Fatty Acid Synthesis

Question 1

• Understand the three stages of fatty acid synthesis.

Answer 1

Three stages of Fatty acid Synthesis (occurs in cytoplasm):

1. TRANSFER of acetyl CoA out of the mitochondria into CYTOPLASM. Citrate is transported into the cytoplasm and cleaved into oxaloacetate and acetyl CoA.
2. second stage; ACTIVATION of Acetyl CoA to form Malonyl CoA.
3. Third stage: REPETITIVE ADDITION and REDUCTION of two Carbon units to synthesize C16 fatty acid. This synthesis occurs on acyl carrier protein, a molecular scaffold

Question 2

What factors inhibit vs activate fatty acid synthesis?

Answer 2

Insulin induces/activates FA synthesis

Glucagon and Epinephrine INHIBIT FA synthesis.

Question 3

Where is citrate synthesized? How is it transported to the cytoplasm?

Answer 3

Citrate is synthesized in the mitochondria and transported to the cytoplasm. Citrate is then cleaved by ATP citrate lyase to generate acetyl CoA for FA synthesis.
(Citrate and ATP and CoASH + H2O to form Acetyl CoA and ADP and Pi and oxaloacetate).

Question 4

What pathways are increased for fatty acid synthesis? What biosynthetic molecule is used?

Answer 4

during fatty acid synthesis, CAC (citric acid cycle) and Pentose Phosphate pathway is increased.
NADH is converted to NADPH which is the molecule used for fatty acid synthesis.
the reverse of CAC occurs (citrate to oxaloacetate to malate to pyruvate)

Question 5

where do the sources of reducing power for fatty acid synthesis come from?

Answer 5

The sources of reducing power from FA synthesis:
- NADPH from Glycolysis (glucose to pyruvate and then pyruvate to FA, gain NADPH), and Pentose phosphate pathway (convert glucose to ribulose 5-phosphate ) to gain NADPH.

Question 6

What is the committed step in Fatty acid Synthesis? What is Malonyl CoA synthesized by?

Answer 6

The committed step in FA Synthesis is formation of Malonyl CoA.
Malonyl CoA is synthesized by Acetyl CoA Carboxylase (allosteric, biotin-requiring enzyme)
formation of malonyl CoA occurs in two steps:
1. biotin-enzyme + ATP + HCO3- to from CO2-biotin + ADP+ Pi + H+
2. CO2-biotin enzyme + acetyl CoA forms Malonyl CoA and Biotin enzyme (irreversible step)

Question 7

What is the purpose of Fatty acid synthase?

Where does fatty acid synthesis occur? Where are intermediates? What enzymes attach substrate to ACP?

Answer 7

Fatty acid synthase- complex of enzymes, that catalyzes the formation of fatty acids.
Fatty acid synthesis occurs on the ACYL CARRIER PROTEIN (ACP), which is a polypeptide linked to CoA.
Intermediates are linked to sulfhydryl group of Pantothenate (VIT B5) attached to ACP
Acetyl transacylase and Malonyl Transacylase attach substrates to ACP.
(Acetyl CoA + ACP form acetyl ACP + CoA; Malonyl CoA + ACP to form malonyl ACP + CoA)

Question 8

What steps do Fatty Acid Synthesis consist of? How many rounds of the steps are there? How long does this occur?

Answer 8

Fatty acid Synthesis consists of Condensation, Reduction, Dehydration, and reduction forming butyryl ACP as product for one round.
Then you have second round- begin with condensation of malonyl CoA with newly synthesized product butyryl ACP, forming C 6-Beta-ketoacyl ACP. The reduction, dehydration, reduction sequence is repeated.
FA synthesis will continue until getting to C 16- acyl ACP, which is cleaved by thioesterase to yield PALMITATE

(you are storing energy in the form of electrons, by going form oxidation to reduction)

Question 9

What is the limit for Fatty acid synthase in terms of length of fatty acids? What are longer fatty acids (longer than C16 palmitate) synthesized by and how does it work?

Answer 9

Fatty acid synthase cannot generate fatty acids longer than C16 palmitate.
Longer fatty acids are synthesized by enzymes attached to ENDOPLASMIC RETICULULM.
These enzymes will extend palmitate by ADDING 2 CARBON units, using MALONYL CoA as substrate.

