Cholesterol Synthesis

Question 1

HMG-CoA Synthase

Answer 1

AcetoAcetyl CoA + Acetyl CoA +H2O-> 3-Hydroxy-3-methylglutary CoA
-lose CoA of Acetyl CoA

HMG
-used to synthesize cholesterol and ketone bodies

Two Isozymes of HMG CoA Synthase:

• Cytoplasm- to synthesize Cholesterol
• Mitochondria-To synthesize Ketone Bodies

Question 2

HMG-CoA Reductase

Answer 2

Committed Step in Cholesterol Synthesis

Integral membrane protein of ER

• catalytic domain projects into cytoplasm
• reactions occur in cytoplasm

HMG-CoA-> Mevalonate (6C)
-Coenzyme: NADPH oxidized to NADP+

Question 3

Mevalonate-> IPP

Answer 3

Mevalonate-> 3-isopentenyl pyrophosphate
3. Kinase-5-Phosphate-mevalonate
4. Kinase- 5-Pyrophosphate-mevalonate
5. Kinase-OH phosphorylated
decarboxylase-releasing CO2 and forming double bond to for 3-isopentenyl pyrophosphate (IPP)

*6 MOLECULES OF IPP ARE USED TO SYNTHESIZE CHOLESTEROL

Question 4

IPP-> DPP

Answer 4

IPP-> 3,3-Dimethylallylpyrophosphate (DPP)

Isomerase

Question 5

Geranyl Transferase

Answer 5

7th step:
Catalyzes a series of transferase reactions using 5C substrates
C5-> C10/ Geranyl-> C15->Farnesyl

DPP+ IPP->GPP- Geranyl (10C)
GPP + IPP-> FPP-farnesyl (15C)

Question 6

Squalene Synthase

Answer 6

8th step

FPP + FPP-> Squalene(30C)

• two FPP molecules connect tail to tail
• NADPH oxidized to NADP+

Question 7

Squalene Monooxygenase

Answer 7

9th Step
Squalene->Squalene Epoxide
-requires molecular oxygen: O2-H2O
-coenzyme: NADPH oxidized to NADP+

Question 8

Oxidosqualene cyclase

Answer 8

10th step
Squalene Epoxide->Lanosterol

complex multistep reaction leading to ring closure
-enzyme holds molecule in appropriate orientation for ring closure

Question 9

SLOS

Answer 9

Smith-Lemli-Optiz syndrome
Due to deficiency of
-7-dehydrocholesterol-7-reductase
-enzyme involved in migration of the double bond

Question 10

Sources of Cholesterol

Answer 10

Diet

De novo synthesis

Question 11

Regulation of Cholesterol Synthesis

Answer 11

Tightly regulated by:

Primary control point:
3-hydroxy-3-methylglutary CoA reductase

Methods/Levels of Regulation:

• Transcription of HMG-CoA reductase mRNA
• Translation of HMG-CoA reductase protein
• Degradation of HMG-CoA reductase
• Phosphorylation of HMG-CoA reductase

Question 12

Orientation of Hydroxyl and Double bond in Cholesterol?

Answer 12

Hydroxyl Orientation:
3 Beta-hydroxyl is below the plane of steroid nucleus
3-alpha-hydroxyl is above the plain of steroid nucleus

Double bond Orientation:
Cis:
-C5 hydrogen is beta
-Found in bile salts
-buckled structure

Trans:

• C5 hydrogen is alpha
• found in steroid hormones
• Planar structure