1
Q
What are lipids?
A
- major form of stored energy
- major parts of cell walls
2
Q
What can lipids become?
A
- pigments
- cofactors
- detergents
- transporters
- hormones
- messengers
3
Q
Requirements for lipid biosynthesis
A
- usually ATP
- NADPH as a reduced electron carrier
4
Q
Anabolic lipid pathways
A
reductive
5
Q
Catabolic lipid pathways
A
oxidative
6
Q
What are the two molecules necessary for lipid formation?
A
- malonyl-CoA
- acetyl-CoA
7
Q
Draw the structure of malonyl CoA
A
.
8
Q
Fatty acid biosynthesis and breakdown pathways
A
two different pathways
9
Q
Fatty acid biosynthesis and breakdown enzymes
A
different enzymes
10
Q
Fatty acid biosynthesis and breakdown location
A
different parts of the cell
- catabolism=mito matrix
- anabolism=cytoplasm
11
Q
Acetyl-CoA carboxylase action
A
- catalyzes the one carbon transfer of a carboxyl group from bicarbonate via biotin to acetyl-CoA
- uses ATP
12
Q
Biotin and Acetyl-CoA carboxylase
A
biotin forms an amide linkage with the enzyme
13
Q
Acetyl-CoA carboxylase structure
A
3 multifunctional domains
- biotin carrier
- biotin carboxylase
- transcarboxylase
14
Q
Fatty acid synthase
A
catalyzes the stepwise addition of acetyl groups by an activated malonyl group forming a fatty acid chain
15
Q
Final product of fatty acid synthase
A
saturated 16 carbon fatty acid called palmitate
16
Q
Fatty acid synthase groups
A
- NADPH serves as a reducing agent
- 2 enzyme thiols serve as activating groups
17
Q
4 steps in fatty acid synthase
A
- condensation
- reduction
- dehydration
- reduction
18
Q
E. coli fatty acid synthase
A
- 7 different active sites
- 7 associated proteins
- thiols on ACP and KS covalently attach and anchor the reaction intermediates
19
Q
Acyl carrier protein
A
- contains 4’-phosphopanthetheine
- 2 other groups identical to coenzyme A
20
Q
4’-phosphopantetheine
A
serves as a flexible arm moving the reaction intermediates from one active site to the next
21
Q
Acetyl-CoA -ACP trancacetylase (AT)
A
catalyzes the transfer of an acetyl group from acetyl-CoA to the Cys -SH group of beta-leto acyl-ACP synthase (KS)
-uses the only acetyl-CoA required in fatty acid biosynthesis
22
Q
Malonyl-CoA -ACP transferase (MT)
A
catalyzes the transfer of a malonyl group from malonyl-CoA to the Cys -SH group of the acyl carrier protein (ACP)
23
Q
Fatty acid synthesis step 1
A
- condensation
- beta-ketoacyl -ACP synthase (KS) catalyzes the condensation of the activated acetyl and malonyl groups to form acetoacetyl-ACP and releasing CO2
24
Q
CO2 released in step 1
A
- same carbon from bicarbonate
- added to acetyl-CoA to activate it
- coupling the decarboxylation and condensation makes step 1 thermodynamically favorable
25
Fatty acid synthesis step 2
beta-ketoacyl -ACP reductase (KR) catalyzes the reduction of the carbonyl group at C-3 to form beta-hydroxybutyryl -ACP
-uses NADPH
26
Fatty acid synthesis step 3
beta-ketoacyl -ACP dehydrogenase (HD) catalyzes the dehydration to form trans-delta2-butenoyl -ACP
27
Fatty acid synthesis step 4
enoyl -ACP reductase (ER) catalyzes the reduction of the carbon-carbon double bond to form butyryl -ACP
-uses NADPH
28
Repriming fatty acid synthesis
- the butyryl group is transferred from the Cys -SH on the acyl carrier protein (ACP) to the Cys -SH on beta-ketoacyl -ACP synthase (KS)
- malonyl-Co A -ACP transferase (MT) transfers another malonyl-CoA to ACP to repeat the process
29
First acyl group in fatty acid synthesis
ends up at the omega end of the fatty acid
30
Fatty acid synthesis reaction
```
converts;
-8 acetyl-CoA
-7 ATP
-14 NADPH
-14 H+
to;
-palmitate
-8 CoA
-7 ADP
-7 Pi
-14 NADP-
```
31
Stearate
- 18 carbon fatty acid
| - small amounts produced
32
Location of fatty acid synthesis
- cytosol
- NADPH is high for biosynthesis of fatty acids, nucleotides, amino acids and glucose
- NADH is now for glycolysis
33
Plant fatty acid synthesis
-in the stoma where light reactions make NADPH
34
Rate limiting step in fatty acid biosynthesis
-acetyl-CoA carboxylase reaction
35
Acetyl-CoA carboxylase regulation
- negatively allosterically regulated by palmitoyl-CoA
- positively by citrate
- hormone triggered phosphorylation inactivates the enzyme
36
Carnitine acyltransferase 1 regulation
inhibited by malonyl-CoA
37
Long chain fatty acid synthesis precursor
palmitate
38
Long chain fatty acid synthesis systems
- in mitochondria
- in smooth ER
- can elongate
- can desaturate
39
Plant long chain fatty acid synthesis
- can desaturate to polyunsaturated fatty acids.
