Cholesterol

Question 1

Cholesterol

Answer 1

Synth in all tissues
Free = membranes; Esters = storagae
Indestructible core

Question 2

Synth

Answer 2

Starts with Acetyl CoA. sequence of around 30 steps = cytosolic and some on ER. Acetly CoA to cytosol via citrate and resynth with ATP dependent Citrate Lyase (Allosteric, Phosphorylation, hormonal)

Question 3

Synth Step 1

Answer 3

3 Acetyl CoA to 6C Mevalonic Acid

Rxns = Thiolase, HMG CoA synthase, HMG CoA reductase (ER bound and sole allosteric reg based on Pi, hormones, transC and degrade)

3 CoASH released, 2 NADPH consumed

Question 4

Synth Step 2

Answer 4

Mavalonate to 5C Isoprene Brick

1. Mevalonate to isopentenyl pyrophosphate (3 phosphorylations and 1 decarboxylation)
2. Isopent Pyro to dimethylallyl PP (bricks)

Question 5

Synth Step 3

Answer 5

Squalene created by 6 isoprene units via exergonic hydrolysis of PPi activating group

3-5C isoprenes combine to 15C farnesyl-PP, 2 15C to squalene (driven by hydrolysis). Uses NAPH and O2

Question 6

Synth Step 4

Answer 6

Squalene cyclized to Lenosterol to Cholesterol

Via squalene monooxygenase (Cyt p450 and NADPH)

Question 7

Cost of synth

Answer 7

216 ATP total

Question 8

Reg of Chol synth

Answer 8

Requires high ATP and active HMP and HMG-CoA reductase

Question 9

TransC control of HMG-CoA reductase

Answer 9

Chol bound by SCAP blocking transC. When chol low, SREBP (SCAP) translocates to nucleus binding at locus and transC begins and enzyme numbers increase

If Chol increases, binds to SCAP and transC inhibited

Question 10

Degradation regulation of HMG CoA Reductase

Answer 10

HMG CoA reductase is anchored in ER membrane and degraded by ubiq. Activated by sterol binding, ubiq binds lysine and enables extraction from memb (with ATPase)and delivered to proteosome. Requires non sterol isoprenoid.

Question 11

HMG-CoA reductase covalent control

Answer 11

Inact: high chol/high glucagon - induced AMPK to HMG-CoA-P = inhib

Act: low chol/high insulin - induced phosphatase - HMG-CoA activated

Question 12

Drug control of HMG-CoA reductase

Answer 12

Statins = competitive inhib of reductase

Question 13

Fate of cholesterol

Answer 13

Becomes chol esters, biliary, bile

Question 14

Chol Ester formation

Answer 14

Via ACAT (hepatic). Acyl CoA chol acyl transferase. FA to OH at C3. Ester= H-phobic so efferent storage, packed in lipoprotein cores and trans to needy cells.

Question 15

Bile Salt synth

Answer 15

Hepatic synth by regulator 7-alpha-hydroxylase (CytP450, NADPH, Vit C needed)

Induced by high chol, inhib by high bile (interlocked with HMG-CoA red reg)

Draw Path

Question 16

Bile Salt conjugation

Answer 16

Bile saltes conjugated with Glycine and Taurine (-SO3 from meth/cysteine) to enhance emulsification. glycine:Tauro - 3:1

Requires ATP, CoASH activated choline causes decrease of pKa from 6.0 so more powerful

Question 17

Bile salt reabs

Answer 17

In ileum for recycle (bact deconjugates amide)

Question 18

Gall stones

Answer 18

Chol precipitation leading to cholestasis leading to jaundice.

Four Fs: Fat, FM, fertile, forty

Question 19

Other fates of Isoprenoids

Answer 19

Ubiquinone = ETC, Dolichol = N-linked oligosacc of glycoprots, Heme A, Farnesyl - memb protein anchors

Question 20

Vitamin D

Answer 20

Chol precursor, UV opens ring 13 on 7-alpha-dehydrochol

Regulates Ca and P metabolism in body