Lecture 15: Lipid Metabolism

lipids are the most efficient way to….

store energy

How oxidized are carbohydrates

partially

Fatty acids contain long chains of highly _____ carbon

reduced

Water requirements-fatty acids are _____ and ____ in aqueous solutions

hydrophobic;aggregate

carbohydrates are_____ and require ______ ____

hydrophilic;more water

Sources of lipids-exogenous

outside self

sources of lipids-endogenous

come from self

pancreatic lipase

enzyme that cleaves fatty acid chain from head group

Fatty acid transport in aqueous medium-fatty acid chains are solubility in the ____ (location in body) with _____ (property) _____ _____ (thing they are solubized with)

gut;amphipathic bile salts

Fatty acid transport in aqueous medium-fatty acid chains are solubized in the _____ (location) by the protein ________

blood;albumin

lipids are transported in different vesicles called

lipoproteins

Lipoproteins contain ____ (____ and ____) and specific proteins that determine their destination

lipids;triglycerides;cholesterol

chlymoicrons

transport dietary (exogenous) lipids from the intestines to the rest of the body, appearing in the blood only after a meal

VLDL (very low density lipoprotein)

produced by the liver export endogenous triglycerides (merely synthesized fat) to peripheral tissues during the fed state)

LDL (Low Density Lipoprotein)

leftover core of VLDL after triglycerides are removed; deliver cholesterol to peripheral cells

HDL (High density lipoprotein)

reverse cholesterol transport,picking up excess cholesterol from tissues and bringing it back to the liver for excretion in bile

hydrolysis of glycerolipids by _____ releases fatty acids for catabolism

lipase

Glycerol is converted into ___ to feed into glycolysis

DHAP

_____ ____ ____ ____ (____ ____ ___C) freely diffuse into the mitochondrial matrix

short chain fatty acids (less than 12C)

_____ ____ ____ ____ (____ ____ ___C) require a mitochondrial shuttle

long chain fatty acids (more than 14C)

All fatty acids need to be ____

activated

What does activation do?

Destabilizes the hydrocarbon chain for breakdown

2 steps of activation

adenylation,formation of the thioester on CoA

Activation is highly

exergonic

Activation consumes

2 ATP equivalents

short chain FA are activiated directly in the ____

matrix

long chain FA are activated in the _____

cytoplasm

cytoplasmic pool can be used for ____ or _____

synthesis;catabolism

Long fatty acids need to be shuttled into the _____ for oxidation

matrix

Carnitine shuttle

long fatty acids cytosol -> matrix

Carnitine shuttle- what is located on the cytosol side?

Carnitine acyltransferase I

Carnitine shuttle- what is located on the matrix side?

Carnitine acyltransferase II and transporter

Compartmentalization-maintain separate pools of CoA and fatty acyl-CoA-cytoplasmic pool is for _____

synthesis

Compartmentalization-maintain separate pools of CoA and fatty acyl-CoA-matrix pool is for _____

oxidation

Fatty acids are broken down via

beta oxidation

stage 1

beta oxidation of the acyl chain -> acetyl-CoA

___ carbons removed as ____-____ each round

2;acetyl-CoA

beta oxidation continues until the call chain is completely ____ ____

broken down

The products of stage 1 feed into ____ __(___ ___ ___) and ____ ___ (______ ______)

stage 2 (citric acid cycle);stage 3 (oxidative phosphorylation)

Beta oxidation is an ____ process

aerobic

4 repeating steps of beta oxidation

dehydrogenation (oxidation), hydration of the double bond, second oxidation, cleavage to form a new thioester

Electron Transfer Flavoprotein (ETF)

shuttles electrons into the Ubiquinone pool

FADH2 is ____-bound

protein

Beta oxidation generates

metabolic energy

Beta oxidation is a major source of ____ ___ for many mammals

metabolic water

1 mol of _____ or _____ generates 1 mol of water

NADH;FADH2

complete oxidation of palmitoyl-COA produces how many ATP

106 ATP

Palmitoyl-CoA energy yield

106/16=6.625 ATP/C

complete oxidation of glucose produces how many ATP

30 to 32 ATP

glucose energy yield

30/6 to 32/6=5 to 5.333 ATP/C

beta oxidation requires

trans-enoyl CoA

saturated fatty acids are

cis (may not align between alpha and beta carbons)

