SYLLABUS 9: Fatty acid biosynthesis

Question 1

when are fatty acids synthesized

Answer 1

when carbohydrate (glucose) and protein (amino acid) levels are high

Question 2

where does fatty acid biosynthesis occur

Answer 2

cytoplasm of most cells, w/ liver the most reactive

Question 3

what happens to excess fatty acids in liver

Answer 3

exported as triglycerides packaged in very low density lipoproteins (VLDL) to adipose tissue, where they’re stored

Question 4

what metabolites does FA synthesis require

Answer 4

ATP, NADPH

Question 5

what elevates/decreases FA synthesis?

Answer 5

insulin: elevates FA synthesis
glucagon: decreases FA synthesis

Question 6

in high glucose conditions, what are the steps that set up fatty acid synthesis in the cytosol?

Answer 6

high glugose => excess FA synthesis

glucose is metabolized by glycolysis, PDH to acetyl CoA

acetyl CoA enters TCA cycle, produces citrate

some of the citrate continues through TCA cycle to produce ATP for FA synthesis; some citrate leaves the mito on TCA carrier to the cyto, where it produces acetyl CoA

cytosolic acetyl CoA enters lipogenesis to produce palmitic acid

Question 7

what happens to palmitate produced by fatty acid synthase?

Answer 7

1) used or store din the liver

or

2) transported as VLDL to adipose tissue, where it’s stored

or

3) converted to longer chain fatty acids (like stearate, C18) by elongation enzymes or monounsaturated fatty acids (eg oleic acid) by desaturation enzymes

Question 8

what happens to acetyol coA in the mito produced from glucose?

Answer 8

cannot leave the mito to become available in cyto for fatty acid biosynthesis

therefore must react w/ OAA to produce citrate which is transported out of mito via citrate shuttle

Question 9

when does the citrate shuttle function/how

Answer 9

mito acetyl CoA cannot leave the mito, so:

mitochodnrial acetyl CoA reacts w/ OAA to produce citrate

citrate transported out of the mito via via the citrate shuttle, on the TCA carrier

citrate is leaved by citrate lyase, an ATP-dependent enzyme, to OAA + acetyl CoA

OAA is reduced to malate

malate 1) reenters the mito, oxidized by to OAA or 2) is oxidized in cyto by malic enzyme to produce NADPH for FA synthesis

Question 10

how is OAA regenerated in the mito

Answer 10

from either Pyruvate via pyruvate carboxylase

or from malate

Question 11

in the high energy state, what happens to glycolysis vs fatty acid synthesis? what enzymes does this impact?

Answer 11

glycolysis slows & fatty acid synthesis is stimulated in the high energy state

isocitrate DH slows

Question 12

what is the rate limiting step of FA synthesis

Answer 12

acetyl coA carboxylase

Question 13

describe the rate limiting step of FA synthesis

Answer 13

FA synthesis requires acetyl CoA and malonyl CoA

malonyl CoA is synthesized from acetyl CoA by acetyl CoA carboxylase, which is the rate limiting enzyme of FA synthesis

**biotin **is the cofactor for the carboxylation

Question 14

what activates vs inhibits acetyl CoA carboxylase?

Answer 14

activators: citrate, insulin - which dephosphorylates it
inhibitors: palmitoyl CoA (product), AMP activated kinase, glucagon/cAMP-PKA

Question 15

is acetyl coA carboxylase activated or inactivated when phosphorylated

Answer 15

inactive when phosphorylated - which is how AMP activated kinase, glucagon/cAMP-PKA inactivate it

Question 16

what are sources of NADPH for fatty acid synthesis?

Answer 16

1) first step of the PPP pathway
2) malic enzyme under lipogenic conditions
3) transhydrogenase

Question 17

describe how palmitate is formed?

Answer 17

acetyl CoA and malonyl CoA from the ACC reaction are transferred to the fatty acyl synthase (FAS) complex

acetyl CoA binds to a cysteine group of the condensing enzyme in teh FAS complex

malonyl CoA binds to the acyl carrier protein (ACP) of the FAS

ATP drives reaction of condensing enzyme making a 4C product from acetyl CoA and Malonyl CoA

This 4C intermediate + CO2 now are produced

the 4C acetyoacetyl CoA is then reduced, hydrated, and reduced again to produce a saturated 4C butyryl CoA

these steps require NADPH

butyryl CoA now repeats teh cycle: attachess cyteine SH of dondensing enzyme, condenses with malony CoA, reduces, hydration, reduction to produce a 6C fatty acid

ULTIMATELY: C16 palmitate is formed, which can’t bind to the cysteine and is released from the FAS complex

Question 18

how is palmitate aka palmitoyl coA used?

Answer 18

1) stored as triglycerides, esp in liver and adipose tissue
2) forms phospholipids needed for membranes
3) can be elongated to produce C18, C20 fatty acids
4) can be desaturated to produce unsaturated fatty acids

Question 19

how does acetyl coa carboxylase regulate fatty acid synthesis

Answer 19

it is the rate limiting enzyme for formation of malonyl coa from acetyl coa

Question 20

how do lipogenic conditions regulate fatty acid synthesis?

Answer 20

high glucose, genes for citrate cleavage enzyme, malic enzyme acetyl coA carobxylase, and FAS are activated by SREBP which itself is activated by insulin and inactivated by glucagon

Question 21

how does malonyl CoA regulate fatty acid synthesis

Answer 21

malonyl CoA is needed for FA synthesis

it’s a powerful inhibitor of acyl carnitine transferases which bring FA into mito for B-oxidation

so FA synthesis and oxidation don’t occur at same time