Question 10

What are the essential fatty acids that humans must obtain in diet?

Answer 10

Lineoate (w-3, 4c) and Linolenate (w-6, 7c) are essential fatty acids that must be obtained in diet

Question 11

What do enzymes bound to endoplasmic reticulum introduce in FA’s
When do mammals lack enzymes?

Answer 11

Enzymes that are bound to enodplasmic reticulum introduce DOUBLE BONDS into SATURATED FA’s. Ex: (stearoyl CoA + NADH + O2 prouce Oleoyl CoA + NAD+ and H2O)
Mammals lack the enzymes that introduce double bonds beyond carbon 9 (ex: oleate)

Question 12

What are Eicosanoid Hormones derived from?

Describe the structure of Arachidonate and where it is derived from. What is the role arachidonate?

Answer 12

Eicosanoid hormones are derived from Polyunsaturated FA’s.
Arachidonate, a 20-carbon FA with 4 double bonds ,that is derived from Linoleate.
Arachidoante is a precursor for a variety of signal molecules 20 carbons long, collectively called eicosanoids.

Question 13

What are the roles and function of Eicosanoids?

Answer 13

Eicosanoids- collective group of variety of signal molecules that are 20 C long. These signal molecules which include prostaglandins, are local mediators because they are SHORT-LIVED and only affect NEARBY cells.
Eicosanoids bind to membrane receptors, and stimulate inflammation, regulate blood flow to organs, control ion transport across membranes, modulate synaptic transmission and induce sleep.

Question 14

Describe the regulation of Fatty Acid Synthesis

What is the commited step in this process and what factors stimulate or inhibit it?

Answer 14

Regulation of fatty acid synthesis based on committed, irreversible step of converting Acetyl CoA to Malonyl CoA using Acetyl CoA Carboxylase 1
Factors that affect committed step:
-Step switched OFF by PHOSPHORYLATION, Switched ON by dephosphorylation
-Insulin stimulates step (form Malonyl CoA from Acetyl CoA) to convert nutrients into energy storage form.
-Glucagon and epinephrine INHIBIT it.

Question 15

Describe how activity of Acetly CoA Carboxylase is regulated by variety of hormones.

Answer 15

Acetyl CoA Carboxylase (Acetyl CoA to Malonyl CoA) Regulation:

1. Glucagon and Epinephrine inhibit the carboxylase by enhancing AMPK activity (AMP protein kinase). As AMPK is activated, you phosphorylate and inactivate carboxylase
2. Insulin stimulates the DEPHOSHPHORYLATION and activation of carboxylase

Question 16

How are the enzymes of fatty acid synthesis regulated?

Answer 16

The enzymes of fatty acid synthesis are regulated by ADAPTIVE control. If adequate fats are not present in the diet, the synthesis of enzymes required for FA synthesis are ENHANCED

Question 17

what activates carboxylase? what makes carboxylase inactive? What are the factors that inhibit or activate AMPK?

Answer 17

Activation of carboxylase is based on phosphorylation or dephosphorylation.
If AMP-activated Protein kinase (AMPK) on, it will phosphorylate carboxylase and INACTIVATE It.
if Protein Phosphatase 2A is on, it will dephosphorylate carboxylase, ACTIVATING it.
Factors that activate AMPK: AMP, Glucagon and Epinephrine
Factors that inhibit AMPK: ATP and Insulin (which activates carboxylase)

Question 18

How does citrate affect Carboxylase enzyme?

Answer 18

Citrate can partially activate carboxylase that has been phosphorylated, due to conformational change in structure (serves a great intermediate)

Question 19

Describe what excess alcohol consumption leads to, including the pathways, compounds and consequences.

Answer 19

The pathway for ethanol processing occurs in two steps, and leads to EXCESS production of NADH.
1. Cytosol- Ethanol + NAD+ form Acetaldehyde(toxic) + NADH+ H+ (use enzyme alcohol DH)
2. Mitochondria- Acetaldehyde + NAD+ H2O form Acetate and NADH + H+ (use enzyme Aldehyde DH)
Excess NADPH inhibit FA degradation or oxidation,

Question 20

What major cellular pathways are impacted with high levels of NADPH?

