Cellular Metabolism 2 - Lipids Flashcards
What are the 5 types of lipids?
- Free fatty acids (COOH)
- Triacylglycerols (or triglycerides)
- phospholipids
- Glyccolipids
- Steroids
How and where are fatty acids stored?
As triacylglycerolds (made of 3 fatty acids + glycerol) in the cytoplasm
The type of bond between a fatty acid and glycerol?
Ester
Why are fatty acids stored this way?
Because the ester linkages neutralise the carboxylic acid groups, helping keep the pH within the cell in a normal range
Why are fatty acids the ideal storage molecule?
Reduced + anhydrous
Which part of respiration does fat metabolism enter?
Fat metabolism leads to Acetyl CoA production, hence entering the Kreb’s/TCA Cycle
What are the 3 main sources of fats?
Diet
De novo biosynthesis (liver)
Adipocyte stores (found in connective tissue, fat stored as semi-liquid state)
Describe the process of lipid digestion:
Lipase breaks down triacylglycerols
Fatty acids, bile salts, cholesterol, fat-soluble lipids and lysophosphatidic acid make micelles
Micelles enter enterocytes (line the small intestine)
Triacylglycerol reformed
Modified into chylomicrons
Enter lymphatic system
Where are bile salts generated and stored, and what occurs if there is a lack of bile salts?
Generated in the liver, stored in the gallbladder. They emulsify fats - aids digestion by increasing surface area for lipases to act on.
Lack of bile salts leads to steatorrhea (fatty stool as a result of fat passing through the gut unabsorbed)
How can medications work to make them effective for treating obesity?
E.g. Orlistat (tetrahydrolipstatin) can be used as a potent inhibitor of gastric and pancreatic lipases, reducing fat absorption by almost 30%, most of which is passed out in the faeces
How do chylomicrons transport the triacylglycerols from the intestine around the body?
As chylomicrons are a type of lipoprotein, once they enter the bloodstream, they aquire apoproteins. The hydrophillic phospholipid monolayer, and apoproteins allow for the transportation of the core hydrophobic cholestrol esters and triacylglycerols
By what and where do chylomicrons get broken down?
They are broken down by lipoprotein lipases, found in the on the capillary endothelial cells lining adipose, heart and skeletal muscle
What happens once the chylomicrons are broken down?
Fatty acids undergo β-oxidation. Glycerol is returned to the liver for use in gluconeogenesis
What are the lipoproteins that transport fat to and from the liver? (Chylomicrons are from the intestine)
VLDL (very low density lipoproteins) - found in the liver and are responsible for endogenous fat transport
IDL (intermediate density lipoproteins) - comes from VLDL and is an LDL precursor (substance from which LDL can be made)
LDL (low density lipoproteins) - comes from IDL and is responsible for cholestrol transport from liver to peripheral tissues
HDL (high density lipoproteins) - comes from LDL and is responsible for reverse cholestrol transport from peripheral tissues to liver
What are cholestrol esters and where are they found?
Synthesized in the plasma from cholesterol and the acyl chain of phosphatidylcholine (lecithin) via a reaction catalyzed by lecithin:cholesterol acyltransferase (LCAT)
Makes up to 40% of the weight of LDL
What are the 3 main steps for making Acetyl CoA from Fatty Acids?
- Acyl CoA molecule made from fatty acids
- Transfer Acyl CoA into mitochondria via carnitine shuttle
- Beta Oxidation - finally produces Acetyl CoA
Step 1: Fatty Acid to Acyl CoA
R-COOH + ATP + HS-CoA —-Acyl CoA Synthetase—-> R-CO-S-CoA + AMP + PPi
Requires 2 high energy bonds, hence ATP is broken down to ADP, then again to AMP (+ 2 Pi)
Step 2: Carnitine Shuttle
Acyl CoA species generated on the outer mitochondrial membrane. It is coupled to the molecule Carnitine to form Acyl carnitine. Acyl carnitine moved into the matix by trabslocase, and is coupled with CoA to regenerate Acyl CoA and Cartinine. The Cartinine is then transported out of the matrix by translocase
What is Primary carnitine deficiency and what are the symptoms?
