Hyperlipidemia II Flashcards
Cholesterol is synthesized from what precursor structure?
What is the basic structure of cholesterol?
Synthesized by acetyl-CoA; derived from carbohydrate, fat or amino acids
Steriod nucleus with 4 rings
3 6-membered, 1 5-membered
What are the 4 major functions of cholesterol?
- component of cell membranes
- backbone of steroid
- bulidnig blok of bile acids & bile salts
- used to synthesize vitamin D
What are the 4 main stages of cholesterol synthesis?
What is the rate limiting step?
- acetyl CoAx3
- Rate limiting step by HMC-CoA Reductase (also NADPH -> NADP+)
- mevalonate
- isopentenyl pyrophosphate x6
- squalene
- cholesterol
Describe the regulation of HMG CoA Reductase transcription
- Transcription of HMG CoA Reductase is regulated by Steriod Response Element Binding Protein (SREBP)
- when it is available to bind to the promoter: Steroid Response Element (SRE), it promotes transcription
- STEBP is sitting in the endoplasmic reticulum plasma membrane attached to its DNA-binding domain, preventing it from entering the nucleus
- Protein SCAP (also in endoplasmic reticulum membrane) is responsible for cutting free the DNA-binding domain of SREBP
- SCAP binds to cholesterol & other related sterols
- when cholesterol is high, it undergoes a change and is not active as a protease & will not activate the SREBP, so you don’t make as much of the rate limiting enzyme in cholesterol synthesis
- SREBP is only activated when cholesterol is low, SCAP changes conformation & cuts free the DNA-bindign domain, which then goes to the nucleus and binds to SRE to promote transcription of HMG CoA Reductase
Describe the metabolic regulation of HMG CoA Reductase
Regulated by metabolic state
- HMG-CoA Reductase is sitting in the ER membrane
- if lots of cholesterol, it will get degraded
- When AMP is high (energy is low), AMP-activated protein kinase kinase will phosphorlyate AMP-activated protein kinase into its active forme (with use of one ATP)
- also activated by glucagon & sterols
- Active AMP-activated protein kinase will convert HMG-CoA reductase to its inactive form (preventing synthesis of cholesterl)
- When cholesterol is low, a phosphatase (activated by insulin) removes a phosphate from the inactive HMG-CoA reductase converting it back to its active form
Describe the production of Isoprenes from mevalonate
- Mevalonate
- add Phosphate (ATP)
- add Phosphate (ATP)
- 5-pyrophosphate mevalonate
- add Phosphate (ATP)
- 3-phospho-5-yrophosphate mevalonate
- CO2 and a phosphate are removed by a enzyme
- one of 2 active isoprenes (delta-3 and dimethylallyl)
- also used to make coenzyme Q and dolichol
Why might someone on statins take a Coenzyme Q10 supplement?
because in addition to preventing the production of cholesterol, statins also inhibit the production of coenzyme Q (isoprene progenitor)
Coenzyme Q is importan in the electron transport chain
inhibition of production coenzyme Q could be the reason people sometimes have muscle symptoms from taking statins
Describe the production of squalene from isoprenes
What is the importance of the structure of squalene?
Where else is squalene found?
- two isoprenes (either) are used to produce geranyl pyrophosphate
- a third isoprene is used to produce farnesyl pyrophosphate
- then two farnesyl pyrophosphates combine (& get rid of both phosphates) to form a squalene
- squalene = 30 carbons, large enough to become cholesterol (27 cabrbons)
Squalene is also found in sebum & is part of the problem of acne
Describe the production of cholesterol from squalene
- Squalene is acted on by squalene monooxygenase (converts O2 to H2O and NADPH to NADP+) to produce an epoxide ring, Squalene 2,3-epoxide
- Through 2 steps of cyclase, squalene 2,3-epoxide is onverted to lanosterol, which through many additional reactions produces cholesterol
- Cholesterol: 1 OH, 4 rings, 27 carbons
