Term
| steps of fatty acid synthesis |
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Definition
| condensation reduction dehydration reduction |
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Term
| Steps of Fatty Acid Degradation |
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Definition
| oxidation hydration oxidation cleavage |
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Term
| the difference between acetyl and malonyl |
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Definition
- acetyl has 2 carbons
- malonyl has 3 carbons including a carboxylate beta to its carbonyl |
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Term
| where is TAG (aka fat) stored |
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Definition
- cytoplasmic lipid droplet inside of adipocytes
- adipocytes accumulate around organs (visceral) and below the skin (subcutaneous) and supply TAG to other tissues i.e. donors of TAG
- Muscle cells have TAG stores for individual needs i.e. they don't share |
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Term
| what is the structure within the adipocyte |
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Definition
- cytoplasmic lipid droplet
- droplet surrounded by protein/phospholipid monolayer: they are actively involved in TAG metabolism |
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Term
| Digesting lipids: leaving the lumen |
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Definition
Pancreas: lipases secreted to intestine
Gall Blader: Bile salts secreted to lumen
Intestine:
- Bile salts solubilize TAGs to form MICELLES and expose their ester bonds on the micelle's surface
- pancreatic lipases cleave down TAG to FFA and MAG
- Micelles interact with intestinal epithelium where FFAs and MAGs are transported across plasma mambrane |
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Term
| Digesting lipids: from intestinal epithelium to target tissues |
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Definition
Intestinal Cells: FFAs + MAGs reform as TAG and packaged with apo B-48 as CHYLOMICRONS
Chylomicron:
- released to lymph and travel fom lymph to blood
Targets:
- adipose and muscle cells express lipases on their surfaces
- Lipases bind chylomicrons and hydrolyze TAG down to FFA and MAG (again!)
- FFA and MAG pass through plasma membrane
- resynthesis of TAG (for the second friggin time) |
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Term
| Where does TAG mobilization occur? |
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Definition
- Adipocytes break down TAG to FFA and glycerol
- Target tissue receives FFA and transports ACTIVATED FFA into mitochondria to link up to CAC (ox phos) |
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Term
| What signals LIPOLYSIS: adipocytes mobilization of TAG? |
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Definition
| Hormonal: Glucagon and Epi |
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Term
| How do Glucagon and Epi lead to TAG mobilization? |
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Definition
PKA pathway:
- 7TMR's/G-protein/A. Cyclase/cAMP
Targets of PKA
- PERILIPIN
- HORMONE-SENSITIVE LIPASE |
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Term
|
Definition
1) alters fat droplet to TAG is more accessible to lipases
2) triggers release of ATGL = adipose triglyceride lipase |
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Term
|
Definition
"Adipose Triglyceride Lipase"
- hydrolyzes TAG to DAG |
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Term
|
Definition
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Term
|
Definition
| hydrolyzes MAG to FFA + glycerol |
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Term
| How do adipocyte's mobilized but insoluble FAs get to targets? |
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Definition
| albumin = blood protein that carries FAs |
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Term
| How do albumin-escorted FAs enter target tissue? |
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Definition
| fatty acid transport proteins |
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Term
| What about the other product of lipolysis: glycerol? |
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Definition
taken up by liver:
- liver phosphorylates ultimately traps it as DHAP |
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Term
|
Definition
Liver enzyme:
glycerol -> Glycerol 3-Phosphate |
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Term
| Glycerol Phosphate Dehydrogenase |
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Definition
Liver enzyme:
Glycerol 3-Phosphate -> DHAP
(it's the 2nd carbon that is oxidzed to a ketone by NAD+) |
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Term
| Future metabolic pathways for glycerol taken up by liver |
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Definition
anything that includes a DHAP intermediate:
- glycolysis (ends as pyruvate)
- gluconeogenesis (ends as glucose) |
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Term
| Some tissues have taken up FA's - how do they get them into mitochondria? |
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Definition
| activation by Acyl CoA Synthetase |
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Term
| Acyl CoA Synthetase: What is it/What does it do? |
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Definition
location:
outer mito membrane
Rxn:
- adds -S-CoA to FA's carbonyl carbon to create activated thioester
- 2 step rxn: intermediate = acyl Adenylate
- driven by PPi hydrolysis |
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Term
| What's the deal with "acyl adenylate"? |
