ECDASEPT 2009

LIPOGENESIS

Fatty acids are formed by the action of fatty acid synthase from acetyl-CoA and malonyl-CoA (a 3-carbon compound) precursors.

LIPOGENESIS In humans, fatty acids are predominantly

formed in the liver and adipose tissue, and in mammary glands during lactation.

Most acetyl-CoA is formed from pyruvate by pyruvate dehydrogenase in the mitochondria. Acetyl-CoA produced in the mitochondria is

condensed with oxaloacetate to form citrate, which is then transported into the cytosol and broken down to yield acetyl-CoA and acetate by ATP citrate lyase.

LIPOGENESIS

Fatty acid synthesis is starts with acetyl-CoA, which is carboxylated to malonyl-CoA.

The ATP-dependent carboxylation provides energy input. The CO2 is lost later during condensation with the growing fatty acid. The spontaneous decarboxylation drives the condensation. 

Acetyl-CoA Carboxylase catalyzes the 2-step reaction by which acetyl-CoA is carboxylated to form malonyl-CoA

LIPOGENESIS As with other

carboxylation reactions (e.g., Pyruvate Carboxylase), the enzyme prosthetic group is biotin. 

ATP-dependent carboxylation of the biotin, carried out at one active site (1), is followed by transfer of the carboxyl group to acetyl-CoA at a second active site (2).

LIPOGENESIS

The overall reaction, which is is spontaneous, may be summarized as:

HCO3- + ATP + acetyl-CoA ADP + Pi +

malonyl-CoA

Acetyl-CoA Carboxylase, which converts acetyl-CoA to malonyl-CoA, is the committed step of the fatty acid synthesis pathway. 

LIPOGENESIS

LIPOGENESIS

Fatty acid synthesis, from acetyl-CoA and malonyl-CoA, occurs by a series of reactions.

NADPH serves as electron donor in the two reactions involving substrate reduction. The NADPH is produced mainly by the Pentose Phosphate Pathway.

Fatty acid synthase, the enzyme responsible for fatty acid synthesis, has many catalytic domains.

LIPOGENESIS Prosthetic groups of Fatty Acid Synthase

include: the thiol of the side-chain of a cysteine

residue in the Condensing Enzyme domain of the complex.

the thiol of phosphopantetheine, which is equivalent in structure to part of coenzyme A.  Phosphopantetheine (Pant) is covalently linked

via a phosphate ester to a serine hydroxyl of the acyl carrier protein domain of Fatty Acid Synthase. The long flexible arm of phosphopantetheine helps its thiol to move from one active site to another within the complex. 

LIPOGENESIS

thiol cysteine residue thiol of phosphopantetheine

LIPOGENESIS

Each of the substrates acetyl-CoA and malonyl-CoA bind to the complex (designated steps 1 & 2) Malonyl/acetyl-CoA Transacylase enzyme domain.

The condensation reaction (step 3) involves decarboxylation of the malonyl moiety, followed by attack of the resultant carbanion on the carbonyl carbon of the acetyl (or acyl) moiety.

LIPOGENESIS

LIPOGENESIS In steps 4-6, the b-ketone is

reduced to an alcohol, by electron transfer from NADPH. Dehydration yields a trans double

bond. Reduction at the double bond by

NADPH yields a saturated chain.

LIPOGENESIS Following transfer of the growing fatty acid

from phosphopantetheine to the Condensing Enzyme's cysteine sulfhydryl, the cycle begins again, with another malonyl-CoA.

LIPOGENESIS

The primary structure of the mammalian Fatty Acid Synthase enzyme is summarized below.

LIPOGENESIS

When the fatty acid is 16 carbon atoms long, a Thioesterase domain catalyzes hydrolysis of the thioester linking the fatty acid to phosphopantetheine. The 16-C saturated fatty acid, palmitic acid, is the final product of the Fatty Acid Synthase complex.

