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Intro to Biochemistry > 26 - Fat and fatty acid Synthesis > Flashcards

26 - Fat and fatty acid Synthesis Flashcards

1
Q

Where does biosynthesis of triacylglycerol take place?

A

Mostly in liver, secreted by VLDL. Other tissues that synthesize TG are usually pathological, rather than physiological.

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2
Q

What are triacylglycerols synthesized from in the body?

A

Glycerol-3-phosphate and fatty acyl CoA

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3
Q

What are sources for glycerol-3-phosphate? (2)

A

Liver - has glycerol kinase which can phosphorylate glycerol to glycerol-3-phosphate

Adipose tissue - No glycerol kinase. Glycerol-3-phosphate from glycolysis (eg. dietary glucose) or de novo (from new) through glyceroneogenesis (similar to gluconeogenesis but stops at glycerol-3-phosphate). Glyceroneogenesis can use pyruvate, lactate and amino acids to make glycerol-3-phosphate.

Glycolysis and glyceroneogenesis cannot be active at the same time

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4
Q

What are sources for fatty acyl-CoA?

A

Acyl CoA synthetase

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5
Q

How is the first fatty acid attached to glycerol-3-phosphate in a new TG? What is this intermediate called?

A

The first acyltransferase (glycerol-3-phosphate acyltransferase) esterifies fatty acid at the sn-1 position using , forming lysophosphatidic acid

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6
Q

How is the second fatty acid attached to glycerol-3-phosphate in a new TG? What is this intermediate called?

A

The second acyltransferase esterifies fatty acids in sn-2 position, forming phosphatidic acid.

Phosphatidic acid is then used for phospholipids or TG synthesis.

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7
Q

How is phophatidic acid turned into a TG?

A

A phosphate is removed to make diacylglycerol.

The esterification (addition) of 3rd fatty acid makes this into a triacylglycerol.

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8
Q

Where are fatty acids synthesized?

A

Liver, adipose tissue and some other tissues.

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9
Q

What does fatty acid synthesis from acetyl-CoA need? (2 things)

A

Acetyl CoA

Cytosolic NADPH

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10
Q

What are fatty acids biosynthesized for?

A

Energy storage and membrane components

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11
Q

What can excess fatty acid synthesis lead to?

A

Inappropriate fat accumulation, often in liver

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12
Q

What are the three stages of fatty acid synthesis?

A
  1. Transfer of acetyl-CoA into cytosol from mitochondria
  2. Activation of acetyl-CoA to malonyl CoA
  3. Intermediates attach to a carrier protein and the chain is synthesized two carbons at a time in a 5-step elongation cycle
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13
Q

What system transfers acetal CoA into cytosol for fatty acid synthesis? How?

A

The tricarboxylate system. Acetyl CoA is made inside mitochondria, it must be transported as citrate out of the mitochondria, which costs ATP.

  1. Citrate synthase turns oxaloacetate and acetyl CoA into citrate,
  2. It is transported across the inner and outer membranes.
  3. In the cytoplasm ATP is used by citrate lysase to cleave citrate to oxaloacetate and acetyl-CoA

Oxaloactetate can then be converted into malate (and transported back) and pyruvate (which can also be transported back in). Malate and pyruvate can both be converted into oxaloacetate in the mitochondrial matrix.

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14
Q

What is the first committed step of fatty acid synthesis?

A

Acetyl-CoA carboxylase catalyzing the carboxylation of acetyl CoA to malonyl CoA (irreversible reaction) using ATP and HCO3.

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15
Q

What type of prosthetic group does acetyl-CoA carboxylase have?

A

A biotin prosthetic group. Biotin binds CO2 (from HCO3) and transfers it to acetyl-CoA.

It is a derivative of vitamin B7 and a cofactor for many CO2 transfer reactions (carboxylation, decarboxylation).

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16
Q

What does malonyl-CoA inhibit? Why?

A

Carnitine palmitoyltransferase (import of fatty acids into mitochondria for oxidation)

As the carboxylation of acetyl-CoA is an irreversible committed step of fatty acid synthesis, this makes sure that synthesis and fatty acid oxidation aren’t happening at the same time!

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17
Q

What are two ways that acetyl CoA carboxylase is regulated?