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Definition
Acyl-AMP:
- common intermediate of reactions that require activation of a carbonyl
= "activation by adenylation"
- seen in fatty acid degradation and protein synthesis |
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Term
| How do Fatty Acyl-CoA's pass the mitochondrial intermembrane space? |
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Definition
carried across as Acyl Carnitine
Need:
Carnitine Acyltransferase I
Translocase
Carnitine Acyltransferase II |
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Term
| Carnitine Acyltransferase I |
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Definition
- conjugates carnitine to Acyl
- CoA released into cytoplasm |
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Term
|
Definition
carries Acyl Carnitine across to matrix
and Carnitine to the intermembrane space |
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Term
| Carnitine Acyltransferase II |
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Definition
| - Conjugates Acyl back to CoA and releases carnitine |
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Term
| What happens if you lack the proteins to transport Acyl-Coa into the matrix? |
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Definition
- insufficient fuel supply for activity
- cramping and weakness |
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Term
| What is the β-oxidation pathway? |
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Definition
| FA oxidation pathway in matrix |
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Term
| β-oxidation pathway reactants |
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Definition
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Term
| β-oxidation pathway products (one cycle) |
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Definition
| Acyl CoA less 2 C's, Acetyl CoA, FADH2, NAD+ |
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Term
| β-oxidation pathway: First reaction |
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Definition
ACYL CoA DEHYDROGENASE:
- oxidation of Acyl CoA to produce an alkene between α-β Carbons
- reductant is enzyme-bound FAD
- products are FADH2 and trans-Δ2-ENOYL CoA
(3 types: long chain, medium chain, short chain) |
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Term
| What is the fate of the electrons transferred to Acyl Coa Dehydrogenase |
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Definition
- flow to Q-Cytochrome C Oxidoreductase through ubiquinol (QH2)
- Acyl CoA Dehydrog. transports them to two other electron-carrying proteins before ubiquinone (Q) accepts them |
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Term
| β-oxidation pathway: Second Reaction |
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Definition
ENOYL CoA HYDRATASE
- hydration of the alkene bond
- β-carbon becomes an alcohol
- product L-3-HYDROXYACYL CoA
(stereospecific: takes a trans product and proudces an L isomer) |
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Term
| β-oxidation pathway: Third Reaction |
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Definition
L-3-HYDROXYACYL DEHYDROGENASE
- oxidation of alcohol to β-ketone
- reductant is NAD+
- products are NADH + H+ and β-KETOACYL CoA |
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Term
| β-oxidation pathway: Fourth Reaction |
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Definition
β-KETOTHIOLASE
- thiol group of a second CoA cleaves off and Acetyl CoA
- reactant is Coa
- products are Acetyl CoA and Acyl-(less 2-C) CoA |
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Term
| ATP yeild of Palmitate oxidation |
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Definition
Palmitate = (16:0) FA
Yield = 106 ATP
From β-oxidation:
- cost of activating the FA = 2 ATP (1 ATP consumed by the hydrolysis of PPi is equivalent to 2 ATP consumed)
- # Carbons = n
- # cleavages = 0.5n-1
- # Acetyl CoA Residues = 0.5n
- β-Ox alone: ATP per cleavage is 4 ATP
- From CAC: ATP per Acetyl CoA is 10 ATP
For n=16: -2 + 7*4 + 8*10 = 106 ATP |
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Term
| Additional enzymes needed to break down unsaturated fatty acids |
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Definition
CIS-Δ3-ENOYL COA ISOMERASE
2,4-DIENOYL COA REDUCTASE |
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Term
|
Definition
(16:1) = cis-Δ9
monounsaturated FA |
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Term
|
Definition
- straight forward β-oxidation for three cycles (6 carbons removed)
- problem: product acyl coa has a δ alkene and we need to have a β alkene
i.e. we have cis-Δ3-Enoyl CoA when what we need is trans-Δ2-Enoyl Coa
- solution: cis-c3-Enoyl CoA Isomerase |
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Term
| cis-Δ3-Enoyl CoA Isomerase |
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Definition
- substrate: cis-Δ3-Enoyl CoA OR trans-Δ3-Enoyl CoA
- product: trans-Δ2-Enoyl Coa
REMEBER: odd numbered double bonds are handled by isomerase because the goal is to shift them over to carbon 2 |
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Term
|
Definition
(18:2) = cis,cis-Δ9, Δ12
polyunsaturated FA |
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Term
|
Definition
looks like palmitoleate for the first 10 carbons:
- three rounds of regular β oxidation
- use cis-Δ3-Enoyl Isomerase to generate a trans-Δ2-Enoyl CoA
- product is new 12C diene: 2,6-dienoyl CoA
Can we just go ahead with regular β oxidation? YUP
- product is 10C cis-Δ4
Can we just go ahead with regular β oxidation? NOPE
- Acyl CoA Dehydrogenase yields 2,4-diene (trans,cis-Δ2,Δ4)
How do we get rid of the problematic cis-Δ4, cis-Δ2 and just leave a trans-Δ2 Acyl Co?
