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Cholesterol Synthesis Thomas Dayspring, MD, FACP Clinical Assistant Professor of Medicine University of Medicine and Dentistry of New Jersey, New Jersey Medical School Diplomate of the American Board of Clinical Lipidology Certified Menopause Practitioner: North American Menopause Society North Jersey Institute of Menopausal Lipidology Wayne, New Jersey St Joseph ’s Regional Medical Center Paterson, NJ Joseph’s 1964 Nobel Prize Physiology & Medicine Cholesterol Synthesis Pathway Konrad Bloch Feodor Lynen A sterol with 27 carbon molecules with an -OH group at the # 3 position Hydrocarbon tail 22 21 18 24 25 20 26 23 CH3 12 19 C27H45OH 1 CH3 2 OH 14 16 15 9 10 8 5 3 13 11 27 17 7 4 6 4 Hydrocarbon Rings 3 Hydroxy cholesterol Sterols are waxy insoluble substances or lipids synthesized from acetyl coenzyme A (CoA). They are steroid-based alcohols having a hydrocarbon (aliphatic) side chain of 8–10 carbons at the 17 position and a hydroxyl group (-OH) at the 3 position (making it an alcohol). Because of the hydrophilicity at the -OH end and hydrophobicity at the hydrocarbon side chain, sterols can be incorporated into the lipid bilayers of the cytoplasmic membrane. Four Stages of Cholesterol Biosynthesis 1 2 The liver is responsible for about 15% of cholesterol synthesis and the remainder is extrahepatic. 3 Cholesterol synthesis is a four-step process starting from its precursor acetate: CH3-COO− 4 Cholesterol Synthesis: Stage 1 Thiolase is an oxidant enzyme (removes electrons) In the first step, two molecules of acetyl-CoA upon the action of thiolase reversibly forms acetoacetyl-CoA Cholesterol Synthesis: Stage 1 Acetyl-CoA condenses with acetoacetyl-Co upon the action of cytosolic hydroxymethylglutaryl (HMG) synthase and becomes HMG-CoA. Cholesterol Synthesis: Stage 1 HMG-CoA β-hydroxy-β-methylglutaryl-CoA The catalytic action (rate-limiting state) of HMG-CoA reductase, an integral part of the smooth endoplasmic reticulum, irreversibly forms mevalonate (a fivecarbon intermediate) with NADPH serving as the reductant. HMG-CoA reductase transcription is tightly regulated by a membrane-bound transcription factor designated as sterol regulatory element-binding protein-2 (SREBP-2) Different from mitochondrial HMG-CoA which plays a role in ketosis Cholesterol Synthesis: Stage 2 5 Carbon units 5 Carbon units In the second step, mevalonate is phosphorylated from ATP to isoprene units or isoprenoids, namely isopentyl pyrophosphate, which can isomerize or interconvert to dimethylallyl pyrophosphate Cholesterol Synthesis: Stage 3 + 10 carbon intermediate Isoprenoids react with each other to form geranyl pyrophosphate. + Condensation with another isopentyl-PP yields farnesyl pyrophosphate. 15 carbon intermediate + Squalene synthase catalyzes the condensation of two molecules of farnesyl-PP with reduction by NADPH to make squalene. 30 carbon intermediate Squalene Cholesterol Synthesis: Stage 4 A series of reactions oxidation, cyclization, and loss of three methyl groups results in conversion of squalene to cholesterol. The fourth step involves conversion of the linear squalene molecule to the four-ringed steroid nucleus. Lathosterol 27carbon molecule Cholesterol Cholesterol Synthesis Acetate Acetoacetyl-CoA HMG synthase Dimethylallyl-PP HMGCoA HMG CoA reductase Mevalonate isomerization Isopentyl-pyrophosphate condensation Farnesyl-pyrophosphate Squalene Squalene synthase Cholesterol Lanosterol 4 ringed structure Isoprenoids 19-20 reactions including Desmosterol, Lathosterol Dayspring T in Chap 14 Davidson, Toth, Maki Therapeutic Lipidology 2008 Natural Products Derived from Activated Isoprene Units Isoprene units or Isoprenoids are a class of largely hydrophobic or nonpolar compounds related by being constructed biosynthetically from five-carbon units.
