Lecture 15 (3-7): Lipid Biosynthesis (Ch. 24) Flashcards
Lipid Biosynthesis Overview
- large portion of the metabolic map
- of immense importance with a variety of compounds that include: fatty acids, sphingolipids, eicosanoids, cholesterol, steroids
Fatty Acid Pathways (differences between fatty acid breakdown and biosynthesis)
- The Biosynthesis and Degradation Pathways are different
- As seen with glycolysis/gluconeogenesis and with glycogen synthesis/breakdown - fatty acid synthesis and degradation go by different routes
- there are four major differences between fatty acid breakdown and biosynthesis
SH Intermediates:
- Oxidation: linked to CoA
- Synthesis: linked to acyl carrier pr.
Enzymes:
- Oxidation: separate enzymes
- Synthesis: part of one polypeptide
Energy Source:
- Oxidation: Uses NADH/NAD+
- Synthesis: Uses NADPH/NADP+
Location:
- Oxidation: mitochondria
- Synthesis: Cytosol
Product/Building Blocks:
- Oxidation: 2C unit (AcCoA)
- Synthesis: 2C unit (AcCoA)
Lipid biosynthesis: Activation by Malonyl-CoA
- Fatty acids are built from 2-C units (-> acetyl-CoA)
- Acetate units are activated for transfer by conversion to malonyl-CoA (-> costs ATP)
- Decarboxylation of malonyl-CoA and the reducing power of NADPH drive chain growth (decarboxylation is exergonic, highly energetic)
- Chain flows to 16-carbons
- Other enzymes add double bonds and/or more C’s (how? elongates and desaturates)
- —– proper elongation and desaturation of FAs are essential –> disruption may have devastating consequences
- —– “Although fatty acids are the simplest form of lipids, the length and pattern of saturation/desaturation of the aliphatic chain is essential for their function. Accordingly, proper elongation and desaturation of fatty acids are essential to the maintenance of lipid homeostasis and disruption of these processes may have devastating consequences”
Lipid biosynthesis: Acetyl-CoA Carboxylase
- “ACC enzyme” commits acetate to FA synthesis
- ACC the only FA biosynthesis component NOT part of the ‘enzyme complex’
- Carboxylation of acetyl-CoA to form malonyl-CoA is the irreversible committed step in FA biosynthesis —–> it’s regulated!!
- ACC uses bicarbonate, ATP —-> BIOTIN!
- Animal enzyme is one polypeptide with all three functions - biotin carboxyl carrier, biotin carboxylase and transcacrboxylase (E. coli enzyme has three separate subunits)
acetyl CoA + bicarbonate + ATP —-(acetyl CoA carboxylase)—> malonyl CoA
The Enzymes of Lipid Biosynthesis
Shuttling:
- citrate synthase
- malate DH
- PDH
- pyr. carboxylase
- ATP-citrate lyase
Synthesis - two components:
- acetyl-CoA carboxylase
- fatty acid synthase complex: malonyl transferase, beta-ketoacyl-ACP reductase, dehydratase
FA Synthesis
- Separate enzymes in a complex in bacteria/plants
- not a multi-enzyme complex
- decarboxylation drives condensation reaction of Ac-CoA and mal-CoA
- other three steps: reduction-dehydration-reduction (reverse of fatty acid degradation which is like TCA)
Fatty Acid Synthesis in Animals: form
- Fatty Acid Synthase (FAS) - a multi enzyme complex
- dimer of identical 250 kD subunits - each subunit a multifunctional polypeptide - arranged in head-to-tail fashion
- three functionally separate domains
Domain 1: acyl and malonyl binding and condensation
- acetyl transferase
- malonyl transferase
- beta-ketoacyl ACP synthase
Domain 2: reduction of domain 1 intermediate
- dehydratase
- beta-ketoacyl reductase
- enoyl-ACP reductase
Domain 3: liberation of palmitate product
- thioesterase
interplay of carbs and fats
lipogenesis
- when there is an oversupply of dietary CHO, excess CHO converted to triacylglycerol
How?
- synthesis of FA’s from acetyl-CoA and esterification of FA’s to triacylglycerol
- desaturation of FA’s (e.g. stearic -> oleic)
Other complex lipids made from assembly of isoprenoids:
- mevalonate pathway is key
- critical in steroidogenesis
Regulation of FA Synthesis
Allosteric modifiers:
- Malonyl-CoA inhibits carnitine acyltransferase: blocking uptake of fatty acylcarnitine by mitochondria and, thus, inhibits beta-oxidation
- Citrate ACTIVATES acetyl-CoA carboxylase
- Fatty acyl-CoAs INHIBITIS acetyl-CoA carboxylase
Phosphorylation & Hormones:
- Hormones regulate ACC thru post-translational modification
- Glucagon: activates lipase to cleave FAs from fat tissue, shut down ACC (Note: glucagon is associated with low blood glucose)
(Carnitine key to transport of long chain fatty acyl groups across the inner mitochondrial membrane)
Lipogenesis of Other Lipids
Series of critical precursors in non-FA lipogenesis:
- Phosphatidic acid -> glycerolipids
- Arachidonic acid -> eicosanoids
- Mevalonate -> cholesterol
- Cermaide -> sphingolipids
Biosynthesis of Other Lipids: Glycerolipids
Phosphatidic acid: is the precursor for all other glycerolipids in eukaryotes
- PA is made either into DAG or CDP-DAG
- precursor for synthesis of: PI, PC, PE, PS, cardiolipin
(membranes)