___-___ ___ ____ are catabolized by conversion to trans-enoyl CoA for beta elimination (isomerization)

fatty-acyl double bonds

Last beta oxidation step yields a ___ carbon compound

3

3 carbon product _____-____ is converted to ____-____ and fed into _____ as an ____ reaction

propionyl-CoA; succinyl-CoA;TCA;anaplerotic

the citric acid cycle is balanced;it is carbon ____

neutral (2 C enter ac-CoA and 2C leave 2 x CO2)

GNG requires the removal of

oxaloacetate (4C)

Problem with fueling the body during fasting

cannot use fat to make new glucose because you oxidize the carbons as you process them

When the citric acid cycle stalls,excess Ac-CoA is used to build an alternative fuel called

ketone bodies

ketogenesis

synthesizing ketone bodies in the liver

the liver lacks enzymes to break down

ketone bodies

But in plants,bacteria,and invertebrates,the _____ ____ allows the conversion of Ac-CoA to glucose

glyoxylate cycle

Seeds store massive amounts of energy in lipids,which they convert to glucose for cell wall synthesis during ____ ___

early growth

synthesis of fatty acid chains takes place in the

cytoplasm

elongation,TAG,and phospholipid synthesis occur in the

smooth ER

___ ATP molecules are consumed per Acetyl-CoA transported

2

Half of the _____ required for FA synthesis comes from the oxidation of malate (other half from pentose phosphate pathway)

NADPH

Malonyl-CoA (C3)

the major carbon source for FA biosynthesis

Malonyl-CoA is formed by what enzyme

acetyl-CoA carboxylase

formation of malonyl-CoA is the ____ step in FA biosynthesis

committed (regulation)

fatty acid synthesis is carried out by _____ ____ ____

fatty acid synthase

In Eukaryotes,fatty acid synthase has ___ active sides on ___ polypeptide/s

7;1

Substrate is ___ bonded to the enzyme and essentially _____ between ____ ____

covalently;swings;active sites

To begin fatty acid synthesis,synthase is loaded with

acetyl-CoA and malonyl-CoA

Fatty acids are synthesized in what four steps?

Condensation, reduction, dehydration, and reduction

FA synthase is first charged with

acetyl-CoA

malonyl-CoA is the source of all other

Cs

_ ___ are added and _ ___ is lost with each cycle

2 Cs;1 CO2

Palmitate synthesis requires a total of ___ cycles

7

_____ ____ of fatty acid synthesis and catabolism

reciprocal regulation

fatty acid synthesis activators

insulin triggers dephosphorylation, citrate

fatty acid synthesis inhibitors

glucagon, epinephrine, palmitoyl-CoA, carnitine actyl transferase I

Palmate can be used to build other ____ ____ and ___ in the cell

fatty acids and lipids (used directly,chain lengthening,desaturation (C=C))

Phosphatidic acid

precursor for triaclygerols and glycerophospholipids

Cholesterol synthesis steps

1.synthesis of melavonate (C6) from acetate (3 C2) 2.Activated isoprene (C5) production 3.Condensation of activated isoprene units 4.Cyclization of squalene

High NADPH costs to produce

mevalonate

High ____ cost to produce mevalonate

NADPH

__ ATP to produce activated isoprene

3

Isoprene acts as a

universal lipid precursor (vitamin A,E,K)

____-___ _____ catalyzes the commitment step in cholesterol biosynthesis

HMG-CoA reductase

Mitochondrial HMG-CoA

ketones (starvation)

cytosolic HMG-CoA

cholesterol (fed state)

input

activated isoprene

output

squalene

____ catalyzes the cascade that closes all 4 rings in a single step

Cyclades

Regulation of cholesterol metabolism-activators

insulin intracellular cholesterol

regulation of cholesterol metabolism-inhibitors

glucagon, low ATP, oxysterol (stimulates proteolysis of HMG-CoA reductase)