Lectures 13-14 - Fatty Acids Flashcards
(82 cards)
1
Q
glucose/glycogen (2) vs fats (3) for energy needs
A
glucose/glycogen: short term E needs + quick delivery
- fats: long term E needs (months), good storage and slow delivery
2
Q
why are TG best storage fuels (4)?
A
- FA chains are highly reduced compounds
- yield >2 fold E than CHO and protein
- insoluble in water = doesn’t increase osmolarity
- relatively inert = no risk of undesirable reactions
3
Q
who relies almost exclusively on fats as source of E? (2)
A
- hibernating animals like grizzly bears
- migrating birds
4
Q
how do lipids yield E?
A
through b-oxidation
5
Q
which 2 organs derive 80% E from FA oxidation?
A
liver and heart
6
Q
what is b-oxidation?
A
4-step enzyme catalyzed process of oxidative removal of 2-C units from FA to form acetyl-CoA
7
Q
what are the 4 sources of fat?
A
- around 40% form diet
- fat stored in adipose tissue as lipid droplets (3 PLACES!)
- fat synthesized in organ/liver and transported to other tissues
- fat obtained by autophagy (degradation of cell’s own organelles)
8
Q
how are lipids/TGs digested/transported in humans? (initial info + 8 steps)
A
- TG is ingested –> needs to be emulsified/solubilized bc insoluble in water
1. bile salts secreted by gall bladder emulsify dietary fats in small intestine, forming mixed micelles
2. mixed micelles increase fraction of lipid accessible to intestinal lipases, which degrade TG into diacylglycerol, monoacylglycerol, free FA and glycerol
3. FA and breakdown products are taken up by intestinal mucosal and converted into TG
4. TG are incorporated with cholesterol and apolipoproteins into chylomicrons.
5. chylomicrons move through lymphatic system and bloodstream to tissues (ie capillaries of myocytes or adipocytes)
6. in capillaries: lipoprotein lipase, activated by apolipoproteinC-II in capillary converts TG to FA and glycerol
7. FA enter cells
8. FA are oxidized as fuel (myocyte) or reesterified for storage (adipocyte)
9
Q
what are apolipoproteins?
- 2 functions of apolipoproteins in chylomicrons
A
- lipid binding proteins that protrude from surface of chylomicron
- responsible for transport + act as signals in uptake/degradation/metabolism of chylomicron contents
10
Q
what are the contents of chylomicrons? (4)
A
- TG (>80% of mass)
- cholesterol/cholesteryl esters
- apolipoproteins
- phospholipids
11
Q
what are the different versions of chylomicrons (4)?
A
- VLDL
- LDL
- HDL
- VHDL
12
Q
where are lipids stored in body (4)?
A
- adipose tissue
steroid synthesizing cells: - adrenal cortex
- ovaries
- testes
13
Q
how are lipids mobilized from storage? (11 steps)
A
- low glucose triggers glucagon –> attaches to GPCR receptor in adipocyte cell membrane
- receptor activates G protein + adenyl cyclase which produces cAMP from ATP
- cAMP activates PKA which phosphorylates Hormone Sensitive Lipase (HSL) and perilipin
- surface of lipid droplet is coated by perilipin protein that is bound to CGI (comparative gene identification) –> makes surface inaccessible = prevents its mobilization
- phosphorylation of perilipin causes dissociation of CGI from perilipin –> CGI activates Adipose TG Lipase (ATGL)
- ATGL converts TG to diacylglycerol
- phosphorylated perilipin is now “free” and binds to phosphorylated HSL, which gives access of membrane of lipid droplet to HSL –> HSL converts diacylglycerol to monoacylglycerol
- Monoacylglycerol lipase (MGL) hydrolyzes monoacylglycerol to FA and glycerol
- FA and glycerol leave adipocyte and enter bloodstream –> bind to serum albumin who will carry FA in blood
- FA released from serum albumin and enters myocyte via FA transporter
- FA is oxidized via b-oxidation, citric acid cycle and respiratory chain –> produces ATP (fuels muscle contraction) and CO2
14
Q
how many FA can serum albumin bind to?
A
up to 10 FA at the same time!
15
Q
lipases are activated by which 2 hormones?
A
glucagon and epinephrine
16
Q
what contributes to 95% of E from TG?
A
the 3 long-chain FA cleaved off of glycerol backbone by lipases
17
Q
where are fats degraded into FA and glycerol?
