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Chapter 16 (Part 4). Synthesis of Eicosanoids, Glycerolipids and Isoprenoids. Glycerolipid Biosynthesis. Important for the synthesis of membrane lipids and triacylglycerol Synthesis occurs primarily in ER Phosphatidic acid (PA) is the precursor for all other glycerolipids in eukaryotes

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chapter 16 part 4

Chapter 16 (Part 4)

Synthesis of Eicosanoids, Glycerolipids and Isoprenoids

glycerolipid biosynthesis
Glycerolipid Biosynthesis
  • Important for the synthesis of membrane lipids and triacylglycerol
  • Synthesis occurs primarily in ER
  • Phosphatidic acid (PA) is the precursor for all other glycerolipids in eukaryotes
  • PA is made either into diacylglycerol (DAG) or CDP-DAG
slide3

Glycerolipid Biosynthesis

  • Phosphatidic acid is the precursor for all other glycerolipids
eicosanoids
Eicosanoids
  • Eicosanoids are important regulatory molecules
  • Referred to as local regulators. Function where they are produced.
  • Two classes: Prostaglandins/thromboxanes, and Leukotrienes
  • Prostaglandins – mediate pains sensitivity, inflammation and swelling
  • Thromboxanes – involved in blood clotting, constriction of arteries
  • Leukotrienes – attract white cells, involved inflammatory diseases (asthma, arthritis, etc..)
eicosanoid synthesis
Eicosanoid Synthesis
  • C20 unsaturated fatty acids (i.e. arachidonic acid (20:4D5,8,11,14) are precursors
  • Prostaglandins and Thromboxanes are synthesized by a cyclooxygenase pathway
  • Leukotirenes are synthesized by a lipoxygenase pathway

cyclooxygenase

slide9
Arachidonic acid present in membrane lipids are released for eicosanoid synthesis in the cell interior by phospholipase A2
cyclooxygenase cox inhibitors
Cyclooxygenase (COX) Inhibitors
  • Two COX isozymes: COX-1 and COX-2.
  • COX-1 – important in regulating mucin secretion in stomach
  • COX-2 – promotes pain and inflammation and fever (involved in prostaglandin synthesis).
  • Asprin (acetylsalicylate) non-specific COX inhibitor. Acts by acetylating an essential serine residue in the active site.
  • Because asprin inhibits COX-1, causes stomach upset and other side effects.
  • New drugs (Vioxx and Celebrex) specifically inhibit COX-2
isoprenoid synthesis
Isoprenoid Synthesis
  • Involves formation of isopentenyl pyrophosphate (IPP) monmers.
  • IPP is conjugated in a head to tail manner to generate polyprenyl compounds.
slide13

Formation of the isopentenyl pyrophosphate (IPP) via mevalonate pathway.

  • Primary pathway for isprenoid synthesis in animals and cytosolic isoprenoid synthesis in plants
slide14

Phosphomevalonate

kinase

pyrohosphomevalonate

decarboxylase

Mevalonate

kinase

Formation of the isopentenyl pyrophosphate (IPP)

bacteria and plants synthesize ipp via non mevalonate pathway
Bacteria and Plants Synthesize IPP via Non-Mevalonate Pathway
  • In plants and most bacteria, IPP is synthesized from the condensation of glyceraldehyde-3-phosphate (3 carbons) and pyruvate (3 carbons).
  • Forms a 5 carbon intermediate through transketolase type reaction (transfer of 2 carbon aldehyde from pyruvate to G-3-P).
  • Occurs in chloroplast of plants. Involved in synthesis of chlorophyll, carotenoids, Vitamins A, E and K.
slide17

Very recent discovery (1996)

Pathway still not fully understood.

New pathway provides enzyme targets for new herbicidal and anti-microbial compounds

condensation of ipp into polyprenyl compounds
Condensation of IPP into Polyprenyl Compounds

IPP

isomerase

Dimethylallyl

pryophosphate

slide19

IPP Isomerase

prenyltransferase

prenyltransferase

Squalene synthase

Cholesterol Synthesis from IPP

slide20

Squalene

monooxygenase

2,3-oxidosqualene

lanosterol cyclase

20 steps

cholesterol

slide21

Regulation of HMG-CoA Reductase

  • As rate-limiting step, it is the principal site of regulation in cholesterol synthesis
  • 1) Phosphorylation by cAMP-dependent kinases inactivates the reductase
  • 2) Degradation of HMG-CoA reductase - half-life is 3 hrs and depends on cholesterol level
  • 3) Gene expression (mRNA production) is controlled by cholesterol levels
slide22

Inhibiting Cholesterol Synthesis

  • HMG-CoA reductase is the key - the rate-limiting step in cholesterol biosynthesis
  • Lovastatin (mevinolin) blocks HMG-CoA reductase and prevents synthesis of cholesterol
  • Lovastatin is an (inactive) lactone
  • In the body, the lactone is hydrolyzed to mevinolinic acid, a competitive (TSA!) inhibitor of the reductase, Ki = 0.6 nM!