脂类代谢 Lipid Metabolism

contents Introduction of Lipids catabolism of Fats biosynthesis of lipids

I. Introduction of Lipids Water insoluble compounds Major functions Energy storage fatty acids, triacylglycerols Structural elements phospholipids, cholesterol

1. Fatty acids Basic formula: CH3(CH2)nCOOH Carboxylic acids with hydrocarbon chains of 4-36 carbons FAs in cells are either: (i) part of a lipid molecule (ii) complex with a carrier protein (e.g. albumin on blood) Saturated or unsaturated

Unsaturated fatty acids

Fully saturated fatty acid pack into nearly crystalline arrays, stabilized by hydrophobic interaction The presence of cis double bonds interferes with the tight packing and results in less stable aggregates

Some Naturally Occurring Fatty acids #C Common Name 12:0 Lauric Acid 14:0 Myristic Acid 16:0 Palmitic Acid (软脂酸) 16:1 Palmitoleic Acid 18:0 Stearic Acid (硬脂酸) 18:1 Oleic Acid (油酸) 18:2 Linoleic Acid (亚油酸) 18:3 Linolenic Acid (亚麻酸) 20:0 Arachidic Acid 20:4 Arachidonic acid (花生四烯酸) 24:0 Ligoceric Acid Essential Fatty acids

2. Triacylglycerol Compose of three fatty acids each in eater linkage with a single glycerol Most naturally occurring triacylglycerol contain two or more different fatty acids

Fatty acid composition in TAG Plant: more unsaturated fatty acids Animal: largely saturated fatty acids

functions:store fuels and provide energy Yield more energy than protein and carbohydrate Fat 9 kcal/g CHO/protein 4 kcal/g

3. Phospholipids Classes of phospholipids (PL) Glycerolphospholipids – glycerol backbone Sphingomyelin – spingosine backbone

Glycerolphospholipids Structure Two fatty acids are attached in ester linkage to the first and second carbon of glycerol A highly polar or charged group is attached by a phosphodiester linkage to the third carbon 12

properties Amphipathic 13

Sphingomyelin 鞘氨醇磷酯 structure Sphingosine

4. Cholesterol structure properties Amphipathic A non-polar body A polar head properties Amphipathic

functions Membrane constituents to modulate membrane fluidity Precursor of steroid hormones and bile acids

II. catabolism of Fats Digestionof fats mobilization and transport of fats Oxidation of Fatty acid Ketone Bodies

1. Digestion of fats Fatty acids have three sources Diet Storage in cells as lipid droplet Cellular biosynthesis

Processing of dietary lipids

2. Fats mobilization and transport the levels of glucose will affect the mobilization of fats Low levels of glucose in blood trigger the mobilization of triacyglycerols . Controlled by hormones: Insulin epinephrine and glucagon

Fatty acids are relased and transported through binding with serum albumin

Glycerol is converted to glyceraldehyde-3-P and enters glycolysis or gluconeogenesis Glycerol contributes only 5% of the biologically available energy of triacylglycerols

3. Oxidation of fatty acids Saturated fatty acids CH3-(CH2)n-CH2-CH2-COOH Major pathway: -oxidation Minor pathway: -oxidation -oxidation

Stages of fatty acid oxidation Oxidative phosphorylation

Mitochondria membrane -oxidation Transport Dehydrogen Hydration Activation Acetyl-CoA Dehydrogen Acetyl-transfer Mitochondria membrane Mitochondria matrix -oxidation

(A) Activation: conversion of fatty acid to fatty acyl-CoA

(B) Transport: via the acyl-carnitine/carnitine transporter

(C) -oxidation : four major steps 脱氢 加水 再脱氢 硫解

-oxidation : four major steps

Question : Complete Oxidation of a Palmitate

4. Ketone bodies Include acetoacetate, D-β-hydroxybutyrate, and acetone Acetyl-CoA in liver can be converted to keton bodies for exporting to other tissues in conditions of starvation and uncontrolled diabetes.

Formation of Ketone bodies (乙酰乙酸) (丙酮) (β-羟丁酸)

use of Ketone bodies β-Hydroxybutyrate synthesized in the liver passes into the blood and thus to other tissues, and it is converted to acetyl-CoA and then used for energy production

Ketone body formation and export from the liver

III. Lipid Biosynthesis Biosynthesis of fatty acids Biosynthesis of other lipids Triacyloglycerols Membrane phopholipids Cholesterol

+ H+ + H+

1. Biosynthesis of fatty acids Fatty acid synthesis is not simply a reversal of the degradation pathway. Fatty acid synthesis and degradation pathways again exemplify the principle that synthetic and degradation pathways are almost always distinct.

Preparation step one: transfer of acetyl groups from mitochondria to cytosol 柠檬酸

Malonyl-CoA is formed from carboxylation of acetyl-CoA Preparation step two: Malonyl-CoA is formed from carboxylation of acetyl-CoA Acetyl-CoA carboxylase has three functional regions: biotin carrier protein (gray); biotin carboxylase, which activates CO2 by attaching it to a nitrogen in the biotin ring in an ATP-dependent reaction transcarboxylase, which transfers activated COz from biotin to acetyl-CoA, producing malonyl-CoA.

The acetyl-CoA carboxylase reaction. The long, flexible biotin arm carries the activated CO2 from the biotin carboxylase region to the transcarboxylase active site

Loading step: transfer of acetyl-CoA and malonyl-CoA to form acetyl-ACP and malonly-ACP Malonyl-CoA-ACP transacylase Acetyl-CoA-ACP transacylase

Four major steps in fatty acids biosynthesis 1.缩合 3.脱水 2.加氢还原 4.加氢还原

Sequence of events during synthesis of a fatty acid Acetyl-CoA- ACP transacetylase Translocation of butyryl group to Cys on KS Malonyl-CoA -ACP transacylase -Ketoacyl-ACP synthase Enoyl-ACP reductase -Ketoacyl-ACP reductase -Dedroxyacyl-ACP dehydratase

Question:how to synthesize a palmitate ? Seven cycles of condensation and reduction : 1Acetyl-CoA + 7 malonyl-CoA + 14NADPH + 14H+ palmitate + 7CO2 + 14 NADP+ + 8CoA + 6H2O 2. Formation of seven malonyl-CoA molecules: 7 Acetyl-CoA + 7CO2 + 7ATP 7 malonyl-CoA + 7ADP + 7Pi 3. Palmitate-ACP + H2O Palmitate + ACP + H2O Palmitoyl thioesterase The overall process: 8 Acetyl-CoA + 7ATP + 14NADPH + 14H+ palmitate + 14 NADP+ + 8CoA + 6H2O + 7ADP + 7Pi

2. Biosynthesis of fats

3. Biosynthesis of Phospholipids Two general strategies for forming the phosphodiester bond of glycerophospholipids

The biosynthesis of sphingolipids

4. Biosynthesis of cholesterol Summary of cholesterol biosynthesis,

The first stage Formation of mevalonate from acetyl-CoA.

The second stage Conversion of mevalonate into activated isoprene units.

The third stage Formation of squalene (30 carbons) by successive condensations of activated isoprene (five-carbon) units

The fourth stage Formation of squalene (30 carbons) by successive condensations of activated isoprene (five-carbon) units