A
in cytoplasm of adipocytes
18
Q
FA are transported to other tissues for fuel through __________
A
blood
19
Q
glycerol contributes to ___% energy from TG
A
5%
20
Q
what is the fate of glycerol? (3 steps)
A
- glycerol is phosphorylated by glycerol kinase to form L-glycerol 3-phosphate
- L-glycerol 3-phosphate is oxidized by glycerol 3-phosphate dehydrogenase to form dihydroxyacetone phosphate (DHAP)
- DHAP isomerized to D-glyceraldehyde-3-phosphate by triose phosphate isomerase –> enters glycolysis!
21
Q
difference between glycerol 3-phosphate dehydrogenase and glyceraldehyde 3-phosphate dehydrogenase?
A
- glycerol 3-phosphate dehydrogenase: converts glycerol-3-P to DHAP
- glyceraldehyde 3-phosphate dehydrogenase: converts GAP (glyceraldehyde 3P) to 1,3 biphosphogycerate
22
Q
FA need to be transported into ___________. why?
A
- mitochondria
- bc all enzymes of FA activation are stored in mitochondria
23
Q
how are FA activated? (2 steps)
- where?
A
- FA –> fatty acyl-adenylate (enzyme bound) through fatty acyl-CoA synthetase (present in outer mitochondria layer + needs ATP)
- fatty-acyl adenylate + inorganic pyrophosphate –> Fatty-acyl CoA + 2 Pi through fatty-acyl-CoA synthetase
- on cytosol side of outer layer of mitochondria
24
Q
2 fates of Fatty-acyl CoA
A
- used for oxidation in mitochondria –> ATP
- used to synthesize longer membrane lipids
25
- b-oxidation of FA occurs where?
- in plant, major site for oxidation is __________
- mitochondria
- peroxisomes
26
transport of FA into mitochondria:
- small FA (<___C)
- vs longer FA (>___C)
- small (<12C): diffuse freely across mitochondrial membranes
- longer (>14C) are transported via acyl-carnitine/carnitine transporter (antiport)
27
how is FA-CoA transported into the mitochondrial matrix? (3 steps)
1. FA-CoA attaches to cartinine to form FA-CoA-cartinine. catalyzed by cartinine actyltransferase 1
2. FA-CoA-carnitine moves into intermembrane sapce (btw outer and inner mitochondrial membrane) through facilitated diffusion. then moves into matrix through the acyl-carnitine/cartinine transporter
3. in the matrix, cartinine acyltransferase II removes acyl groups from FA-CoA-carnitine --> regenerating FA-CoA + carnitine that will return to outer-mitochondrial membrane by same transporter to take up another FA
28
what can inhibit carnitine acyltransferase 1?
malonyl-CoA --> first intermediate in FA synthesis --> prevents simultaneous synthesis and degradation of FA
29
3 stages of FA oxidation in mitochondria?
1. oxidative conversion of 2C unit into acetyl-CoA via b-oxidation with concomitant generation of NADH and FADH2
2. oxidation of actyl-CoA into CO2 via citric acid cycle with concomitant generation of NADH and FADH2
3. step 3 generates ATP from NADH and FADH2 via the respiratory chain
30
4 steps of b-oxidation of saturated FA
1. dehydrogenation of FA by acyl-CoA dehydrogenase --> produces trans double bond! + FADH2
2. hydration of trans-enoyl-CoA by enoyl-CoA hydratase --> removes double bond
3. oxidation of L-b-hydroxy-actyl-CoA by b-hydroxyacyl-CoA dehydrogenase --> produces NADH
4. thiolytic cleavage of b-ketoacyl-CoA by acyl-CoA acetyltransferase (thiolase) --> forming acyl-CoA (shorter by 2C) + acetyl-CoA
*NADH and FADH2 enter respiratory chain
31
what bond does acyl-CoA-acetyltransferase (thiolase) cleave?
thiolester bond
32
b-oxidation of 16C FA yields what? (4) = how much ATP and how much H2O?
- 8 Acetyl-CoA
- 7 NADH (x 2.5 ATP)
- 7 FADH2 (x 1.5 ATP)
- 7 H+
yields: 28 ATP + 7 H2O
33
how many acetyl-CoA, ATP and H2O molecules generated from b-oxidation of myristic acid?
- 7 acetyl-CoA
- 24 ATP
- 6 H2O
34
4 enzymes for b-oxidation?
- gram-positive bacteria + mitochondrial short chain specific --> ?
- vs mitochondrial very-long-chain specific system --> ?
1. acyl-CoA dehydrogenase
2. Enoyl-CoA hydratase
3. L-b-hydroxyacyl-CoA dehydrogenase
4. Thiolase
- short chain --> 4 enzymes are separate
- long chain --> 3 polypeptides embedded in inner membrane of mitochondria --> 2nd and 3rd enzymes are merged together
35
naturally occurring unsaturated FA contain _____ double bonds = NOT a substrate for ?
