lipid metabolism

Lipid Metabolism

BIOL 430 Dr. Mauricio Bustos

http://www.umbc.edu/

http://www.umbc.edu/biosci/Faculty/bustos.html

Lipid Biosynthesis and Degradation




Steps in fatty acid oxidation

1. Activation (cytosol)

FA + ATP + CoA acyl-CoA + AMP + PPi 2 Pi

2. Transport across the mitochondrial membrane: long chain FAs cannot cross the mit membrane. The process requires a transporter

3. -oxidation

Acyl-CoA Synthetase Pyrophosphorylase


Carnitine



Matrix

Acyl dehydrogenases and a tri-functional EH/HAD/KT work together to perform:

1. Oxidize C to a ketone group (-ketoacyl-CoA)

2. Claisen ester cleavage with addition of one molecule of CoASH

3. Production of acyl-CoA that is 2C shorter, and one molecule of acetyl-CoA




Fatty acid biosynthesis: translocation of acetyl-CoA

1. Transport of mitochondrial acetyl-CoA to the cytosol

• Citrate synthase

Oxaloacetate + acetyl-CoA = citrate

• Citrate transported

• ATP-citrate lyase

Citrate + ATP + CoA = acetyl-CoA + ADP + Pi + oxaloacetate




2. Acetyl-CoA carboxylase catalyzes the synthesis of malonyl-CoA. This is the first committed step of FA biosynthesis

3. ACC has both catalytic and regulatory roles.

Acetyl-CoA carboxylase and FA synthase




4. FA synthase is a multifunctional enzyme5. Malonyl-CoA is first transferred to Malonyl-ACP by the enzyme MAT

Acetyl-CoA carboxylase and FA synthase

Synthase (KS)

Reductase (KR)

Dehydrase (DH)

Reductase (ER)





Acyl carrier protein (ACP) contains a prosthetic group derived from pantothenic acid (vitamin) same as CoASH



Acetoacetate and -hydroxybutyrate are produced in the liver and consumed in peripheral tissues: heart, skeletal muscles, and brain (during starvation)

Ketone bodies: water soluble products from fats



Synthesis of triacylglycerols

1. Acyl-CoA and glycerol-3-P (or DHAP) are esterified by glycerol-3-P acyltransferase (or DHAP acyltransferase) yielding lysophosphatidic acid

2. The resulting lysophosphatidic acid is then converted to triacylglycerol by successive addition of two more acyl groups

Lysophosphatidic acid (1 acyl chain+ phosphate)

Phosphatidic acid (2 acyl chains+phosphate)

Diacylglycerol (2 acyl chains, no phosphate)

Triacylglycerol (3 acyl chains, no phosphate)

+ acyl-CoA

+ acyl-CoA

- phosphate


Synthesis of membrane diacylglycerophospholipids

1. Head group (ethanolamine or choline) is phosphorylated by a KINASE

2. CDP-activated phosphate esters of the head groups are made by cytidyltranferases from CTP and phosphoethanolamine (choline)

3. Activated CDP-ethanolamine(choline) react with the C3OH group of the triacylglycerol precursor 1,2-diacylglycerol. The CMP group is displaced.

4. Products: Phosphatidylethanolamine or phosphatidylcholine (lecithin)

5. Phosphatidylserine is made by a head group exchange between serine and phosphatidylethanolamine

6. In the synthesis of phosphatidylinositol and phosphatidylglycerol, the hydrophobic tail rather than the head group is CDP activated. The corresponding precursor is CDP-diacylglycerol


Steps of cholesterol biosynthesis

1. Acetyl-CoA is first converted to hydroxymethylglutaryl-CoA (HMG-CoA)

2. HMG-CoA reductase (rate limiting and key regulatory enzyme) converts HMG-CoA into mevalonate

3. A series of reactions takes mevalonate into isopentenyl-pyrophosphate

4. Six isopentenyl-pyrophosphate molecules are condensed to form the C30, non-cyclic, cholesterol precursor squalene

5. Squalene is cyclized to form cholesterol

6. Cholesterol is either converted into bile acids (liver), or esterified with acyl-CoA by acyl-CoA:cholesterol acyltransferase (ACAT) to form cholesteryl ester (highly hydrophobic compounds)

7. Cholesteryl esters are packaged with lipoproteins into VLDLs and transported throughout the body



Cholesterol is removed from the blood stream by LDL-receptor mediated endocytosis

lipid metabolism

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