Block 3 Cholesterol Biosynthesis Flashcards

1
Q

Describe the structure of cholesterol.

A

27 C, 4 rings, 8C tail. Hydrophobic except OH at C3, used for esterification with FFA to form CE

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What are cholesterol esters?

A

Very hydrophobic, transported form of Ch (in LPs), stored intracellularly as lipid droplets, processed for excretion as bile acids

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What two enzymes are involved in CE formation? What enzyme hydrolyzes CE?

A

LCAT in plasma (LP formation) & ACAT in some cells (lipid droplets); CE hydrolase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are the stages of cholesterol biosynthesis? Where are the enzymes located?

A

Acetate -> isoprenoid intermediates -> squalene -> cyclization product -> cholesterol
Enzymes in cytosol & ER (rxns in cytosol)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What are the required reactants for 1 mole chol synth?

A

Source of 18 AcCoA (B-ox of FA in perox/mitos, dehydrog of pyr in mito, ox of ketogenic aa’s in cytosol), 16 NADPH, 36 ATP

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is the first stage of chol synth?

A

Acetate as AcCoA -> isoprenoid intermediate by 4 steps. AcCoA -> HMG-CoA -> mevalonate -> P-mevalonate -> 5-pyro-P-mevalonate -> isopentenyl pryo-P

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What enzymes are used in the first stage of chol synth?

A

HMG-CoA reductase + 2 NADPH; mevalonate P-transferase + ATP; P-mevalonate kinase + ATP; pyro-P-mevalonate DC + ATP

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is the fate of HMG-CoA in mito vs. cytosol?

A

In mito -> ketone bodies

In cytosol -> chol biosynth

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is the most highly regulated step of stage 1 of chol synth?

A

HMG-CoA reductase is rate-determining and most elaborately regulated

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is stage 2 of chol synth?

A

Dimethylallyl-PP (C5) isopentenyl-PP (C5) –> geranyl-PP (C10) -> farnesyl-PP (C15) -> squalene (C30, condensation of 6 isoprene units)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What are stages 3 and 4 of chol synth? Where are the enzymes located?

A

Squalene cyclization -> lanosterol -> 19 steps to -> cholesterol (requires ox and loss 3 methyl). *All rxns require NADPH and O2. Enzymes are in ER membrane.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is the role of isopentenyl-PP aside from chol synth?

A

Makes isopentenyl tRNA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is the role of farnesyl-PP aside from chol synth?

A

Farnesylated proteins (15C isoprene addition), dolichol, haem A, ubiquinones

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is the role of intermediates between lanosterol and 7-dehydrocholesterol & 7-DHC?

A

Int: meiosis activating sterols

7-DHC: vitamin D formation in skin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What is the role of cholesterol?

A

Bile acids, steroids, hedgehog proteins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

How is HMG-CoA reductase regulated short-term? Long-term?

A

Short: statins (competitive inhibition), allosteric effects (AMP, to conserve energy), covalent mod with reversible P (at Ser 871, P form less active)
Long: modulating synth or degradation rates

17
Q

What are the allosteric activators and inhibitors of HMG-CoA reductase?

A

Act: insulin
Inh: glucagon (fasted) or epi (stress) -> cAMP -> PKA

18
Q

What is SREBP?

A

Sterol regulatory element binding protein, binds region in HMG-CoA red gene promotor SRE

19
Q

How does SREBP exert its effects?

A

ER -> binds SCAP chaperone in ER -> Golgi -> 2 proteolysis (S1P, S2P proteases) -> nucleus

20
Q

How do cholesterol levels affect SREBP/SCAP?

A

Low chol: binds COP2 and goes to Golgi

High: interacts with Insig proteins, holds complex in ER by preventing intxn with COP2

21
Q

How is HMG-CoA Red regulated at post-transcriptional level?

A

Sterol-depleted cells: slow degradation (half life >12 hr)
Sterol-loaded: rapid degradation (h/l <1 hr), facilitated by Insig binding
*Lanosterol more potent than cholesterol

22
Q

Describe the circadian rhythm of chol synth.

A

Peaks 6 hrs after dark, high for 12 hrs after last meal, minimum 6 hr after light exposure. *ACTH, estrogen, other hormones involvement hypothesized

23
Q

What is Smith-Lemil-Opitz Syndrome (SLOS)?

A

Most common chol synth disorder, autosomal recessive; deficiency 7-DHC reductase; microcephaly, short nose, small/posterior chin, syndactyly, feeding difficulty, FTT, MR, behavior probs; severity assc. with plasma chol levels

24
Q

How is SLOS treated?

A

Chol may help, lovastatin (HMG-CoA inh) in KO mice (suggests acc toxic sterols > reduced chol)

25
Q

Why doesn’t chol supp to pregnant mothers prevent morphogenic and developmental abnormalities in SLOS?

A

Transport LDL via megalin limited to 1st trimester, chol not BBB permeable = requires local biosynthesis

26
Q

How does cholesterol modify hedgehog proteins?

A

Hh undergoes autocatalytic cleavage at Gly-Cys-Phe motif, C-terminal removed, chol added to C-terminal domain, then palmitoylated at N-terminal Cys. Chol tethers protein to PM (restricts tissue localization to trigger signaling pathway for txn activation for patterning & morphogenesis)