- cis
- not a substrate for enoyl-CoA hydratase
36
what do monounsat (1) and polyunsat (2) FA require to be b-oxidized?
monounsat: enoyl-CoA isomerase: converts cis starting at Carbon 3 to trans
- polyunsat: enoyl-CoA isomerase + 2,4 dienoyl CoA reductase (removes a double bond/reduces cis doubles bonds not at carbon 3)
37
What is a common odd number carbons FA?
- who has them? (2)
propionyl-CoA
- some plants and marine organisms
38
b-oxidation of FA with odd number carbons ( 4 steps)
1. propionyl CoA --> D-methylmalonyl-CoA through propionyl-CoA carboxylase using HCO3-, ATP and BIOTIN!
2. D-methylmalonyl-CoA converted to L-methylmalonyl-CoA by methylmalonyl-CoA epimerase
3. L-methylmalonyl-CoA converted/rearranged to succinyl-CoA by methyl-malonyl-CoA mutase with COENZYME B12
4. succinyl-CoA enters citric acid cycle
39
what is the point of commitment to b-oxidation?
carnitine shuttle (when FA enters mitochondria)
40
b-oxidation occurs only when there is a need for ?
energy
41
Fatty acyl-CoA synthesized in cytoplasm --> 2 fates
1. directed to b-oxidation in mitochondria
2. directed to TG synthesis in cytosol
42
what stimulates (1) and inhibits (3) b-oxidation?
- stimulates: low ATP (low ATP/AMP ratio) stimulates AMPK leading to activation of carnitine shuttle
- inhibits:
1. malonyl-CoA = first intermediate of FA synthesis inhibits carnitine acetyltransferase 1 = inhibits FA oxidation when liver is supplied with glucose as fuel
2. High NADH/NAD+ ratio inhibits b-hydroxacyl-CoA dehydrogenase (3rd enzyme)
3. high acetyl-CoA inhibits thiolase (4th enzyme)
43
the 4 enzymes of b-oxidation are regulated by both ________ _______ and ________
- transcription factors
- kinases
44
where does w-oxidation occur?
liver and kidney contain enzymes for omega-oxidation
45
what are the 4 steps of w-oxidation?
1. FA of 10-12C --> add OH group on methyl end of FA using mixed-function oxidase + NADPH + O2
2. oxidize OH group to carbonyl group (C=O with H) using alcohol dehydrogenase + NAD+
3. oxidize carbonyl group to carboxylic acid using aldehyde dehydrogenase + NAD+ --> resulting in FA with carboxylic group at both ends
4. both ends of FA yields acetyl-Coa through b-oxidation
46
2 fates of acetyl-CoA
- enter citric acid cycle
- becomes a ketone body and is exported to other tissues
47
ketone bodies:
- soluble in what?
- ________ molecules
- produced in ?
- 3 types?
- water soluble
- energy
- liver
- acetone, acetoacetate, D-b-hydroxybutane (BHB)
48
how are the 3 ketone bodies "used"?
+ brain?
- acetone --> low levels --> exhaled
- acetoacetate and BHB transported to other tissues and converted back to acetyl-CoA
- brain can adapt and use acetoacetate and BHB when glucose is unavailable
49
how are ketone bodies synthesized? (4 steps)
1. thiolase condenses 2 acetyl-CoA together into acetoacetyl-coA
2. acetoacetyl-coA (condenses with another acetyl-CoA) is converted to HMG-CoA by HMG-CoA synthase
3. HMG-CoA cleaved to form acetoacetate by HMG-CoA lyase
4. acetoacetate either decarboxylated by acetoacetate decarboxylase to form acetone OR reduced to D-b-hydroxybutane by D-b-hydroxybutyrate dehydrogenase
50
what is the parent compound of all 3 ketone bodies?
acetoacetyl-CoA
51
where does synthesis of ketone bodies occur?
where are HMG-CoA synthase and HMG-CoA lyase present in?
- matrix of mitochondria in liver
- synthase: mitochondria and cytoplasm
- lyase: ONLY mitochondria
52
how are ketone bodies catalized?
1. D-b-hydroxybutyrate oxidized to acetoacetate by d-b-hydroxybutyrate dehydrogenase + NAD+
2. acetoacetate + succinyl-CoA --> acetoacetyl-CoA through b-ketoacyl-CoA transferase
3. acetoacetyl-CoA --> 2 acetyl-CoA through thiolase + CoA-SH
53
what organ/tissue is producer vs consumer of ketone bodies? why/how come?
producer: liver!