- 2,4 DIENOYL COA REDUCTASE ->
trans-Δ3-Enoyl Coa
- cis-Δ3-Enoyl isomerase ->
trans-Δ2 Enoyl CoA
Proceed with regular β oxidation for the 10 product |
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Term
| 2,4-Dienoyl CoA Reductase |
|
Definition
Substrate: 2,4-dienoyl CoA
Product trans-Δ3-Enoyl CoA
REMEMBER: even numbered double bonds are handled by reductase THEN isomerase. Reductase gets us down to one double bond in the C3 position and isomerase shifts it into the C2 position |
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Term
| Odd chain fatty acid degradation |
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Definition
| Last acyl CoA is Propionyl CoA |
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Term
| Can Propionyl CoA enter the CAC |
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Definition
YES: Enters as succinyl CoA so it needs another Carbon
- Enzymes = PROPIONYL COA CARBOXYLASE and METHYLMALONYL COA MUTASE |
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Term
| Propionyl CoA Carboxylase |
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Definition
- biotin enzyme like Pyruvate Carboxylase (REMEMBER: biotin arm takes an activated carboxylate and conjugates it to the target)
- Cost = 1 ATP hydrolyzed to ADP + Pi
- product: D- and L-Methylmalonyl (not at succinyl CoA yet) |
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Term
|
Definition
(Remember Malonyl is like Proionyl but with a terminal COOH therefore METHYL-malonyl just has a C2 methyl substituent)
- sunccinyl CoA is NOT branched; Methylmalonyl IS
- prosthetic = cobalamin aka B12 (has cobalt core); promotes radical reaction |
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Term
| Degradation of FA in peroxisomes |
|
Definition
- not as common as mitochondrial
- degrades down to octanoyl (8:0) CoA
- Does NOT yield as much ATP as β-oxidation in mitochondria: Acyl CoA Dehydrogenase still reduduces FAD -> FADH2 but FADH2 does not hand off to ubiquinone.
FADH2 + O2 -> H2O2 |
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Term
|
Definition
Peroxisome enzyme
- converts peroxide from FADH2 to O2 + H2O |
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Term
| Does fatty acid metabolism involve carbohydrates? |
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Definition
YES!
