BBMB 405 1nd Edition Lecture 21 Mar 4Outline of Last Lecture XVIII. Chapter 26: The Biosynthesis of Membrane Lipids and SteriodsA. Phosphatidate is common intermediate in synthesis of phospholipids and triacylglycerolsOutline of Current Lecture XVIII. Chapter 26: The Biosynthesis of Membrane Lipids and SteriodsB. Cholesterol is synthesized from acetyl coenzyme A in three stagesC. The complex regulation of cholesterol biosynthesis takes place at several levelsCurrent LectureXVIII. Chapter 26: The Biosynthesis of Membrane Lipids and SteriodsB. Cholesterol is synthesized from acetyl coenzyme A in three stages1. The synthesis of mevalonate, which is activated as isopentenyl pyrophosphate, initiates the synthesis of cholesterola. Synthesis of mevalonate from acetoacetyl CoA and Acetyl CoA is committed step of cholesterol formationb. HMG-CoA reductase is enzyme that catalyzes this step, is an intergral membrane protein in endoplasmic reticulumc. These notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.2. Squalene (C30) is synthesized from six molecules of isopentenyl pyrophosphate (C5)a. Synthesis of cholesterol starts with isomerization of isopentenyl pyrophosphate to dimethylallyl pyrophosphateb. c. 3. Squalene cyclizes to form cholesterola. Squalene cyclizes to intermediate lanosterol via oxidosqualene cyclaseb. c. Lanosterol is converted to cholesterol in a lot of steps that we don’t need to knowi. Steps involve NADPH which is why the pentose phosphate pathway is so importantii. One intermediate: 7 dihydrocholesterol in skin, when irradiated create vitamin Diii. Multistep process involves- Remove 3 methyl groups- Reduce double bond in tail- Movement of double bondC. The complex regulation of cholesterol biosynthesis takes place at several levels1. Cholesterol Synthesis regulationsa. Mammals can either consume or synthesis cholesterol, feedback regulation is mediated primarily by changes in amount and activity of HMG CoA reductaseb. Sterol regulatory element binding protein (SREBP) controls the rate of synthesis of reductase mRNA; SREBP binds to short DNA sequence sterol regulatory element (SRE) to enhance transcription when cholesterol levels are low; inactivated SREBP is associated with SREBP cleavage activating protein (SCAP) in endoplasmic reticulum membrane; SCAPsenses cholesterol and activates SREBP if low cholesterol levels or release of SREBP is blocked is high levels of cholesterolc. d. Specifically when cholesterol is low SCAP binds to protein that facilitates transport of SREBP to activate genes; when cholesterol is high, SCAP binds to cholesterol which causes structural change in SCAP so it binds to Insig (also increases degradation of HMG CoA reductase)e. Rate of translation of reductase mRNA is inhibited by nonsterol metabolites derived from mevalonate2. Lipoproteins transport cholesterol and triacylglycerols throughout organism: Lipoprotein B100 is protein that binds to LDL receptor and internalizes it; LDL is major carrier of cholesterol3. The blood levels of certain lipoproteins can serve diagnostic purposes: the ratio of HDL to LDL can be used to evaluate person’s susceptibility to heart disease4. Low-density lipoproteins play central role in cholesterol metabolisma. Apolipoprotein B100 binds LDL receptorb. Complex is endocytosedc. After fusion with lysosome, LDL is degradedd. Unesterified cholesterol used by membranes or stored as CEe. f. LDL receptors important in maintaining LDL levels in blood; cholesterol can be stored in blood5. The absence of LDL receptor leads to hypercholesterolemia and atherosclerosis6. Mutations in LDL receptor prevent LDL release and result in receptor destructiona. Result: more cholesterol in bloodb. Acidic environment removes LDL and receptor goes back to membrane and is recycledc. When mutation occurs recycling doesn’t occur and receptor gets degraded which leadsto
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