Cholesterol synthesis Flashcards
Function
structural component of cell membrane
precursor for bile acids, steroid hormones, vitamin D
component of plasma lipoproteins
Location
liver
intestines
adrenal cortex
reproductive organs
- Acetyl CoA + Acetyl CoA -> Acetoacetyl CoA
- CoASH
- enzyme: THIOLASE
- in cytosol
- Acetoacetyl CoA + Acetyl CoA -> HMG CoA
- CoASH
- enzyme: HMG CoA SYNTHASE
- in cytosol
- HMG-CoA -> Mevalonate
- reduction 2NADPH-> 2NADP+
- CoASH
- enzyme: HMG-CoA REDUCTASE
- COMMITTED STEP, RATE LIMITING
- in ER
Regulation of HMG CoA reductase
inhibited by: high cholesterol phosphorylation AMP glucagon glucocorticoids statins (comp. inhibitor) bile salts
Activated by: low cholesterol dephosphorylation ATP insulin thyroxine
4.Mevalonate -> 5-phosphomevalonate
- ATP->ADP
- enzyme: MEVALONATE KINASE
- 5-phosphomevalonate -> 5-pyrophosphomevalonate
- ATP->ADP
- enzyme: PHOSPHOMEVALONATE KINASE
- 5-pyrophosphomevalonate -> 3-phospho-5-pyrophosphomevalonate
ATP->ADP
-enzyme: MEVALONATE 5 PYROPHOSPHATE DECARBOXYLASE
- 3-phospho-5-pyrophosphomevalonate -> Isopentenyl pyrophosphate
- CO2
- enzyme: MEVALONATE 5 PYROPHOSPHATE DECARBOXYLASE
- IPP -> Dimethylallyl pyrophosphate
- reversible
- enzyme: IPP ISOMERASE
- IPP + DPP -> Geranyl pyrophosphate
- ppi
- enzyme: PRENYL TRANSFERASE
10.GPP + IPP -> Farnesyl pyrophosphate
- ppi
- enzyme: PRENYL TRANSFERASE
- FPP + FPP -> Squalene
- ppi
NADPH->NADP+
-enzyme: SQUALENE SYNTHASE
- Squalene -> Squalene Epoxide
+O2
-H2O
NADPH-> NADP+
-enzyme: SQUALENE MONOOXYGENASE
- Squalene Epoxide -> Prosterol Cation
+ H+
-enzyme: LANOSTEROL SYNTHASE
- Prosterol Cation -> Lanosterol
enzyme: LANOSTEROL SYNTHASE
- Lanosterol -> Cholesterol
- formic acid
- 2 CO2
19 steps
Long term control
1.Transcription level: control rate at which HMG CoA reductase mRNA is made
2. Translational level
dietary cholesterol inhibits
3. Proteolytic level
ACAT
acyl coA cholesterol acyltransferase
ACAT1: macrophages
ACAT2: intestines, liver
cholesterol -> cholesterol ester
NPC1L1
Riemann Pick C1 Like 1
in GI epithelial cells + hepatocytes
absorbes cholesterol
inhibition: ezetimibe
HSL
hormone sensitive lipase
cholesterol ester -> cholesterol
TAG -> free fatty acids
ABCA1
ATP-binding cassette transporter (CERP)
regulator of efflux of cellular cholesterol + phospholipid homeostasis
transports to apoA1 + apoE
LXR
liver X receptor ligand: oxysterol effects: CYP7A1, ABCA1,IDOL increase in bile synthesis, cholesterol efflux decrease in LDL repectors
