(3) De Novo FA synthesis

De novo fatty acid synthesis occurs under conditions of

excess energy intake

Fatty acids synthesis is most active in the —-, in the —-- state, and in —------

liver; postprandial(fed) ; lactating mammary glands

Four steps of de novo fatty acid synthesis

citrate exits mitochondria and enter cytoplasm of hepatocytes, production of cytoplasmic acetyl-CoA from the citrate, production of malonyl-CoA from Acetyl-CoA, and then de novo fatty acid synthesis via FA synthase

What three tissues synthesize only a minor amount of FAs?

adipose tissue, brain, and kidney

t/f de novo FA synthesis is costly and highly regulated

true

Citrate movement to cytoplasm occurs under what conditions

high insulin, high glycolysis rate (PFK1 active due to high [F2,6BP]), glucose is being converted to pyruvate and pyruvate is being fed into the CAC

How is cytoplasmic acetyl-CoA produced?

citrate lyase catalyzes the reaction, which uses cytoplasmic citrate, CoA, and an ATP to produce cytoplasmic acetyl CoA, ADP, Pi, and an oxaloacetate which can be returned to citric acid cycle

How is malonyl-CoA produced?

acetyl-CoA carboxylase uses one ATP and CO2 to produce it from Acetyl-CoA

acetyl-CoA carboxylase is regulated by what?

fatty acyl-CoA inhibits it while insulin stimulates it

Most important control point of FA synthesis

conversion of cytoplasmic Ac-CoA to Malonyl-CoA

Describe the process of de novo fatty acid synthesis via fatty acid synthase

acetyl CoA is used as a primer then 3 carbon malonyl CoAs are added to the chain in a stepwise manner. After each malonyl CoA is added, the intermediate loses a CO2 which releases enough energy to make the process irreversible. Each 2 C extension costs 2 NADPH and 1 ATP.

Each 2 carbon extension in the FA synthesis costs

2 NADPH and 1 ATP

Fatty acid synthase

dimer of a protein that contains all enzyme activities necessary for FA synthesis

FA synthases is on the —- surface of the —--

cytosolic surface of the endoplasmic reticulum

Acyl carrier protein (ACP)

during FA synthesis, growing fatty acid chain is attached to ACP, which passes the chain from catalytic site to catalytic site of fatty acid synthase. Accordingly, the intermediates are often written as intermediate-ACP

ACP contains —- which is also found in CoA

pantothenate (vitamin b5)

Overall stoichiometry to synthesize a palmitate (C16 fatty acid)

2 sources of NADPH for FA synthesis in liver

pentose phosphate pathway and malic enzyme

How does the pentose phosphate pathway provide NADPH for FA synthesis in the liver?

creates 2 NADPH per glucose in the pathway.

How does malic enzyme provide NADPH for FA synthesis in the liver?

converts malate into pyruvate to produce 1 NADPH per malate

—% of fatty acids in adipocytes come from diet

95

Regular fatty acid synthesis go up to about C–

C16 (palmitate)

Any fatty acids longer than 16 carbons must be synthesized via —-

elongation

Very-long-chain fatty acids

fatty acids that have greater or equal to 20 carbons

The — makes particularly long fatty acids

brain

Elongation of fatty acids is important for longer fatty acids needed to

regulate membrane fluidity (phospholipids in brain) or synthesize eicosanoids

t/f FA elongation resembles synthesis, but is catalyzed by different enzymes

true

Show the 2 steps of fatty acid elongation using palmitate

1st step is activation by esterification with CoA and 2nd step is addition of 2 C atoms from malonyl-CoA

Desaturation of fatty acids

uses desaturase to introduce double bonds into fatty acids which change physiochemical properties

Desaturase

position-specific enzyme involved in desaturation of fatty acids. may only introduce double bonds between Carbon 1 and carbon 9 of a FA and it can only introduce cis double bonds (NO TRANS)

2 limitations of desaturation in humans

desaturase may only introduce double bonds between Carbon 1 and carbon 9 of a FA and it can only introduce cis double bonds (NO TRANS)

Trans vs cis fatty acids

Cis fats have hydrogen on the same side, causing a bent chain and liquid state, while trans fats have hydrogen on opposite sides, creating a straight, solid, and often artificial fat that increases heart disease risk

Symbiotic bacteria in ruminants can give rise to — FAs which are incorporated into the host body, thus the meat of ruminants are high in this kind of FA.

trans

t/f the human body can degrade BOTH cis and trans fatty acids

true

Common sources of trans fatty acids

meat (particularly red meat), oil heated to high temperatures, and partial hydrogenation of fatty acids (seen in margarine)

Hydrogenation of poly-unsaturated triglycerides

done by bubbling H2 through oil in presence of nickel catalyst to produce margarine. Increases stability of the fat (less likely to go rancid). Converts unsaturated fatty acids with cis bonds to mostly saturated FAs with little double bonds are that are more likely to be trans

Trans fatty acids are associated with higher risk of —

Cardiovascular disease

The US department of agriculture recommends intake of trans fatty acids that amount to less than — % of daily calories. Americans typically consume about –% of their calories as trans fatty acids

1; 2-3

A person’s risk for heart disease depends on the balance of intake of

both saturated fatty acids and unsaturated trans fatty acids

t/f FAs that contain >=2 double bonds after C9 must be synthesized

false, they must come from diet

2 essential fatty acids

linoleate (omega-6) and linolenate (omega-3)

What fatty acid is this?

linoleate (omega-6)

What fatty acid is this?

linolenate (omega-3)

Why can we not make essential fatty acids?

they include double bonds past carbon 9

What foods are a good source of linolenate

fish, seafood, flax seeds, eggs, and avocado

The body converts some linolenate to —- and — in –/– steps

EPA and DHA in 3/4 steps

EPA

omega-3 FA synthesized from linolenate. Made from 2 desaturations and 1 elongation of linolenate

DHA

omega-3 FA synthesized from linolenate.Made from 2 desaturations and 2 elongations of linolenate

DHA is the most abundant —- FA in the —- and —-

omega-3 ; brain and retina

What foods are good source of linoleate

nuts, olive oil, and eggs

The body converts some linoleate to — in – steps. What are these steps?

arachidonate; 3 steps; 2 desaturations and 1 elongation

Arachidonate becomes essential if — is deficient

linoleate

How many of each essential fatty acids do we need a day

~250 to 500 mg/day of linolenate and 11-22 g/day of linoleate

Eicosanoid

omega-6 signalling lipids derived from oxidation of arachidonic acid ( C20

Majority of arachidonic acid in the body are in the form of —-

phospholipids

Phospholipase A2

enzyme that catalyzes release of arachidonic acid from phospholipids in the cell membrane

NSAIDs

anti-inflammatory drugs like aspirin or ibuprofen that inhibit COX-½ to prevent prostaglandin synthesis

Cyclooxygenase (COX1/2)

enzyme that converts arachidonic acid into prostaglandin (lipid hormone)

Two functions of aspirin

inhibits prostaglandin synthesis by inhibiting COX-1/2 (ant-inflamatory, analgesic, and antipyretic action) inhibits thromboxane A2 synthesis (antiplatelet agent<-- prevents platelets from sticking together to form clots)

Thromboxane A2

eicosanoid that plays a role in coagulation. Activated platelets synthesize and release thromboxane A2, which then activates other platelets nearby

How does low does aspirin low risk of heat attack and stroke

it is an anti-platelet agent as it inhibits thromboxane A2 production