CH2 CO

O

CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3

LIPOGENESIS Regulation of Acetyl-CoA

Carboxylase by local metabolites: Palmitoyl-CoA, the product of Fatty Acid

Synthase, inhibits Acetyl-CoA Carboxylase , diminishing production of malonyl-CoA, the precursor of fatty acid synthesis. This is an example of feedback inhibition.

Citrate allosterically activates Acetyl-CoA Carboxylase. Citrate concentration is high when there is adequate acetyl-CoA entering Krebs Cycle. Excess acetyl-CoA is then converted via malonyl-CoA to fatty acids for storage.

LIPOGENESIS

KETOGENESIS

Ketogenesis is the process by which KETONE BODIES or compounds are produced from acetyl CoA molecules as a result of fatty acid degradation.

KETOGENESIS

Ketone bodies are produced mainly in the mitochondria of hepatocytes.

Its synthesis occurs in response to low glucose levels in the blood, and after exhaustion of cellular carbohydrate stores, such as glycogen.

The production of ketone bodies is then initiated to make available energy that is stored as fatty acids.

KETOGENESIS

However, if the amounts of acetyl-CoA generated in fatty-acid β-oxidation challenge the processing capacity of the TCA cycle or if activity in the TCA cycle is low due to low amounts of intermediates such as oxaloacetate, acetyl-CoA is then used instead in biosynthesis of ketone bodies via acetoacyl-CoA and β-hydroxy-β-methylglutaryl-CoA (HMG-CoA).

KETOGENESIS

REVIEW! Fatty acids undergo

β-oxidation to form acetyl-CoA.

Normally, acetyl-CoA is further oxidized and its energy transferred as electrons to NADH, FADH2, and GTP in the Krebs cycle.

KETOGENESIS

KETOGENESIS The three ketone bodies are:

Acetoacetate - if not oxidized to form usable energy, it is the source of the two other ketone bodies below.

Acetone - is not used as an energy source, but is instead exhaled or excreted as waste.

β-hydroxybutyrate - it is not technically a ketone according to IUPAC nomenclature.

Each of these compounds are synthesized from acetyl-CoA molecules.

KETOGENESIS

Ketogenesis may or may not occur, depending on levels of available carbohydrates in the cell or body. When the body has ample carbohydrates

available as energy source, glucose is completely oxidized to CO2.

When the body has excess carbohydrates available, some glucose is fully metabolized, and some of it is stored by using acetyl-CoA to create fatty acids.

KETOGENESIS

When the body has no free carbohydrates available, fat must be broken down into acetyl-CoA in order to get energy. Acetyl-CoA is not being recycled through the citric acid cycle because the citric acid cycle intermediates (mainly oxaloacetate) have been depleted to feed the gluconeogenesis pathway, and the resulting accumulation of acetyl-CoA activates ketogenesis.

Ketogenesis provides energy for vital organs’ functions during prolonged starvation

KETOGENESIS

KETOGENESIS

KETOGENESIS

Ketone bodies are created at moderate levels in our bodies, such as during sleep and other times when no carbohydrates are readily available.

However, when ketogenesis is happening at higher than normal levels, the body is said to be in a state of ketosis. Ketone bodies accumulation in the body may result to negative long term effects.

KETOGENESIS

Abnormally high concentration of ketone bodies in the body results in the decrease of pH level of the blood. This state is called ketoacidosis.

Ketoacidosis is very rare to occur. It is, however, more seen in people suffering from untreated Diabetes mellitus (DM) and in those alcoholics after binge drinking and subsequent starvation.

Diabetes and Ketoacidosis When there is not enough insulin in the

blood, glucose is not used efficiently to produce energy. Thus, the body must break down lipids for its energy.

Lipid degradation leads to ketones build up in the blood. Ketone then spill over into the urine so that the body can get rid of them. Acetone can be exhaled through the lungs. This gives the breath a fruity odor. Ketones that build up in the body for a long time lead to serious illness and coma. (Diabetic ketoacidosis)

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