A

Allosterically

  • Activated by citrate (promotes polymerization)
  • Inactivated by palmitoyl-CoA

Enzyme Modification

  • Inactivated by phosphorylation by AMP activated kinase or protein kinase A
  • Activated by phosphorylation by phosphoprotein phosphatase 2A
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18
Q

What activates phosphoprotein 2A and what inhibits it? Hint, phosphoprotein phosphatase 2A activates the inactive monomer of acetyl CoA carboxylase (makes it polymerize by dephosphorylation)

A

Insulin activates it, causing CoA carboxylase to become active and to start the synthesis of fatty acids

Epinephrine inhibits CoA Carboxylase, inhibiting synthesis of fatty acids

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19
Q

Does insulin promote or inhibit the synthesis of fatty acids? How?

A

Promotes the synthesis of fatty acids by activating phosphoprotein phosphatase 2A, which acts to dephosphorylate CoA Carboxylase (catalyzes first committed step of fatty acid synthesis)

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20
Q

What is fatty acid synthase?

A

The enzyme complex that contains all activies necesary for the reaction steps of fatty acid synthesis.

It catalyzes the synthesis of fatty acids up to C16:0

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21
Q

What does the ACP (acyl carrier protein) part of fatty acid synthase do?

A

Acts as a tether and prosthetic group for the acyl group (CH3) of the growing chain.

ACP has phosphopantetheine group similar to CoA

ACP binds and activates acyl groups similar to CoA

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22
Q

What is the condensation step of fatty acid synthesis? (after carboxylation to malonyl-CoA)

A

Acetyl-CoA and Malonyl-CoA are transferred to acyl carrier protein ACP

  1. Acetyl-CoA and Malonyl-CoA are transferred onto ACP
  2. Acetyl group is transferred from ACP to ketoacyl synthase
  3. Ketoacyl synthase catalyzes the condensation and decarboxylation of acetyl and malonyl group to form acetoacetyl-ACP
23
Q

What is the reduction step of fatty acid synthesis? (After condensation of acetyl-CoA and malonyl-CoA to acetoacetyl-ACP)

A
  1. Acetoacetyl-ACP is reduced to ketogroup by ketoacyl reductase, using NADPH (which is oxidized to NADP+)

This forms β-3-hydroxybutyryl-ACP which is dehydrated by dehydratase in the next step to crotonyl-ACP

24
Q

After reduction of acetoacetyl-ACP to a ketogroup in fatty acid synthesis, what are the next steps?

A
  1. Dehydration by dehydratase, which forms a C=C double bond
  2. Reduction again, formation of saturated carbon chain (reducatase) using NADPH
  3. Elongation cycles, where another malonyl-CoA is condensed to the growing chain by the same reaction sequences as the first malonyl-CoA went through. 2 NADPH are oxidized per full circle.
  4. The last step is hydrolysis to form palmitate
25
Q

How many NADPH are oxidized in fatty acid synthesis?

A

2

26
Q

What are the steps of fatty acid synthesis? (10)

A
  1. The tricarboxylate system transfers acetyl CoA into cytosol from the mitochondrial matrix by converting it to citrate first
  2. Acetyl-CoA carboxylase carboxylates acetyl-CoA to malonyl-CoA
  3. Acetyl-CoA and malonyl-CoA are transferred to acyl carrier protein (ACP) on fatty acid synthase
  4. The acetyl group is transferred form ACP to ketoacyl synthase
  5. Ketoacyl synthase catalyzes condensation and decarboxylation of acetyl and malonyl group
  6. Reductase reduces ketogroup to hydroxygroup using a NADPH
  7. Dehydratase forms a C=C double bond
  8. Reductase uses another NADPH to form a saturated carbon chain
  9. Another malonyl-CoA is condensed to the growing chain, this happens again and again in elongation cycles until the chain is long enough (causing chain to grow by two carbons, using NADPH with the addition of every C2)
  10. Hydrolysis forms palmitate

In summary, fatty acids are synthesized by consecutive addition of C2 units from malonyl-CoA to the growing chain

27
Q

Addition of C2 from malonyl-CoA to a growing fatty acid chain (in fatty acid synthesis) needs what four steps? (in order) Where are the C2 units added?

