Fatty acid synthesis

Question 1

Essential amino acids

Answer 1

Linoleic 18:2ω6 (–>arachidonic acid–>eicosanoids including prostaglandins) (arachidonic essential if ther eis no linoleic)
α-linoleic acid (linoleNic acid) 18:3ω3

Question 2

Fatty acids found in milk

Answer 2

4-10 carbons

Question 3

Necssary precursors and coenzymes for fatty acid synthesis

Answer 3

Ac-CoA, ATP, NADPH, CO2

Question 4

ATP-citrate lyase

Answer 4

located in cytosol, forms Ac-CoA as precursor for fatty acid synthesis

Citrate + ATP + CoA –> Ac-CoA + ADP + Pi + OAA

Question 5

Citrate shuttle

Answer 5

To get Ac-CoA from mitochondria where it is initally formed to cytosol, react with citrate synthase to make citrate, transport citrate to cytosol, use ATP-citrate lyase to make new Ac-CoA.

Fed state–>mitochondrial [ATP] high–>IDH inhibited (TCA stops, pyruvate carboxylase used for OAA)

Question 6

Sources of cytosolic Ac-CoA

Answer 6

oxidation of pyruvate (PDH, major source in fed state, needs citrate shuttle), degredation of fatty acids, degredation of ketone bodies, degredation of amino acids

Question 7

Malic Enzyme

Answer 7

cytosolic, source of NADPH for synthesis
Malate + NADP+ —> CO2 + pyruvate + NADPH

malate formed by cytosolic malate dehydrogenase from OAA, oxidizes an NADH (e- goes to the NADPH)

Question 8

Acetyl-CoA Carboxylase (ACC)

Answer 8

Biotin
Ac-CoA + CO2 + ATP ———> Malonyl-CoA (3 carbons)+ ADP

Rate limiting enzyme for fatty acid synthsis. Needs biotin

Active as polymer
Activators: citrate (increases polymerization); insulin(–>protein phosphotase–>ACC active

Inhibitors: palmitoyl-CoA (ups dimers); glucagon, epinephrine, norepinephrine (–>cAMP–>AMPK (AMP kinase)–|ACC-Pi)

Long term regulation:
High carb, low fat diet–> upregulation of ACC, increased FA synthesis
Hight fat diet, fasting, glucagon –> downregulation of ACC, decreased FA synthesis

Question 9

Fatty Acid Synthase

Answer 9

Multifunctional enzyme (7 active sites): important parts-condensing enzyme domain, acyl carrier peptide
Active as dimer, upregulated by insulin
Forms palmitoyl-CoA from malonyl-CoA 2 carbons at a time
14 NADPHs, 7 ATPs

Question 10

FA synthesis: Step 1

Answer 10

Condensing domain

Cys residue acetylated by Ac-CoA–>Ac-cys-CE + CoA

Question 11

FA synthesis: Step 2

Answer 11

Malonyl transferase

Malonyl-CoA + ACP—->malonyl-ACP + CoA

Question 12

FA synthesis: step 3

Answer 12

Ac-CE + malonyl-ACP —-> β-keto-ACP HCO3- (aka CO2) + CE

Question 13

FA synthesis: step 4

Answer 13

β-ketoreductase–>terminal ketone reduced to alcohol (NADPH)

Question 14

FA synthesis: step 5

Answer 14

β-hydroxyacy dehydratase: alcohol to trans-alkene

Question 15

FA synthesis: step 6

Answer 15

enoyl reductase: reduce dbl bond, uses NADPH, 4 carbon unit transfered back to CE. Repeat til 16 carbons

Question 16

FA synthesis: step 7

Answer 16

Thioesterase: cleave palmitoyl-ACP, release palmitate

Question 17

FA Synthesis overview

Answer 17

Take Ac-CoA and Malonyl-CoA hook up to FAS (CE and ACP respectively). Transfer acyl group, make C-C bond. Reduce terminal carbonyl–>alcohol (NADPH)–>trans dbl bond –> single bond (NADPH)–>repeat–>cleave palmitate off

Question 18

Fatty acid elongation

Answer 18

mostly takes place in ER, adding malonyl-CoA to palmitate

Question 19

Fatty acid desaturation

Answer 19

ER. Fatty acyl-CoA desaturases can introduce dbl bonds at positions 5, 6 and 9. Requires cyt b5 (reductase), desatruase, and NADPH

Question 20

Polyunsaturated fatty acid (PUFA synthesis)

Answer 20

start with α-linoleic acid, use Δ5 and Δ6 desaturases and elongase to get to EPA (20:5_, use more elongases, Δ6, and peroxisomal oxidation to get to DHA (22:6)

Question 21

Glycerol-P-dehydrogenase

Answer 21

Liver and adipose

DHAP + NADH —-> Glycerol-Pi + NAD+

Question 22

Glycerol kinase

Answer 22

Liver only

Glycerol + ATP —> Glycerol-Pi + ADP

Question 23

TAG synthesis

Answer 23

Glycerol phosphate + 3 acyl-CoAs
acyltransferase acyltransferase
————> lysophaphatidic acid——-> DAG-Pi

phosphotase acyltransferase
————-> DAG—————–> TAG

In intestinal mucosal cells start with 2-MAG and 2 acetylransferase steps