- consumer: all tissues except liver because b-ketoacyl-CoA transferase is absent in liver
54
10 biological functions of lipids
1. energy storage (TG)
2. constituents of membranes
3. anchors for membrane proteins (IP2, PIP3)
4. cofactors for enzymes (vit. K)
5. signaling molecules (eicosanoids, IP3)
6. pigments (retinal)
7. detergents (bile salt)
8. transporters
9. antioxidants (vit A)
10. hormones (sex hormones)
55
catabolism of FA:
- produces (2)
- takes place in ?
anabolism of FA:
- requires (3)
- takes place in ?
catabolism:
- produces acetyl-CoA + electron donors (NADH)
- mitochondria
anabolism:
- requires acetyl-CoA + malonyl-CoA + electron donor NADPH
- cytosol in animals
56
2 general steps of biosynthesis of FA?
1. formation of malonyl-CoA from acetyl-CoA
2. addition of 2 carbons to fatty acyl chain
57
phase 1 of biosynthesis of FA?
- reversible?
- catalyzed by what?
- 3 functional regions of enzyme?
- formation of malonyl-CoA from acetyl-CoA
- irreversible
- acetyl-CoA carboxylase (ACC)
- biotin carboxylase + biotin carrier protein + transcarboxylase
58
phase 2 of biosynthesis of FA?
- catalyzed by what?
- 7 catalytic domains of enzyme?
- 2 types of the enzyme? in what (2 each)
- addition of 2C to fatty acyl chain
- fatty acid synthase
- ACP, KR, ER, DH, MAT, KS, TE
- Type 1: vertebrates and fungi
- type 2: bacteria and plant
59
phase 2 of biosynthesis of FA
- 2 initial steps --> results in?
- 5 steps
1. acyl group of Acetyl-CoA transferred to ACP, than transferred to KS domain --> catalyzed by MAT domain
2. transfer of malonyl to ACP --> catalyzed by MAT domain
- both acetyl-CoA and Malonyl-CoA are activated
1. condensation of activated malonyl-CoA and acetyl-CoA by KS, forming b-ketobutyryl-ACP
2. reduction of b-keto group by KR using NADPH + H+ (adds 2 H+) forming b-hydroxybutyryl-ACP
3. b-hydroxybutyryl-ACP dehydrated to form trans-butenoyl-ACP (double bond) by DH
4. reduction of souble bond by ER to form butyryl-ACP with NADPH as e- donor
5. transolation of butyryl group from ACP to cys of KS --> produces 4C saturated FA chain
60
synthesis of palmitate from acetyl-coa:
1. formation of how many of what?
- 3 things --> 3 things (include stoichiometry coefficients)
2. __ cycles of _________ and ___________
- 4 things --> 5 things
1. 7 malonyl-CoA
- 7 acetyl-CoA + 7 CO2 + 7 ATP --> 7 malonyl-CoA + 7 ADP + 7 Pi
2. 7 cycles of condensation and reduction
- acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+ --> palmitate + 7 CO2 + 8 CoA + 14 NADP+ + 6 H2O
61
Overall equation of synthesis of palmitate
8 acetyl-CoA + 7 ATP + 14 NADPH + 14 H+ --> palmitate + 7 ADP + 7 Pi + 8 CoA + 14 NADP+ + 6 H2O
62
how to cleave synthesized palmitate off of ACP?
TE domain (thioesterase) will cleave/release palmitate when synthesis is complete
63
long chain FA are produced where? and also in ?
- smooth ER
- mitochondria
64
what is the precursor of long-chain FA?
palmitate
65
palmitate and stearate are desaturated by what? by what type of reactions?
- what does desaturated mean?
- Fatty acyl-CoA desaturase
- oxidative reactions
- adding double bond
66
palmitoleate and oleate have double bonds btw which carbons?
C9 and C10
67
which 2 FA are essential and cannot be produced by mammals?
- why can't they be produced?
- why are they essential?
- linoleate and linolenate
- because mammals cannot do desaturation of oleate or linoleate
- because linoleate is precursor for arachidonate (20:4) and linolenate is precursor for EPA and DHA
68
2 sources of acetyl-CoA?
- formed where?
1. pyruvate decarboxylation
2. aa catabolism
- mitochondria
69
how is acetyl-CoA transported from mitochondria to cytoplasm? (7 steps cycle ish
no transporter to carry acetyl-CoA from mito to cyplasm
1. acetyl-CoA + oxaloacetate --> citrate, using citrate synthase
2. citrate passes through citrate transporter and enters cytoplasm
3. citrate is cleaved and regenerates acetyl-CoA and oxaloacetate, by citrate lyase, uses ATP!