A
  1. Condensation
  2. Reduction
  3. Dehydration
  4. Reduction

The C2 units are added between the growing chain and the ACP (acyl carrier protein)

28
Q

What are two NADPH generating pathways?

A
  • Pentose phosphate pathway

- Tricarboxylate transport system (malic enzyme)

29
Q

How many NADPH are made per 1 acetyl-CoA transported into the cytosol (via tricarboxylate transport system)

A

1

30
Q

What type of fatty acid does fatty acid synthase make?

A

It only makes a fatty acid that is saturated and no longer than 16 carbon

31
Q

What enzyme makes fatty acids that are longer than C16? Where does this synthesis take place?

A

Fatty acids longer than C16 are made by elongase in the ER or mitochondria.

32
Q

How does elongase make fatty acids? (what two things are required)

A

Addition of C2 units to fatty acyl chains using acetyl-CoA or malonyl-CoA.

It is a four step reaction requiring 1 NADPH and 1 NADH

33
Q

What enzyme catalyzes the synthesis of unsaturated fatty acids?

A

Desaturases

34
Q

How does desaturase make unsaturated fatty acids?

A

Introduces double bonds. Eg. Δ4-desaturase makes a double bond 4 carbons away from COOH

35
Q

What types of desaturases do animals only have? (4)

A

Δ4, Δ5, Δ6, Δ9 desaturases, there is no insertion of double bonds beyond C9 (counting begins at the carbonyl carbon as C1)

36
Q

How is a double bond ‘moved’ down a fatty acid chain during unsaturated fatty acid synthesis?

A

Elongation occurs at the side of the carboxygroup, desaturation coupled with elongation moves the double bond down the chain.

A chain is made (eg. C16:0), elongase adds two more carbons (C18:0) while desaturase desaturates at a location (eg. C18:1Δ^9)

37
Q

Why cant animals synthesize linoleic acid but plants can? (Both can do palmitoleic acid and longer saturated fatty acid)

A

Because in the pathway from acetyl-CoA to palmitic acid with fatty acid synthase (C16:0) to stearic acid with elongase (C18:0) to oleic acid with Δ9-desaturase (C18:1 n-9)

and THEN Δ12-desaturase to linoleic acid, animals only have Δ4, Δ5, Δ6, Δ9 desaturases and so can’t convert oleic acid to linoleic acid (no enzyme to dehydrate the double bond).

Because animals can’t synthesize linoleic fatty acid, it is en essential fatty acid

38
Q

What are longer omega-6 and omega-3 fatty acids made from? Why is it conditionally essential?

A

α-linoleic acid, it is conditionally essential because humans can make omega 6 fatty acids (arachidonic acid) using Δ6-desaturase, but we can’t make omega 3 fatty acids because we don’t have Δ15-desaturase to make EPA and DHA (omega-3s)

39
Q

What are four ways to regulate fatty acid synthesis?

A
  1. Tricarboxylate system (export of acetyl CoA into cytosol) is controlled by ATP levels (high ATP stimulates as it promotes the ATP citrate-lyase reaction needed to cleave citrate from acetyl-CoA and oxaloacetate in the cytoplasm)
  2. Citrate activates acetyl-CoA carboxylase (ACC), palmitoyl inhibits it.
  3. Phosphorylation inhibits Acetyl-CoA carboxylase
  4. Phosphorylation of ACC is regulated by energy levels (AMP-activated kinase) and by hormonal status (glucagon and epinephrine activate protein Kinase A, which will phosphorylate ACC to inhibit it)
40
Q

What are three ways to regulated fatty acid oxidation?

A
  1. Availability of fatty acids: plasma fatty acids, hydrolysis of triacylglycerol
  2. Control by activity of carnitine palmitoyl transferase and import of fatty acdis into mitochondria
  3. Malonyl-CoA inhibits carnitine palmitoyl transferase so that when synthesis is active, fatty acids are not imported into mitochondria.
41
Q

Insulin causes fat to?

A

Insulin stimulates synthesis of fatty acids

In reciprocal regulation with glucagon

42
Q

Glucagon stimulates…?

A

Lipolysis, breakdown of fat for energy. In reciprocal regulation with insulin.

43
Q

GLucagon and epinephrine do what with fatty acid metabolism? How?

