bmsc 230 module 9 fatty acid synthesis

other than fuel, what purpose does fatty acids play?

signalling molecules

Important components of membranes

what are some physiological conditions that require fatty acid synthesis?

embryonic development, lactation, and certain illnesses

what does acetyl coA serve as in fatty acid synthesis? what about the keto groups?

acetyl CoA is the building block for fatty acids and the keto groups are reduced using NADPH

T/F fa synthesis is not a repetitive process

False - it is a repetitive process

What is the initial product of fa synthesis?

palmitate, a saturated 16-carbon fatty acid

where does fa synthesis occur?

cytosol

What is the first stage of fa synthesis?

Acetyl Coa (mitochondria) —> Cytosol

What is the second stage of fa synthesis?

Acetyl Coa—> Molonyl Coa

What is the third stage of fa synthesis?

Palmitate formed in 5 step elongation

is fa synthesis how is acetyl coa activated?

acetyl CoA is activated by combining it with HCO3-, the form of CO2 in water via Acetyl CoA carboxylase ; driven by hydrolysis of ATP

What is the commited step of fa synthesis?

Acetyl Coa combining with HCO3- via acetyl coA carboxylase

Acetyl Coa carboxylase contains a ___ prosthetic group which is a ___ used in carboxylation reactions

a- vitamin b, substrate
b- vitamin b, coenzyme
c- biotin, substrate
d- biotin, coenzyme

d- biotin, coenzyme

How many carbons are in Palmitate?

16

Palmitate is classified as a ___?
a- protein
b— lipid
c- saturated fatty acid
d- unsaturated fatty acid

c- saturated fatty acid

what is the name of the enzyme complex that catalyzes fatty acid synthesis?

fatty acid synthase - it is a dimer

ACP stands for?

acyl carrier protein

phosphopantetheine forms a ___ bond in the same way the Acetyl Coa does

a- esther
b- hydrogen
c- electrostatic
d- covalent
e- thioester

e- thioester

phosphopantetheine carries ___ from one catalytic site to the next

substrate

what is the prosthetic group of ACP called?

phosphopantetheine

How many catalytic sites (in total) are there of the fatty acid synthase?

7 - everything but acp

thioesterase cleaves ____ bond between palmitate and ___

thioesterase , acp

thioesterase thus, _ palmitate from fa synthase complex

frees

what is the difference in catalytic activitues in yeats vs vertebrates?

yeast: all catalytic activities present in 2 polypeptides

vertebrates: all of the enzyme activities are contained within one large polypeptide

t/f the mechanism of fatty acid synthesis is highly conserved

True

What is a major component of Coenzyme A? (also in ACP)

phosphopantetheine

phosphopantetheine has a free ___ group and it is to this group that the ____ of fatty acid synthesis are linked

sulfhydryl, intermediates

ACP acts as an ___ ?
word choices (substrate, enzyme, coenzyme, crane, arm, glue)

crane, arm - moves fatty acid intermediate from one enzyme to the other

what must happen before fa synthesis can begin?

acetyl coa and malonyl coa are linked to ACP via sulfhdyryl group to form acetyl ACP and malonyl transacylase respectively

what carbon number will the acetyl group in acetyl -ACP end up being in palmitate?

carbons 15 & 16

FA synthesis starts from which end?

opposite end of carboxyl group (numbering of carbons is from the carboxyl group end)

___ (odd/even) chain fatty acids are synthesized beginning with ____ a ___(1,2,3) carbon molecule rather than ____ (malonylCoa/acetylCoa)

odd, propionyl CoA, 3, acetyl CoA

what are the four types of reactions in fa synthesis (in order)

condensation, reduction, dehydration reduction

what happens the the butyryl ACP that is formed at the end of the 4 steps in stage 2?

The butyryl ACP that is formed reacts with another malonyl ACP and the reaction sequence is repeated

How many times is the 4 steps repeated?

until a 16C fatty acid chain is formed so 7 rounds total -

what is the first step?

Acetyl ACP + Malonyl ACP —-> Acetoacyl ACP
via B- ketoacyl synthase

what is the second step?

Acetoacyl ACP + NADPH —> D- Hydroxybutyryl ACP + NADP+
via B- ketoacyl reductase

what is the third step?

D- 3- Hydroxybutyryl ACP —> Crotonyl ACP
via 3- hydroxyacyl dehydratase

what is the fourth step?

Crotonyl ACP + NADPH —> Butyryl ACP + NADP+

Why is the first step significant in context of thermodynamics and favourability?

The release of CO2 and ACP releases a lot of energy, drives reaction forward, thus energetically favourable

The acetoacyl group is __ linked to ACP

a- physically
b- chemically
c- electrostatically
d- hopefully

a- physically

what is the reducing agent in step two?

NADPH

The dehydration reaction leaves a __?
a- single bond
b- double bond
c- lost carbon

b - double bond

What happens to the double bond in the next step?

it is reduced via consuming NADPH

What is the yield at the end of the 7 rounds of fa synthesis?

