Chapter 4 metabolism of tag 2015819

• Fatty acid are synthesized and degraded by different pathways– from acetyl CoA – in the cytosol – intermediates are attached to the acyl carrier protein ACP – the activated donor is ma

• Fatty acid are synthesized and degraded by different pathways

– from acetyl CoA

– in the cytosol

– intermediates are attached to the acyl carrier

protein (ACP)

– the activated donor is malonyl–ACP

– reduction uses NADPH + H+

– stops at C16 (palmitic acid)

Fatty Acid Biosynthesis

Acetyl coenzyme A is a source of an acetyl

group toward biological nucleo philes (it is an

acetyl transfer agent)

Formation of malonyl–CoA is the committed

step in fatty acid synthesis

Formation of Malonyl Coenzyme A

• The intermediates(acetyl-ACP and malonyl-ACP) in fatty acid synthesis are covalently linked to the acyl carrier protein (ACP)

Formation of Acetyl ACP and Malonyl ACP

– To start an elongation cycle, Acetyl–CoA and

Malonyl–CoA are each transferred to an acyl carrier protein

O

||

CH3—C—S—ACP ( Acetyl-ACP)

O ||

-O—C—CH2—C—S—ACP ( Malonyl-ACP )

Condensation and Reduction

In reactions 1 and 2 of fatty

• Reduction converts a ketone

to an alcohol using NADPH

(reaction 2)

Dehydration and Reduction

• Reduction converts the

double bond to a single

bond using NADPH

(Reaction 4)

Lipogenesis Cycle Repeats

Fatty acid synthesis continues:

• Malonyl-ACP combines with

the four-carbon

butyryl-ACP to form a

six-carbon-ACP.

• The carbon chain lengthens

by two carbons each cycle

Lipogenesis Cycle Completed

• Fatty acid synthesis

• Endoplasmic reticulum systems introduce double

bonds into long chain acyl–CoA's

– Reaction combines both NADH and the acyl–

CoA's to reduce O2 to H2O

Elongation and Unsaturation

• convert palmitoyl–CoA to other fatty acids

– Reactions occur on the cytosolic face of the

endoplasmic reticulum

– Malonyl–CoA is the donor in elongation reactions

Summary of Fatty Acid Biosynthesis

The synthesis of TAG

(for dietary fat digestion and absorption)

pancreatic lipase

FA

pancreatic lipase

CH 2 OCOR

TAG

CH 2 OH CHOCOR

CH2OH

MAG

CH2OCOR CHOCOR

CH2OCOR

TAG

2 Di acyl glycerol pathway (DAG pathway) (for TAG synthesis of in adipose tissue, liver and kidney)

CH2O-PO3H2CO

CH2OH

dihydroxyacetone phosphate

liver adipose tissue NADH+H

+ NAD+

phosphoglycerol dehydrogenase CH2O-PO3H2

RCO¡« SCoA

HSCoA

CH2O-PO3H2CHOH

CH2OCOR

lysophosphatidate

acyl CoA transferase

acyl CoA transferase

RCO¡« SCoA

HSCoA

phosphatidate

CH2O-PO3H2CHOCOR

CH2OCOR

H2O

Pi

CH2OH CHOCOR

CH2OCOR

diacylglycerol

RCO¡«SCoA HSCoA

acyl CoA transferase

glucose

CH2OH CHOH

Catabolism of TAG

In normal metabolic pathway, acetoacetate and

b-hydroxybutyrate are the ketone bodies which are converted to acetyl - CoA However, during starvation

and in uncontrolled diabetes, conc of acetoactate is very high and supply of oxaloacetate (a TCA component) is insufficient, thus acetoacetate spontaneously decarboxylated to acetone - KETOSIS

 A 4-carbon acid (oxaloacetate) is needed to react with excess

acetyl-CoA and form citrate

 When OAA is not available, excess acetyl - CoA in liver are condensed to form ketone bodies

 OAA is limited during scarcity of glucose for glycolysis In starvation and diabetes, glycogen is broken down Fatty acids of fat depots are metabolized to supply ATP needs producing excess of the ketone bodies

Ketone Bodies

Most of the acetyl-CoA product during fatty acid oxidation is utilized

by the citric acid cycle or in isoprenoid synthesis In a process called ketogenesis, acetyl–CoA molecules are used to synthesize

acetoacetate, b-hydroxy butyrate and acetone , a group of molecules called the ketone bodies

Ketone body formation occurs within mitochondria

Ketone bodies are used to generate energy by several Tissues, e.g., cardiac and skeletal muscle and brain