- Acetyl CoA can't enter the CAC unless there is OAA (Citrate Synthase reaction)
- Pyruvate Carboxylase produces OAA from pyruvate |
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Term
| What promotes Carbohydrate depletion? |
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Definition
fasting, diabetes:
brain and RBC need glucose (glycogen degradation and gluconeogenesis) |
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Term
| Fate of Acetyl CoA that can't enter CAC |
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Definition
Ketone Bodies: Acetoacetate + D-3-Hydroxybutyrate
1) THIOLASE Condensation:
2 Acetyl Coa -> Acetoacetyl Coa + CoA
2) Citrate Synthase-like reaction:
Acetoacetyl CoA + Acetyl CoA + H2O -> HMG CoA
3) Cleavage:
HMG CoA -> Acetoacetate + Acetyl CoA
Sum so far:
2 Acetyl CoA + H2O -> Acetoacetate + 2 CoA + H+
4a) D-3-Hydroxybutyrate Dehydrogenase (runs in the hydrogenase direction if enough NADH):
Acetoacetate + NADH + H+ -> D-3-hydroxybutyrate
4b) Acetone production |
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Term
| Are ketone bodies useless |
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Definition
NO:
- Liver mitochondria makes it for fuel for heart and kidney respiration
- The brain can use it preferentially in prolonged fast |
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Term
| How to burn Ketone bodies for fuel |
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Definition
Remember that D-3-Hydroxybutyrate runs in both directions i.e. we can make Acetoacetate if enough NAD+
1) CoA TRANSFERASE: activation of acetoacetate
succinyl CoA + acetoacetate -> Acetoacetyl CoA + succinate
2) THIOLASE Cleavage:
Acetoacetyl CoA + CoA -> 2 Acetyl CoA |
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Term
| Does the liver burn Ketone's for fuel |
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Definition
NOPE
- liver lacks thiolase: it can't activate acetoacetate with CoA |
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Term
| Consequence of overproduction of ketone bodies |
|
Definition
Diabetic Ketosis:
- seen in TIDM (insulin-dependent)
- liver does not take up Glc without Ins: body runs out of OAA for the CAC
- Adipose keeps releasing FAs
- Liver turns them into ketone bodies
- ketoacidosis affects nervous system
HOWEVER:
- the ketogenic diet is part of treatment for epilepsy (high fat, low carb) |
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Term
| Can FA's be converted to Glc |
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Definition
It would be great for the brain during times of starvation but no :(
- lack enzymes that can turn acetyl CoA into pyruvate or OAA |
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Term
|
Definition
cyoplasmic complex of enzymes for de novo FA synthesis
- de novo synthesis best accomplished in liver and adipose
- Start with Acetyl CoA, end with Palmitate. Other unassociated enzymes modify palmitate.
- Homodimer:
monomers are not active
- Two compartment types:
1-selecting and condensing malonyl + acyl units
2-modification (reductions and dehydrations) |
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Term
| Is FA synthesis just the reverse of FA degradation |
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Definition
NOPE. FA Synthesis:
- takes place in cytoplasm to keep pathways distinct
- No CoA activation. ACP-activation instead (they are both thiol-linked)
- enzymes are in a complex, not separated
- not just tacking on a two carbon unit: must cleave an activated 3-C unit
- this is biosynthesis so must use NADPH (reductive biosynthetic electron donor) |
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Term
| FA synthesis committed step |
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Definition
ACETYL COA CARBOXYLASE: biotin-enzyme (carboxybiotin intermediate)
Acetyl CoA + HCO3- + ATP ->
Malonyl CoA + ADP + Pi + H+
*This is not part of the FA Synthase Complex |
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Term
|
Definition
"Acyl Carrier Protein"
- has a serine residue that forms thioester linkage
- Activating group of FA synthesis |
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Term
| First Reaction of FA Synthase Complex |
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Definition
ACETYL TRANSACYLASE AND MALONYL TRANSACYLASE:
Acyl CoA + ACP -> Acyl ACP + CoA
Malonyl CoA transacylase can only use malonyl
Acetyl CoA Transacylase actually can use propionyl CoA to make propionyl ACP for use in synthesizing odd-chain FAs |
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Term
| Second Reaction of FA Synthase Complex |
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Definition
β-KETOACYL SYNTHASE: condensing enzyme
Acetyl ACP + Malonyl ACP -> Acetoacetate ACP + CoA + CO2
Why malonyl? Why not just stick together 2 Acetyls?
- CO2 release aka decarboxylation is a exergonic event that drives the reaction.
