACC being dephosphorylated and active in fed state

Insulin signaling activates protein phosphatase 2A which activates ACC

59

Mechanism of ACC being phosphorylated and inactive in fed state

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

60

AMPK activated by? Inhibited by?

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

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

Normally a dimer —> polymerizes to become active

Active as a polymer.

62

Positive allosteric modifier of Acetyl CoA Carboxylase

How?

Citrate

Activates ACC by facilitating the polymerization of the inactive dimer.

63

Negative allosteric modifier of Acetyl CoA Carboxylase

How?

Palmitoyl CoA

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

64

Citrate’s effect on phosphorylated ACC

Importance:

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

What enzyme extends the fatty acid chain?

Fatty acid synthase

66

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

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

67

3 reaction types in fatty acid extending chain

1. Condensation
2. Reduction
3. Dehydration

68

Condensation

Put 2 molecules together

69

Reduction

Requires NADPH

70

Dehydration

Get rid of all double bonds to make saturated fatty acid

71

4 important structural domains of fatty acid synthase

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

72

Modification domain

Where reduction and dehydration reactions occur

73

Thioesterase

Split fatty acid chain and release it from complex

74

Acyl carrier protein (ACP)

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

75

2 important steps to occur before elongation

1. Priming reaction
2. Condensation

76

Priming reaction

Acetyl CoA + ACP —> Acetyl-ACP + CoA

Malonyl CoA + ACP —> Malonyl-ACP + CoA

77

Explain what happens during priming reaction.

Enzyme?

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

Enzyme: Malonylacetyl transferase (MAT)

78

Important prosthetic group on ACP

- from vitamin phosphopantetheine
- identical to portion of CoA
- SH group is point of attachment

79

ACP does what?

Shuttles intermediates (similar to what lipoamide arm does)

80

Condensation reaction

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

81

Process of condensation reaction

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

Decarboxylation reaction purpose

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

83

Synthesize fatty acid from _____ end to ______ end

Omega end to Carboxy terminus end

84

Growing end of the fatty acid is on the

Acyl carrier protein

85

Elongation involves a step wise reduction of ________ to __________

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

86

Acetyl CoA goes in as acetyl CoA when?

ONLY THE FIRST ONE that makes up the omega end

87

The liver being the primary site of FAS also explains why

Glycolysis increases in the fed state in the liver

88

ATP in the fed state

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

Biosynthetic reactions occur when

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

Order of reaction type in FAS

Condensation —> reduction —> dehydration —> reduction

91

Products formed (in order) during fatty acid synthesis

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

Introduction of double bonds occurs in

The endoplasmic reticulum

93

Mammals cannot add double bond beyond?

C-9

94

2 essential fatty acids

Linoleate (omega-6)

Linolenate (omega-3)

95

Linoleate (omega-6) structure and use?

18:2 ; double bond at carbon 9 and 12

Used to synthesize arachidonic acid (20:4)

96

Arachidonic acid use

Precursor for prostaglandins, leukotrienes, thromboxanes

97

Aspirin does what?

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

98

Lineolenate (omega-3) structure

18:3
Double bonds at carbon 9,12,15

99

Pentose Phosphate Pathway has?

2 branches- oxidative and nonoxidative

100

Oxidative branch of pentose phosphate pathway chemistry

Reaction?

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

Step 1 of oxidative branch of pentose phosphate pathway

Enzyme?

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

Step 2 of oxidative branch of pentose phosphate pathway

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

- Goes from closed structure to open structure
- C=O —> CO2 with resonance

103

Step 3 of oxidative branch of pentose phosphate pathway

Enzyme:

DECARBOXYLATION

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

Enzyme: 6-phosphogluconate dehydrogenase

104

Non oxidative branch of pentose phosphate pathway primary function

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

- where ribose and deoxyribose come from

105

Which branch of pentose phosphate pathway is favored?

Depends on needs of cell