| - double bonds at 9, 12 and 15
40
Desaturation of fatty acids precursors
- palmitate
| - stearate
41
Desaturation of fatty acids enzyme
Fatty acyl-CoA desaturase
42
Fatty acyl-CoA desaturase
- catalyzes the oxidation of the saturated fatty acid to a monosaturated fatty acid
- mixed function oxidase
- NADPH and fatty acids are oxidized and O2 is reduced to H20
43
Eicosanoid synthesis
-from arachidonate
44
Cyclooxygenase (COX)
- bifunctional
| - formation of prostaglandins from arachidonate
45
COX inhibitors
-aspirin and NSAIDs stop the formation of prostaglandins
46
Aspirin
acetylates a Ser in the active of COX irreversibly deactivating it
47
NSAIDs
probably inhibit by mimicking the structure of the substrate or reaction intermediate
-competitive inhibitors
48
Problems with aspirin
- block thromboxanes -> clotting is reduced
| - decreases stomach mucus, causes problems
49
Thromboxanes
produced by blood platelets
- constrict BV
- facilitate platelet aggregation
50
Uses of aspirin
low doses can reduce the probability of heart attacks and stroke
51
Leukotrienes
- signal smooth muscle contraction
| - not effected by COX therefore aspirin and NSAIDs are not a problem
52
Fatt acid fates
- triacyglycerols for energy storage
| - glycerophospholipids for membranes
53
Triacylglycerol and glycerophospholipid common precursors
- fatty acyl-CoA
| - glycerol 3-phosphate
54
Glycerol 3-phosphate
- from dihydroxyacetone phosphate in glycolysis
| - by glycerol 3-phosphate dehydrogenase
55
Fatty acyl-CoA
-from fatty acids and CoA via acyl-CoA synthetase
56
Acyl transferases
catalyze the transfer of the fatty acyl groups from fatty acyl-CoA to the free hydroxyl groups of glycerol 3-phosphate to form phosphatidic acid or diacylglycerol 3-phosphate
57
Phosphatidic acid
precursor to triacylglycerols
58
Complex glycerophospholipid synthesis
adding a head group to the phosphate of phosphatidic acid
59
Phosphatidic acid phosphatase
catalyzes the hydrolysis of the phosphate group to form 1,2-diacylglycerol
60
Formation of triacylglycerol
1,2-diacylglycerol gets another fatty acid
61
Regulation of triacylglycerol synthesis
- hormones (insulin)
| - very little regulation
62
Insulin
promotes the conversion of carbohydrates and amino acids to triacylglycerols via acetyl-CoA production
63
High blood cholesterol
strong correlation with incidence of human cardiovascular disease
64
Cholesterol functions
- cell membranes
- precursor to steroid based hormones
- precursor to bile salts
65
Cholesterol in the diet
- not required
| - synthesized by every cell in the body
66
Carbons if cholesterol
all are from acetate molecules
67
Isoprene molecules
essential intermediates between acetate and cholesterol
68
Cholesterol synthesis step 1
acetly-CoA to mevalonate
- uses 3 acetyl-CoA's condensed to form HMG-CoA with thiolase and HMG-CoA synthase
- HMG-CoA reductase catalyzes the reduction of HMG-CoA to mevalonate
69
Cholesterol synthesis step 2
mevalonate to 2 isoprenes
- 3 phosphates from ATP go to mevalonate to form 3-phospho-5-pyrophosphomevalonate
- loses the 3-phospho group and a carboxyl to yield delta3-isopentyl pyrophosphate
- isomerization then makes dimethyallyl pyrophosphate
70
Cholesterol synthesis step 3
6 isoprenes to squalene
- isopentenyl pyrophosphate and dimethylallyl pyrophosphate condense to make geranyl pyrophosphate which condenses with another isopentenyl to make farnesyl pyrophosphate
- 2 farnesyl pyrophosphates condense to form squalene
71
Cholesterol synthesis step 4
squalene to steroid nucleus
- squalene converted to squalene 2,3-epoxide via squalene monooxygenase
- convert to lanosterol via cyclase enzyme
- 20 reactions from lanosterol to cholesterol
72
Where is cholesterol made?
synthesized in the liver
73
Fates of cholesterol
- bile acids
- cholesteryl esters
- billary cholesterol
74
Bile acids/salts
- hydrophillic
| - aid lipid digestion by emulsification
75
Cholesteryl esters
- have fatty acids attached to hydroxyl group
- very hydrophobic
- transferred to other tissues by lipoproteins
76
Cholesterol and lipid transport
- lipoproteins carry in blood plasma
| - different lipoproteins
77
Lipoprotein types
- chylomicrons
- VLDL
- LDL
- HDL
78
Chylomicrons
- largest
| - move triacylglycerols from the intestines to other tissues
79
VLDL
- formed in the liver from excess dietary fat
- converted to triacylglycerols
- travel to muscle and adipose
80
LDL
- move cholesterol from liver to extrahepatic tissue for uptake
- "bad" cholesterol
81
HDL
- made in the liver and small intestine
| - moves through blood converting phospholipids and cholesterol to cholesteryl esters for transport back to the liver
82
Saturated fats
can be used to make cholesterol
83
Cholesterol synthesis rate limiting step
-conversion of HMG-CoA to mevalonate
84
Regulation of cholesterol sythesis
- rate limiting step
- insulin and glucagon regulate HMG-CoA reductase
- High cholesterol levels
85
High cholesterol level regulation
- upregulate cholesteryl ester formation
| - downregulate transcription of LDL receptor
86
Atherosclerosis
excess cholesterol build up in the arteries, creates obstruction
87
Statins
- structural analogs of mevalonate
| - inhibit HMG-CoA reductase
88
Alternative fates of activated isoprene
- vitamins
- hormones
- quinone based electron carriers
Biochemistry II
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