- acetyl-CoA used in FA synthesis
4. oxaloacetate can't directly go back to mitochondria bc no transporter --> reduced to malate by malate dehydrogenase and NADH
5a. malate enters malate-a-ketoglutarate transporter
6a. malate converted to oxaloacetate by malate dehydrogenase
5b. however, most malate will generate NADPH being converted to pyruvate by malic enzyme
6b. pyruvate transported into mito using pyruvate transporter
7b. pyruvate converted to oxaloacetate using pyruvate carboxylase + ATP
70
which 2 steps require ATP for transporting acetyl-CoA out of mito? (cycle)
- citrate to oxaloacetate by citrate lyase
- pyruvate to oxaloacetate by pyruvate carboxylase
each cycle: 2 ATP per 1 acetyl-CoA
71
how is the NADPH needed for FA synthesis generated? (2)
- half from converting malate to pyruvate
- half taken for pentose phosphate pathway
72
what is the rate limiting enzyme for biosynthesis of FA?
acetyl-CoA carboxylase (acetyl-CoA --> malonyl-CoA)
73
what accelerates (1) /inhibits (2) ACC?
- accelerate: citrate from mito is an activator
inhibits ACC:
- palmitoyl-coA is a feedback inhibitor
- glucagon and epinephrine trigger phosphorylation of ACC = inactivation of ACC
74
what are the 2 enzymes that coordinate FA synthesis and b-oxidation?
- Acetyl-CoA carboxylase
- carnitine- acyl-transferase I
75
regulation of FA syntehsis and b-oxidation:
- high blood glucose --> ?
- low blood glucose --> ?
4 steps each
high blood glucose:
1. increase insulin
2. insulin increases phosphatase activity -> dephosphorylates ACC = ACC becomes active
3. active ACC converts acetyl-CoA to malonyl-CoA
4. malonyl-CoA goes on to FA synthesis AND inhibits carnitine acyl-transferase I activity = blocks b-oxidation
low blood glucose
1. increases glucagon
2. increases PKA, AMPK --> phosphorylates/inactivates ACC
3. no more malonyl-CoA produced = carnitine acyl-transferase I is NOT inhibited
4. b-oxidation can occur (fatty-acyl CoA to fatty acyl carnitine)
76
most of FA from ingestion have 2 fates?
1. incorporate in TG (chylomicron)
2. incorporated in phospholipids for membrane
77
what are the 2 precursors for TG and glycerophospholipids?
- glycerol 3P and fatty-acyl CoA
78
biosynthesis of TG
- first step: 2 possibilities/2 precursors
- 2nd step
- 3rd step: 2 possibilities
1a. DHAP --> glycerol 3-phosphate, using glycerol 3P dehydrogenase + NADH
OR
1b. glycerol --> glycerol 3-phosphate, using glycerol kinase + ATP
2. Glycerol 3P -->acetylation of free OH groups using acyl transferase + ATP to form phosphatidic acid
3a. phosphatidic acid --> 1,2 diacylglycerol, using phosphatidic acid phosphatase
4a. 1,2 diacylglycerol --> TG, using acyl transferase
OR
3b. phosphatidic acid --> glycerophospholipid for membrane
79
4 steps for biosynthesis of cholesterol
1. condensation of 3 acetate to form mevalonate
(also using HMG-CoA synthase to convert acetate to HMG-CoA, and then HMG-CoA to mevalonate through HMG-CoA reductase)
2. phosphorylation ox mevalonate to form an activated isoprene
3. polymerization or condensation of activated isoprene to make squalene
4. cyclization of squalene to produce cholesterol
80
how is cholesterol synthesis regulated?
by intracellular concentration of cholesterol
- cholesterol is NOT essential
81
what is the rate limiting step/commitment step for cholesterol biosynthesis?
HMG-CoA reductase
82
how to increase (2) vs decrease (4) cholesterol synthesis activity?
increase:
- insulin: casacade leads to dephosphorylation
- sterol regulatory element binding proteins activate HMG-COA reductase
decrease:
- AMP dependent protein kinase: AMP rises = AMPK phosphorylates HMG CoA reductase = decrease activity
- glucagon and epinephrine: cascase leads to phosphorylation = decrease activity
- insulin-induced gene protein triggers ubiquitination of HMG-CoA reductase
- statins/lipitor = drug to inhibit HMG-CoA to treat high cholesterol