- It took an ATP to stick that HCO3- on in the first place (Acetyl CoA Carboxylase). Removing releases that energy. |
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Term
| Third Step of FA Synthase Complex |
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Definition
β-KETOACYL REDUCTASE:
Acetoacyl ACP + NADPH + H+ ->
3-Hydroxybutyryl ACP + NADP+ |
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Term
| Fourth Step of FA Synthase Complex |
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Definition
3-HYDROXYACYL DEHYDRATASE:
3-Hydroxybutyryl ACP -> Crotonyl ACP + H2O |
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Term
|
Definition
- trans-Δ2-Enoyl ACP
- produced by dehydrating 3-hydroxybutyryl ACP
- reduced by enoyl reductase to Butyryl ACP |
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Term
| Fifth Step of FA Synthase Complex |
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Definition
ENOYL REDUCTASE:
Crotonyl ACP + NAPDH + H+ -> Butyryl ACP + NADP+ |
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Term
| Synthesizing FA's beyond Butyrate: |
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Definition
| - malonyl ACP condenses with butyryl ACP (β-Ketoacyl Synthase) |
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Term
| How to free palmitate from palmityl ACP |
|
Definition
THIOESTERASE:
- hydrolysis of a C16 acyl ACP
- acts like a miter saw |
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Term
| How much NADPH and ATP are needed for Palmitate synthesis? |
|
Definition
Need 7 malonyls (and 1 acetyl in the first rxn)
- it takes 7 ATP to make 7 malonyl from acetyl CoA carboxylase
Each round of Synthesis has two reductions so need 2 NADPH per round
= 14 NADPH and 7 ATP |
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Term
| If FA degradation and FA synthesis are in separate compartments, how do we get acetyl CoA from the mitochondria to the cytoplasm for synthesis. |
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Definition
Citrate-Pyruvate Cylce:
Matrix = citrate synthase
= Acetyl CoA + OAA -> Citrate + CoA
Citrate Transported across both membranes
Cytoplasm =
1) ATP CITRATE LYASE
= Citrate + ATP + CoA + H2O -> Acetyl COA + ADP + Pi + OAA
*Acetyl freed!
2)MALATE DEHYDROGENASE
= OAA + NADH + H+ -> Malate + NADP+
3)MALIC ENZYME (NADP+ Linked Malate Enzyme)
= Malate + NADP+ -> pyruvate + CO2 + NADPH
Pyruvate Transported across both membranes
4)PYRUVATE CARBOXYLASE
= pyruvate + CO2 + ATP + H2O -> OAA + ADP + Pi + H+
Yield = 1 NADPH per acetyl CoA crossing the mito |
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Term
| Where are enzymes that elaborate on palmitate to produce other FAs? |
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Definition
| cyoplasmic side of ER membrane |
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Term
| To what end of palmitate to they add Carbon to? |
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Definition
| Add 2-C units (from malonyl CoA decarboxylationi rxn) to the carboxy terminal |
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Term
| Why is NADH needed to produce Oleoyl CoA (16:1) from Stearoyl CoA (16:0)? |
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Definition
- Oleate has a double bond and is more oxidized than Stearate yet the reaction still consumes two electrons from NADPH + H+
- The electrons are necessary cuz the reaction is an OXIDASE reaction: the enzyme uses its iron prosthetic to bind O2 and oxidize stearate. BUT: if its iron is Fe3+, it can't bind O2 (just like myoglobin). The NADPH promotes Fe2+ and O2 binding. |
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Term
|
Definition
| 20C molecules derived from polyunsaturated FAs |
|
|
Term
|
Definition
- 20:4 FA
- precursor of Postaglandin H2 and its derivatives = local hormones |
|
|
Term
|
Definition
- blocks arachidonate entry into prostaglandin H2 synthase active site
- diverse effects because of the diverse hormones that are derived from arachidonate (anti-inflammatory, gastric ulceres, antipyretic, blood thinner) |
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Term
| What is the major control point for the equilibrium between FA synthesis and FA degradation? |
|
Definition
| Acetyl CoA Carboxylase Activity
Reversible phosphorylation:
- AMPK (AMP-activated Protein Kinase) turns synthesis off
- PP2A (Protein Phosphatase 2A) turns synthesis on
Allosteric Effectors - Alter dimerization of FA Synthase:
- palmitoyl CoA turns synthesis off (neg feedback)
- Citrate turns synthesis on: reflects high energy charge and lots of precursors. Citrate will mediate the effects of PP2A (even if synthase is phosphorylated, if citrate is bound it won't be totally inactive)
Hormonal Effectors:
- Glucagon and Epi turn synthesis Off (augment AMPK)
- Ins turns synthesis on indirectly (stimulates PP2A activity)
(Acetyl CoA Carboxylase also impacts the equilibrium: xs malonyl CoA inhibits Carnitine Acyltransferase I) |
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Term
|
Definition
AMP-Activated Protein Kinase A:
- fuel guage = active at low energy charge
- inhibits Acyl CoA Carboxylase and FA synthesis |
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|
Term
|
Definition
Protein Phosphatase 2A
- Acitvates Acyl CoA Carboxylase if energy charge is high (low AMP)
(not to be confused with PP1: inhibits glycogen breakdown and promotes glycogen syntehsis) |
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