A 16C long molecule, all Carbons reduced except one - a carboxyl group linked to ACP via a thioester bond , palmitoyl ACP is the name of this 1c attached to ACP

What has to be done is order to complete the synthesis of a free fatty acid?

palmitate has to released from ACP via thioesterase

How does thioesterase detach palmitate from ACP?

by hydrolytically (H2O) cleaving the link of the carboxyl group (of the fa) and the sulfhydryl group (of ACP)

What is the overall stoichiometry of Palmitate synthesis?

8 Acetyl Coa + 7 ATP + 14NADPH —> palmitate + 14 NAD+ + 8coA + 6H2O + 7ADP + 7Pi

How many molecules of NADPH are consumer for every fatty acid synthesized?

14

Aside from the PPP, where does the NADPH come from for fa synthesis? how is this achieved?

via acetyl coA being transported from mitochondrial matrix to the cytosol - achieved by reduction of OAA to malate using NADH, followed by malate -> pyruvate (ox decarboxylation) generating NADPH

How many molecules of NADPH are required for palmitate synthesis? How much comes from the PPP? from the mitochondria -> cytosol shuttle?

14
6
8

For every __ molecule of acetyl coA transported from mitochondrial matrix to the cytosol ____ molecules of NADPH and produced

1, 1

What is the relationship between fa synthesis and tumour cells? What does this imply in context of treatments?

Normal - not very high fa synthesis due to dietary intake sufficiency
Tumour - fast growing so higher rates of fa synthesis

• offers chance for intervention via inhibition of B- ketoacyl ACP synthase inducing apoptosis

How long are most fatty acids?

between 18 and 26 carbons

How are longer fatty acids made?

by adding two carbon units to the carboxyl end of both saturated and unsaturated fatty acids, using malonyl CoA as the substrate

Where are the specialized enzyme for longer chain fatty acid synthesis located?

on the cytoplasmic side of the ER membrane

T/F bacteria lack the ability to introduce double bonds beyond carbon 9

False - mammals lack this ability not bacteria

What must be done to have double bonds form after C number 9 in mammals?

dietary requirements via linoleate (2 kinds) or better known as omega fatty acids or w-6 and w-3 fatty acids

Give an example of linoleate as a precursor for other important biomolecules

arachidonate (has 4 double bonds) synthesized from linoleate,
arachidonate is a precursor from eicosanoids (signalling molecules - local hormones)

What do eicosanoids do? (function)

inflammation, blood flow, ion transport, synaptic transmission, and sleep

How does aspirin work?

promotes addition of acetyl group to an aminos acid in active site of an enzyme that catalyzes conversion of archidonic acid to prostaglandin H2

• the addition of the acetyl group inactivates the enzyme, reducing synthesis of eicosidoids

what is the first commited step in fa synthesis?

synthesis of malonyl coa from acetyl coa via acetyl coa carboxylase

When is fa synthesis highest?

when carbohydrates are plentiful and fa levels are low - lots of carbs = lots of glucose = lots of pyruvate = lots of acetyl coa

when is fa synthesis inhibited?

when energy levels are low and there is a need for fa degradation more than synthesis

What two ways is Acetyl Coa carboxylase regulated?

covalent modification, & allostery

When Acetyl Coa carboxylase is phosphorylated by ___ it is ___?

AMPK (AMP- activated protein kinase), inhibited (inactive)

What inhibits AMPK

ATP - high energy state

What activated AMPK?

high AMP levels - low energy state

What does Protein Phosphatase 2A do?

dephosphorylate Acetyl Coa carboxylase - activating it

What ACetyl coA carboxylase in dephosporylated it is ___?

active

Acetyl coa carboxylase is allosterically _ by citrate?

activated

Citrate represents a __ blank energy state of the cell

high

Citrate ___ fa synthesis

activates

What is special about the interaction between citrate and acetyl coA carboxylase?

inactive acetyl coa carboxylase is a dimer of identical subunits - citrate induces polymerization into active filaments

• citrate may partially reverse inhibition caused by phosphorylation

How does palmitoyl coa affect fa synthesis?

induced depolymerization of the acetyl coa carboxylase into inactive dimer form

What does insulin do to fa synthesis? why

stimulates acetyl coa carboxylase thus stimulates fa synthesis - release of insulin follows a meal eaten, represent high carbs or fed state

What does insulin do to ampk

inhibits

what does insulin do to protein phosphatase 2a

activates

glucagon and epinephrine _ fa synthesis?

inhibit - represents a hungry low energy state

works through ampk

what is desaturation?

the removal of two hydrogen atoms with the creation of a double bond.

what are essential fatty acids?

unsaturated fatty acids that our bodies cannot synthesize and thus are required in our diet. The two primary ones are linoleate (or linoleic acid) and α-linolenate (or α-linolenic acid).