LIPOGENESIS

What is Lipogenesis?

It is the metabolic pathway by which fatty acids are synthesized from Acetyl-CoA.

It is not simply a reversal of the steps of degradation of fatty acids (the β-oxidation pathway).

Some Differences Between Lipogenesis and β-oxidation pathway

Oxidation Synthesis

Reaction site Mitochondria Cytosol

Enzymes involved (Independent ) Fatty acid synthase

Intermediates carrier Coenzyme A Acyl carrier protein

Coenzymes FAD, NAD+ NADPH

Carbon atoms Removed two at a time Added two at a time

THE CITRATE – MALATE SHUTTLE SYSTEM The acetyl CoA is the starting material for

lipogenesis.

Because acetyl CoA is generated in mitochondria and lipogenesis occurs in the cytosol, the acetyl CoA must be transported to the cytosol.

It exits the mitochondria through a transport sytem that involves citrate ion.

The outer mitochondrial matrix is freely permeable to acetyl CoA, as well as many other substances such as citrate, malate, and pyruvate.

The inner mitochondrial membrane, however is not permeable to acetyl CoA.

THE CITRATE – MALATE SHUTTLE SYSTEM

THE CITRATE – MALATE SHUTTLE SYSTEM

Mitochondrial acetyl CoA reacts with oxaloacetate to produce citrate, which is then transported through the inner mitochondrial membrane by a citrate transporter.

Once in the cytosol, the citrate undergoes the reverse reaction to its formation to regenerate the acetyl CoA and oxaloacetate, with ATP involved in the process.

The acetyl CoA so generated becomes the “fuel” for lipogenesis; the oxaloacetate so generated reacts further to produce malate, in an NADH dependent change.

The malate reenters the mitochondrial matrix through a malate transporter, and is then converted to oxaloacetate, which can then react with another acetyl CoA molecule to form citrate and the shuttle process repeats itself.

ACP COMPLEX FORMATION

Two simple ACP complexes are neede to start the lipogenesis process.

They are acetyl ACP, a C2–ACP, and malonyl ACP, a C3 --ACP .

Additional malonyl ACP molecules are needed as the lipogenesis process proceeds.

Cytosolic acetyl CoA is the starting material for the production of both of these simple ACP complexes. Acetyl ACP is produced by direct reaction of acetyl CoA with and ACP molecule.

O acetyl transferase O

CH3—C—S—CoA + ACP—S—H CH3—C—S—ACP + CoA—S—H

Acetyl CoA Acetyl ACP CoA

The reaction to produce malonyl, ACP requires two steps . The first step is a carboxylation reaction with ATP involvement.

O O O

CH3—C—S—CoA + CO2 - 0—C—CH2—C—S--CoA

Acetyl CoA ATP ADP + Pi Malonyl

CoA

This reaction occurs only when cellular ATP levels are high. It is catalyzed by acetyl CoA carboxylase complex, which requires both Mn2+ ion and the B vitamin biotin for its activity. The malonyl CoA so produced then reacts with ACP to produce malonyl ACP.

o o o o malonyl transferase- 0—C—CH2—C—S—CoA + ACP—SH -

0—C—CH2—C—S—ACP +CoA—S—H

malonyl CoA ACP malonyl ACP CoA

THE CHAIN ELONGATION

Four reactions that occur in a cyclic pattern within the multienzyme fatty acids synthase complex constitute the chain elongation process used for fatty acids.

The reactions of the first turn of the cycle, in general terms

Acetyl ACP Malonyl ACP

Crotonyl ACP

Acetoacetyl ACP

Butyryl ACP

β-Hydroxybutyryl ACP

+

1. CONDENSATION

2. HYDROGENATION

3. DEHYDRATION

4. HYDROGENATION

ACP

CO2

NADPH/H+

NADP+

H2O

+

NADPH/H+

NADP+

CHAIN ELONGATION

STEP 1: CONDENSATION.

Acetyl ACP and malonyl ACP condense together to form acetoacetyl ACP.