A

Promotes lipolysis and inhibits fatty acid synthesis

  1. cAMP dependent activation of protein Kinase A and phosphorylation activation of hormone sensitive lipase
  2. cAMP dependent activation of protein kinase A contributes to inhibition acetyl-CoA carboxylase through phosphorylation (FA synthesis inhibited)
44
Q

Insulin does what with fatty acid metabolism? How?

A

Promotes fatty acid synthesis

  1. Upregulation of lipoprotein lipase (uptake of TG fatty acids into adipose tissue)
  2. Insulin-dependent dephosphorylation of acetyl-CoA carboxylase (increases FA synthesis)
  3. Insulin stimulates synthesis of acetyl-CoA carboxylase and fatty acid synthase (long term regulation)
45
Q

How does insulin achieve long term regulation of fatty acid synthesis (promotes it)?

A

By stimulating synthesis of acetyl-CoA carboxylase and fatty acid synthase

46
Q

What is AMP kinase and what is it responsible for?

A

It is an enzyme under hormonal regulation. It is activated by AMP and regulates many metabolic pathways:

  • Glucose uptake (+)
  • Glycolysis (+)
  • Fatty acid transport (+)
  • Fatty acid oxidation (+)
  • Cholesterol synthesis (-)
  • Gluconeogenesis (-)
  • Glycogen synthesis (-)
  • Lipolysis (-)
  • Lipogenesis (-)
  • Fatty acid synthesis (-)

Dont really need to know above, just be familiar and know that AMP kinase, when activated, acts to mostly stimulate energy production and inhibit energy storage. It knows when to do this because AMP signals the amount of energy available (high AMP means that ATP needs to be made, and therefore AMP kinase is activated)

47
Q

What is cholesterol synthesized from? What is required?

A

Synthesized from acetyl-CoA
- NADPH and ATP are required

Because cholesterol is in our diet and produced by our bodies, enogenous synthesis is balanced

48
Q

HMG-CoA reductase is the target of what type of drug?

A

Cholesterol lower drugs (called statins) inhibit HMG-CoA reductase so that it cannot convert HMG-CoA into mevalonate (second step of cholesterol synthesis)

49
Q

What is the main regulatory point of cholesterol synthesis?

A

The conversion of HMG-CoA (derived from acetyl-CoA) to mevalonate, using HMG-CoA reductase

50
Q

What two things control cholesterol biosynthesis?

A

According to cellular cholesterol levels gene transcription and energy available (AMP-Kinase)

51
Q

List the intermediates andmain regulatory enzyme of cholesterol synthesis

A 
Acetyl-CoA
HMG-Coa
 - HMG-CoA reductase (main regulatory point enzyme)
Mevalonate
Farnesyl pyrophosphate
Squalene
Cholesterol
52
Q

What three things can cholesterol be made into?

A

Bile acids and salts
Steroids
Membrane components

53
Q

When is cholesterol synthesis downregulated? Why?

A

When cellular energy is low, this is because cholesterol synthesis requires a lot of ATP and NADPH, also AMP activates AMP-kinase which converts HMG-CoA reductase into HMGR-phospho (inactive)

Also, glucagon signal activates protein kinase A, which phosphorylates and activates an inhibitor of phosphoprotein phosphatase (PPI), which prevents dephosphorylation and activation of HMGR (HMG-CoA reductase)

54
Q

What organelle senses cellular cholesterol levels and regulates cholesterol synthesis and uptake? How?

A

The Endoplasmic reticulum (ER).

  • In a nutshell, low levels of cellular cholesterol increase cholesterol uptake (LDL receptor) and cholesterol synthesis (HMG-CoA reductase)
  • For more detail look at the mess of info below

Low levels of cellular cholesterol increase cholesterol uptake (LDL receptor) and cholesterol synthesis (HMG-CoA reductase)

LDL receptor and HMG-CoA reductase have a sterol response element in their promoter, so transcription is activated when the transcription factor SRE-binding protein (SREBP) translocates into the nucleus and binds to the promotor.

SREBP is usually retained in the ER, and is only cleaved to the active form when cholesterol levels in the ER become too low.

High levels of cholesterol lead the cell to produce less LDL receptor and less HMG-CoA reductase, which causes uptake and synthesis of cholesterol to decrease.

Intro to Biochemistry (28 decks)

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