BIOLCHEM 415 1st Edition Lecture 25Outline of Last Lecture I. Fatty acid synthesis follows a different pathway then fatty acid oxidationII. This committed step is conversion of acetyl CoA to malonyl CoAIII. Synthesis occurs in the cytosolIV. Elongation and desaturation occur in the endoplasmic reticulumOutline of Current Lecture V. Phospholipids, sphingolipids, and cholesterol are the three major classes of lipidsVI. Cholesterol synthesis occurs mostly in the liverVII. HMG-CoA is highly regulatedCurrent LectureMembrane lipids- 3 classes- based on structural distinctions (backbones)1 – Phospholipids (glycerol backbone)2 – Sphingolipids/glycolipids (sphingosine backbone)3 – cholesterolPhospholipids- glycerol backbone- fatty acids- one phosphate group- alcohol groupsGlycerophospholipids- phosphatidateThese 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.- intermediary of fat synthesis- can either continue to fatty acids or phospholipids- activated intermediate- CDP-diacylglycerol- energy comes from CTP- reacts with hydroxyl group of an alcoholSynthesis via activated alcohol- phosphoryl-alcohol formed with ATP- phosphoryl-alcohol activated by CTP (CDP-alcohol)- reacts with diacylglycerolPhospholipids and disease- respiratory distress syndrome- can cause death in newborns- failure of the synthesis of dipalmitoylphosphatidylcholine- usually this lubricates the lungs- when not lubricated there is too much pressure on the lungsSphingolipids- sphingosine backbone- fatty acid, phosphodiester, alcohol- gangliosides- sugar unit instead of the phosphodiester and alcohol- backbone derived from palmitoyl CoA and serine- Ceramide- either (1) sphingomyelin or (2) cerebroside1 – component of myelin sheath- without nerves would be compromised2 – attachment of sugar- sugar activated by UTP- results in gangliosidesGangliosides- can have up to seven sugar residues- can contain aminosugars or 9C sugars- molecules of recognitionTay-Sachs Disease- inability to degrade gangliosides- N-acetyl galactosamine builds up- 4 sugarganglioside- defect in the enzyme hexosaminidase- normally this cleaves a sugar from the galactosamine- neurons swell with lipid-filled lysosomes- carriers are common (especially Ashkenazy(European) Jews)- recessive gene- first genetic disease elucidatedCholesterol- all 27 C atoms of cholesterol are derived from acetyl CoA- synthesis occurs in liver (some in the small intestine)- eukaryotic lipid- regulates membrane fluiditySynthesis of Cholesterol1 – acetyl CoA mevalonatevia HMG-CoA (Fatty Acids for synthesis)- pathway to ketone bodiesHMG-CoA reductaseCommitted step (highly regulated)NADPH NADP+2 – isopentenyl pyrophosphate activated isoprene unitmevalonateisopentenyl pyrophosphateactivated isoprene (5C unit)3 – 6 molecules of isopentenyl pyrophosphate condensed into squalinesqualine C30reactive double bond4 – squaline cyclized and converted to cholesterol squaline cyclizes to lanosterollanosterol cholesterol in 19 stepsRegulation of body cholesterol- cholesterol intake- cholesterol synthesis- regulated at the HMG-CoA reductase step~ 800 mg/day produced from liverRegulation of HMG-CoA reductase- DNA mRNA protein degradation- cholesterol regulates these- low cholesterol levels stimulate transcription- high levels of metabolites inhibit translation- energy state- off at low energy levelsTransport/deposition of fat/cholesterol- lipoprotein transport- target specific tissuesChylomicrons - dietary fat/cholesterol into intestine and broken down by bile salts- packaged on to chylomicrons- transport to adipose/peripheral tissuesEndogenous cholesterol and lipids- lipoprotein carriers- starts in liver- low density lipoproteins (LDL) transport to peripheral tissuesLDL transport- tissues has specific LDL receptors- LDL internalized by endocytosis- LDL releases cholesterol- can either exit cell or be digested by lysosomeRegulation of cholesterol synthesis and deposition- high serum levels of cholesterol- LDL oxidized and taken in by macrophages form Foam Cells- Foam cells get trapped in artery walls (atherosclerotic plaques)- plaque causes arteries to narrow leading to heart attacksHigh density lipoproteins (HDL) (“good cholesterol”)- carries cholesterol from periphery tissues to the liver- further synthesisTreatment of high cholesterol- statins- competitive inhibitors (HMG-CoA reductase)Steroid hormones derived from cholesterol- cholesterol scaffold- five classes- progestagens- prepare uterus for ovum during pregnancy- glucocorticoids- cortisol- stimulates gluconeogenesis- inhibits inflammation- mineralocorticoids- mineral absorption- keeps ion levels balanced- sex hormones- androgens (C19 ketal groups)- estrogen (C18 hyrdoxyl groups)Hydroxylation reactions (add –OH group)- catalyzed by mono-oxygenases- cholesterol steroid- cytochrome p450 mono-oxygenase- detoxifyxenobiotics (foreign substances)- drug metabolism - varies from person to person based on structure of mono-oxygenaseNatural steroids- stimulate gene expression involved in muscle developmentSynthetic anabolic steroids- receptor agonists- doping agents- excessive use = testicular atrophy (men), facial hair (women)Vitamin D synthesis- bond splitting activity of
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