O O O II II II CH3—C—S—ACP+ -O—C—CH2—C—S—

ACP O O II II CH3—C—CH2—C—S—ACP + CO2 +

ACP—SH

Acetyl ACP

Malonyl ACP

Acetoacetyl ACP

STEP 2: FIRST HYDROGENATION.

The Keto group of the acetoacetyl complex, which involves the β-carbon atom, is reduced to the corresponding alcohol by NADPH.

O O OH O

II II I II

CH3—C—CH2—C—S—ACP CH3—CH—CH2—C—S—ACP

NADPH/H+

NADP+

Acetoacetyl ACP

β-Hydroxybutyryl ACP

STEP 3. DEHYDRATION

The alcohol produced in STEP 2 is dehydrated to introduce a double bond into the molecule (between α and β carbons.)

OH O O l ll llCH3—CH—CH2—C—S—ACP CH3—CH=CH—

C—S—ACP β-Hydroxybutyryl ACP

Crotonyl ACP

H2O

STEP 4: SECOND HYDROGENATION

The double bond introduced in step 3 is converted to a single bond through hydrogenation. As in step 2, NADPH is the reducing agent.

o o

trans ll ll

CH3—CH=CH—C—S—ACP CH3—CH2—CH2

—C—S—ACP

Crotonyl ACP

Butyryl ACP

NADPH/H+

NADP+

O IICH3—C—S—ACPAcetyl ACP

O llCH3--(C2)14—C—O-

C16 Fatty acid

O IICH3—CH2—CH2—C—S—ACPC4 Fatty acid

O IlCH3—CH2—CH2— CH2--CH2 C—S—ACPC6 Fatty acid

Cycle repeats

Malonyl ACP

CO2

Malonyl ACP

Malonyl ACP

Malonyl ACP

CO2

CO2

CO2

BIOSYNTHESIS OF CHOLESTEROL

The biosynthesis of cholesterol, a C27 molecule , occurs primarily in the liver.

Its production consumes 18 molecules of acetyl CoA and involves at least 27 separate enzymatic steps.

Acetyl CoA C2

Mevalonate C6

Cholesterol

Multiring C27

Lanosterol

Multiring C30

Squalene

Acyclic C30

Isopentyl Pyrophosp

hate C5

Several

Steps

Several

Steps

Several

Steps

Several

Steps

Several

Steps

OVERVIEW OF THE BIOSYNTHETIC PATHWAY FOR CHOLESTEROL SYNTHESIS

In the first phase of cholesterol synthesis, three molecules of acetyl CoA are condensed into a C6 mevalonate ion.

The C6 mevalonate undergoes a decarboxylation to yield a C5 isoprene derivative called isopentenyl pyrophosphate and CO2 . Three ATP molecules are needed in accomplishing this process.

The next stage of cholesterol biosynthesis involves the condensation of six isoprene units to give the C30 squalene molecule.

The multistep squalene-to-lanosterol transition involves the formation of four ring systems.

A decrease in double bonds from six to two.

The migration of two methyl groups to new locations, and the addition of an –OH group to the C30 system.

Addition of the –OH group requires the use of molecular oxygen; the O of the –OH group comes from the molecular O2 .

SQUALENE LANOSTEROL

The transition from lanosterol to cholesterol involves removal of three methyl groups (C30 to C27 ), reduction of the double bond in the side chain, and migration of the other double bond to a new location.

Once the cholesterol has been formed, biosyhthetic pathways are available to convert it to each of the five major classes of steroid hormones: progestins, androgens, estrogens, glucocorticoids, and mineralocorticoids, as well as to bile acids and vitamin D.

CholesterolC27

Progestins C21

Mineralocorticoids

C21

Androgens C19

Glucocorticoids C21

Estrogens C18

Biosynthetic Relationship among Steroid Hormones

THANK YOU…

TO GOD BE THE GLORY

PREPARED BY:LEIZEL A. DESPI

BSED 2C