chapter 9 key concepts

how do fatty acids enter mitochondria

• how are the following involved:

  • CoA-SH

  • carnitine

  • carnitine-palmitoyl transferases I & II

  • carnitine carrier proteins

• small FAs (<12 C) can diffuse through the membrane

• larger FAs → transported via carnitine transporter

  • CoA-SH carries the acyl group in the cytosol and the matrix

  • carnitine carries the acyl group through the carrier protein

  • carnitine-palmitoyl transferase I transfers the acyl group from CoA-SH to carnitine in the cytosol

  • carnitine-palmitoyl transferase II transfers the acyl group from carnitine to CoA-SH in the matrix

  • carnitine carrier proteins facilitate acyl-carnitine transport through the inner mitochondrial membrane

steps of beta-oxidation for saturated fatty acids with an even number of carbons

• enzymes and cofactors

• products made

1. oxidation

   1. acyl-CoA dehydrogenase

   2. consumes 1 FAD

   3. makes trans-∆2-enoyl-CoA

2. hydration

   1. enoyl-CoA hydratase

   2. makes 3-L-hydroxyacyl-CoA

3. oxidation

   1. 3-L-hydroxyacyl-CoA dehydrogenase

   2. consumes 1 NAD+

   3. makes beta-ketoacyl-CoA

4. thiolysis

   1. beta-ketoacyl-CoA thiolase

   2. makes fatty acyl-CoA that undergoes further beta-oxidation

   3. uses CoA-SH to make acetyl-CoA for the citric acid cycle or ketone body biosynthesis

what are the products of saturated fatty acids with an odd number of carbons

• propionyl-CoA (3C) that can be converted to succinyl-CoA (4C)

what are some important biological functions of lipids

• phospholipids → membranes

• cholesterol → membrane fluidity

• steroid hormones → development, reproduction, mineral balance

• triacylglycerols → in adipose tissue, insulate/cushion vital organs

• eicosanoids → signalling molecules

where in cells does lipid synthesis occur

the cytosol

what is required for lipid synthesis

• sources of carbon, electrons, and energy

• reducing equivalent NADPH

  • energy source

  • electron source

• malonyl-ACP

  • carbons source

  • thioester bonds → energy source

lipid synthesis vs. lipid catabolism

• synthesis

  • requires acetyl-CoA and malonyl-CoA

  • requires reducing power (NADPH)

  • takes place in the cytosol in animals, chloroplast in plants

• catabolism

  • produces acetyl-CoA

  • produces reducing power (NADH)

  • occurs in the mitochondrial matrix

how is malonyl-CoA made and what is the source of the three malonyl carbons

carbon sources

• CO2 (1C)

• acetyl-CoA (2C)

where does malonyl-CoA synthesis occur

smooth ER

describe how malonyl-CoA is involved in the regulation of fatty acid metabolism

• why is it better for regulating FA synthesis than acetyl-CoA

• malonyl-CoA inhibits FA import into the mitochondria

  • inhibits CPT1

• better for regulating FA synthesis than acetyl-CoA since it is not used for other pathways but acetyl-CoA is

what is the function of fatty acid synthase

synthesize fatty acids → palmitate (16:0)

how is palmitate (16:0) synthesized in mammalian cells

• roles of:

  • acetyl-CoA carboxylase (ACC)

  • fatty acid synthase (FAS)

  • acyl carrier protein (ACP)

• summarize reactions

  • where do they occur

1. acetyl-CoA is transferred to the ACP domain of FAS

2. acetyl-ACP transfers the acetyl group to the KS domain of FAS

3. malonyl-CoA is transferred to the ACP domain of FAS

   1. ACC synthesizes malonyl-CoA in the smooth ER and releases it into the cytosol

4. condensation of malonyl- and acetyl-ACP by NADPH/H+ in the KS domain of FAS

5. beta-keto group is reduced to a beta-hydroxyl group by the KR domain of FAS

6. dehydration of the alcohol to an alpha-beta double bond

7. reduction of the double bond by NADPH/H+ in the KR domain of FAS

8. repeat 3-7 six times to generate palmitoyl-ACP

9. palmitoyl-ACP is cleaved by thioesterase to release palmitate and ACP

why are only 7 malonyl-CoA required for palmitate synthesis

the other two carbons needed to form palmitate come from acetyl-CoA

describe/diagram how acetyl-CoA from mitochondria is moved to the cytosol for FA synthesis, include:

• intermediates

• enzymes

• return of intermediates to the mitochondrial matrix

relate the cellular location of FA synthesis with pathways that serve as sources of NADPH

• FA synthesis occurs in the cytosol

  • consumes NADPH

• pathways that generate NADPH in the cytosol provide it for FA synthesis

describe how FA synthesis in cytosol can be reciprocally regulated by malonyl-CoA

malonyl-CoA is needed to proceed through the first step of FA synthesis since it is the 2C donor

describe how citrate and palmitoyl-CoA act as regulators

• how is acetyl-CoA carboxylase activity affected by glucagon and epinephrine

• citrate activates acetyl-CoA carboxylase

  • signals that excess energy must be converted to fat

• palmitoyl-CoA inhibits acetyl-CoA carboxylase through feedback inhibition

• glucagon and epinephrine stimulates PKA which phosphorylates acetyl-CoA carboxylase, making it less active

what are two modifications to palmitate that can form additional kinds of fatty acids

• elongation

• desaturation

in what cellular compartment are fatty acids elongated

endoplasmic reticulum

describe the activity of fatty acid desaturases

• oxidative desaturation

• directly removes two e- and associated H from stereoyl-CoA (18:0) to create oleyl-CoA (18:1∆9)

briefly describe the overall pathway in the liver leading from acetyl-CoA to the ketone bodies:

• acetone

• acetoacetate

• D-beta-hydroxybutyrate

• acetone = breakdown product formed by the spontaneous decarboxylation of acetoacetate

what is one serious physiological consequence of the overproduction of ketone bodies

ketoacidosis

how are steroids made from cholesterol, is it the same pathway as FA synthesis

• overall pathway

1. oxidative cleavage of the cholesterol side chain

2. oxidation of the hydroxyl group → progesterone

3. most other reactions of steroid hormone biosynthesis happen in the ER during cleavage

why are HMG-CoA reductase and mevalonate important in cholesterol synthesis

• HMG-CoA reductase catalyzes the irreversible reduction of HMG-CoA to mevalonate

  • committed step in cholesterol synthesis

  • key regulation point

• mevalonate levels regulate HMG-CoA reductase

  • inhibits active HMG-CoA reductase through negative feedback

  • directly inhibits cholesterol synthesis

describe one example of how an eicosanoid signalling molecule can be synthesized from a membrane phospholipid

• overal pathway

  • role of phospholipase A2

• phospholipase A2 destroys cell membranes to liberate arachidonic acid from phospholipids

• arachidonic acid can be converted to various eicosanoids

which class of enzyme converts arachidonic acid to prostaglandins (with cyclic structure)

cyclooxygenases (COX)

which class of enzyme converts arachidonic acid to leukotrienes

5-lipoxygenase (5-LO)