BBMB 405 1nd Edition Lecture 21 Mar 4 Outline of Last Lecture XVIII Chapter 26 The Biosynthesis of Membrane Lipids and Steriods A Phosphatidate is common intermediate in synthesis of phospholipids and triacylglycerols Outline of Current Lecture XVIII Chapter 26 The Biosynthesis of Membrane Lipids and Steriods B Cholesterol is synthesized from acetyl coenzyme A in three stages C The complex regulation of cholesterol biosynthesis takes place at several levels Current Lecture XVIII Chapter 26 The Biosynthesis of Membrane Lipids and Steriods B Cholesterol is synthesized from acetyl coenzyme A in three stages 1 The synthesis of mevalonate which is activated as isopentenyl pyrophosphate initiates the synthesis of cholesterol a Synthesis of mevalonate from acetoacetyl CoA and Acetyl CoA is committed step of cholesterol formation b HMG CoA reductase is enzyme that catalyzes this step is an intergral membrane protein in endoplasmic reticulum c 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 pyrophosphate b c 3 Squalene cyclizes to form cholesterol a Squalene cyclizes to intermediate lanosterol via oxidosqualene cyclase b c Lanosterol is converted to cholesterol in a lot of steps that we don t need to know i Steps involve NADPH which is why the pentose phosphate pathway is so important ii One intermediate 7 dihydrocholesterol in skin when irradiated create vitamin D iii Multistep process involves Remove 3 methyl groups Reduce double bond in tail Movement of double bond C The complex regulation of cholesterol biosynthesis takes place at several levels 1 Cholesterol Synthesis regulations a Mammals can either consume or synthesis cholesterol feedback regulation is mediated primarily by changes in amount and activity of HMG CoA reductase b 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 SCAP senses cholesterol and activates SREBP if low cholesterol levels or release of SREBP is blocked is high levels of cholesterol c 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 mevalonate 2 Lipoproteins transport cholesterol and triacylglycerols throughout organism Lipoprotein B100 is protein that binds to LDL receptor and internalizes it LDL is major carrier of cholesterol 3 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 disease 4 Low density lipoproteins play central role in cholesterol metabolism a Apolipoprotein B100 binds LDL receptor b Complex is endocytosed c After fusion with lysosome LDL is degraded d Unesterified cholesterol used by membranes or stored as CE e f LDL receptors important in maintaining LDL levels in blood cholesterol can be stored in blood 5 The absence of LDL receptor leads to hypercholesterolemia and atherosclerosis 6 Mutations in LDL receptor prevent LDL release and result in receptor destruction a Result more cholesterol in blood b Acidic environment removes LDL and receptor goes back to membrane and is recycled c When mutation occurs recycling doesn t occur and receptor gets degraded which leads to hypercholesterolemia
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