Ketone Body Formation

b-Hydroxybutyrate

b-Hydroxybutyrate dehydrogenase

NAD +

NADH

Citric Acid Cycle

Oxidation of ketone bodies

in brain, muscle, kidney, and intestine

Succinyl CoA synthetase = loss of GTP

Conversion of Ketone Bodies to Acetyl-CoA

The significance

of ketogenesis and ketogenolysis

• Ketone bodies are water soluble , they are convenient to

transport in blood, and readily taken up by non-hepatic tissues

In the early stages of fasting, the use of ketone bodies by heart, skeletal muscle conserves glucose for support of central nervous system With more prolonged starvation, brain can take up more ketone bodies to spare glucose consumption

• High concentration of ketone bodies can induce ketonemia and ketonuria, and even ketosis and acidosis

When carbohydrate catabolism is blocked by a disease of diabetes mellitus or defect of sugar source, the blood

concentration of ketone bodies may increase,the patient may suffer from ketosis and acidosis

Lipolysis – Diagrammatic View

b Oxidation and Fatty Acid Synthesis

Fatty Acid Formation

• Shorter fatty acids undergo fewer cycles

• Longer fatty acids are produced from palmitate using special enzymes

• Unsaturated cis bonds are incorporated into a carbon fatty acid that is elongated further

10-• When blood glucose is high, insulin stimulates

glycolysis and pyruvate oxidation to obtain acetyl CoA to form fatty acids

• The stoichiometry of palmitate synthesis:

– Synythesis of palmitate from Malonyl–CoA

– Synthesis of Malonyl–CoA from Acetyl–CoA

– Overall synthesis

Stoichiometry of FA synthesis

• The malate dehydrogenase and NADP+–linked malate enzyme reactions of the citrate shuttle exchange

NADH for NADPH

Sources of NADPH

Metabolism of phospho lipids

Biosynthesis of glycerophospholipids

1 DAG shunt is the major pathway for biosynthesis of phosphatidyl choline (lecithin) and phosphatidyl ethanolamine (cephalin)

HO-CH2-CH-COOH

NH2serine

CO2HO-CH2-CH2-NH2ethanolamine 3(S-adenosylmethionine) HO-CH2-CH2-N(CH+ 3)3

choline

ATP ADP

ADP

kinase

P -O-CH 2 -CH2-NH2phosphoethanolamine P -O-CH2-CH2+-N(CH3)3

phosphocholine CTP

H2C

O C R1O

H O

CMP

serine

Phosphatidic acid

2 CDP-DAG shunt is the

major pathway for the

synthesis of phosphatidyl

serine , phosphatidyl

inositol and cardiolipin

- in this pathway, DAG is

activated as the form of

OO

-CH2CH

Degradation of glycerophospholipids

H2C C

H2C

O C R1O

H O

C

O

R2

O P O O

X

_

_

H 2 C C

H2C

O C R 1

O H O

C

O

R2

OH diglyceride

phospholipase C

XOH

H2C C

H2C

O C R1O H O C

O

R2

O P OH O

O_phosphatidic acid

phospholipase D glycerophospholipid

OH C

O

R1

phospholipase A1

H2C C

H2C

OH H O C

O

R2

O P O O O

H2C

OH H HO

O P O O O

X

_

phospholipase A2

OH C

O P O O O

X

_

lysophospholipid 1

OH C

O

R1

phospholipase B1

(glycerophophocholine)

Metabolism of sphingolipids

x = monosaccharide cerebroside

x = sulfated galactose ( = cerebroside sulfate) sulfatide

x = oligosaccharide + sialic acid ganglioside

note: sialic acid = N-acetylneuraminic acid

Sphingolipids are a class of lipids containing sphingosine instead of glycerol

The structure of phosphosphingolipids

The structure of glycosphosphingolipids

P

fatty acidR

phosphate choline sphingosine

H3C ( C H2)1 2 C H C H C H C H C H2 O

O H N H

C O

O O

sugar

Metabolism of cholesterol

HO 2 C-CH 2 -C-CH 2 COSCoA

OH

CH 3

glutaryl CoA ( HMG CoA )

-Hydroxy-beta-methyl-HMG CoA Synthase

CoASH NADP + NADPH

+ H + Key control step Liver is primary site of cholesterol biosynthesis

Isoprenoid Condensation

H

OPOP OPOP

Head

Tail Head

Tail

Isopentenyl Pyrophosphate (IPP)

OPOP

Farnesyl Pyrophosphate (FPP)

Head to tail condensation

of IPP and GPP

Tail to tail condensation

3 Conversion of Squalene to Cholesterol

Lipoproteins biosynthesis

Cholesterol Ester Synthesis

HO

Cholesterol

COOH

COO COO OPOO N

+

Cholesterol Ester

COO

COO COO OPOO N

+

Lysolecithin Lecithin-Cholesterol Acyl Transferase (LCAT) Acyl-Cholesterol Acyl Transferase (ACAT)

Metabolism of TAG (triacylglycerol)

1 Biosynthesis of TAG

2 Catabolism of TAG

- Fatty acid beta oxidation

3 Lipogenesis: Fatty Acid Synthesis