Answer 20

High Levels of NADPH:
Inhibits:
1. gluconeogenesis- no glucose produced
2. Fatty acid Oxidation/degradation- because this process is reliant on transfer of electrons(does not occur with excess NADPH)
3. CAC- inhibits enzymes Isocitrate DH, and Alpha-Ketoglutarate

High levels of NADPH promote: Fatty acid synthesis leading to accumulation of fats in liver (fatty liver). It will also enhance Lactate production leading to lactic acidosis.
a high level of acetate will led to high amount of acetyl CoA and hence ketone bodies- lactic acidosis.

Question 21

How does excess alcohol consumption alter energy metabolism in Liver? Why is the acetyl CoA not processed?

Answer 21

Liver can convert some of the acetate generated by Aldehyde dehydrogenase into acetyl CoA.
However the Acetyl CoA cannot be processed by CAC because of the paucity (scarce) of NAD+
The build up of acetyl CoA can lead to ketone body secretion of liver, which exacerbates acidosis caused by lactate accumulation.

Question 22

What happens when acetate cannot be processed?

What is the role of acetaldehydes and what can occur due to protein damage?

Answer 22

When acetate cannot be processed, acetaldehyde accumulates. Acetaldehyde is very reactive and modifies reactive groups of proteins, causing loss of protein function.
As protein damage accumulates, liver function can fail.

Question 23

What are the pathways that insulin activates? inhibits? Differentiate between the way glucose is transported to liver vs muscle.

Answer 23

Insulin activates glycogen synthesis, glycolysis and lipogenesis, CAC.
Insulin inhibits gluconeogenesis, glycogen degradation and fatty acid degradation
Glucose transport in muscle and adipose tissue- mediated by GLUT-4 transporter and is INSULIN dependent.
Glucose transporter in liver (GLUT-2) is insulin-independent.

Question 24

What pathways do glucagon activate? inhibit? What organ are the actions of glucagon confined to?

Answer 24

Glucagon activates gluconeogenesis, glycogenolysis,and fatty acid degradation.
Glucagon mobilizes glucose from every source.
Glucagon also increases lipolysis and ketogenesis from acetyl-COA

Question 25

What occurs in the metabolism of diabetes mellitus?

Answer 25

In diabetes mellitus *(T1D) here is a decreased ability of tissues to use glucose, due to lack of insulin or defective insulin. Hyperglycemia will now result from combined effect of impaired glucose uptake and increased liver gluconeogenesis
The excess FA’s available to liver, along with less efficient TCA cycle, causing accumulation of acetyl CoA and conversion into diabetes mellitus.

Question 26

What occurs in metabolism during Starvation (prolonged fast) vs post absorptive fast?

Answer 26

Metabolism during overnight fast (post absorptive)- in this state, liver metabolism changes from glucose utilization to glucose production (through gluconeogenesis stimulated by glucagon)
Glucagon stimulates glycogenolysis and inhibits glycolysis. The substrates for gluconeogenesis are alanine, lactate ,and glycerol. Alanine and lactate transported to liver from muscle. glucose uptake by muscle and adipose tissue decreases. degradation of TAG and FA oxidation are stimulated (provide energy)

Metabolism during prolonged fast (starving)- glycogen stores become depleted, and supply of metabolic fuels depend on gluconeogenesis and lipolysis, Ketone bodies are produced from large amounts of acetyl-CoA (generated from B-oxidation) that are important energy source for muscle. Decreased demand for glucose, decreases demand for alanine (glucogenic), “Sparing muscles”

Question 27

What occurs in the metabolism of Fed state (after a meal)?

Answer 27

Metabolism in Fed (postprandial) State
Carbs, aa, fats are absorbed in intestine and insulin secretion stimulated. Insulin directs metabolism towards storage and synthesis. In liver, glucose is taken up by GLUT 2 transporter and is channeled into glycolysis and glycogen synthesis.
aerobic glycolysis supplies acetyl-CoA, TAG form by being esterified by glycolysis-derived glycero. TAG packed for transport to tissues.
In muscle: glycogen synthesis, aa uptake and protein synthesis stimulated .
in adipose tissue- VLDL TAG are hydrolyzed and fatty acids are taken up by cells. TAG resynthesized intracellularly, becoming adipocyte storage material (DHAP)