Autosomal recessive disorder, where a mutation on the gene that codes for the carnitine transporter results in reduced ability of cells to take up carnitine
Symptoms appear during infancy - cardiomyopathy (disease of the cardiac muscle), muscle weakness, hypoglycaemia (deficiency of glucose in the bloodstream)
What are the 4 reactions that happen to the Fatty Acyl CoA to produce Acetyl CoA?
- Oxidation
- Hydration
- Oxidation
- Thiolysis (Reaction with thiol R-SH, that cleaves one compound into two)
Step 3: Beta Oxidation Cycle
This cycle removes 2C from the fatty acyl CoA on each repeat, until the fatty acyl CoA is fully broken down:
1. Fatty acyl coA is oxidised to give off 2 hydrogens, accepted by FAD to form FADH2
2. Hydration, H2O added to the oxidised fatty acyl CoA
3. Fatty acyl CoA oxidised to give off a hydrogen, accepted by NAD+ to form NADH
4. Thiolysis as the acyl CoA molecule is split using HS-CoA into an acetyl CoA molecule, and leaves behind an acyl CoA molecule shortened by 2 carbons
HS-CoA comes and takes off 2C, acetyl coA is formed using Beta-ketothiolase
What happens on the final Beta Oxidation Cycle?
On the final cycle (4-carbon fatty acyl CoA intermediate), two acetyl CoA molecules are formed
Equation of palmitic acid (16C) generating Acetyl CoA:
Palmitoyl CoA + 7FAD + 7 NAD+ + 7H2O + 7CoA ——> 8 acetyl CoA + 7 FADH2 + 7 NADH
When can acetyl coA from beta oxidation enter TCA?
When beta oxidation and carbohydrate metabolism are balanced as oxaloacetate is needed
When is acetyl CoA from fatty acids used to make ketone bodies?
When fasting, fat metabolism overtakes glucose metabolism, so more acetyl CoA than oxaloacetate is produced. The excess Acetyl CoA is then used to make ketone bodies instead (as it cannot enter the TCA cycle without a corresponding oxaloacetate)
Which ketone bodies does Acetyl CoA make?
Forms acetoacetate, D-3-hydroxybutyrate and acetone known collectively as ketone bodies
How does palmitate metabolism compare to glucose metabolism in terms of no. of ATP produced?
Almost twice as many ATP molecules are produced per mole of lipid, compared to per mole of glucose
Which family of enzymes catalyse the initial step in each cycle of fatty acid β -oxidation?
Family of different Acyl-CoA-dehydrogenases
What is a disease to do with lipid metabolism?
Medium chain acyl coA dehydrogenase deficiency (MCADD)
Autosomal recessive disorder, diagnosed with the heel prick test. The infant must not fast, fed every 10-12 hours at least, must have a high carbohydrate diet
What is lipogenesis?
The biosynthesis of fatty acids from acetyl CoA/ malonyl CoA (reverse of beta oxidation)
Which 2 enzymes are involved in biosynthesis of lipids (lipogenesis)?
Acetyl CoA carboxylase
Fatty acid synthase
What are the 4 reactions of lipogenesis? (and enzymes involved)
Decarboxylative Condensation
Reduction (ketoreductase)
Dehydration (dehydratase)
Reduction (enol reductase)
Step 1: Decarboxylative Condensation
Acetyl CoA —-acetyl CoA carboxylase—-> Malonyl CoA
Requires ATP to form ADP + Pi, and a bicarbonate ion (HCO3-) which donates a C, to make malonyl CoA (3C)
Malonyl acts as a donor of carbons, but before malonyl CoA can donate carbons to the acetyl CoA, both must be associated with carriers called ACP.
Acetyl CoA —-ACP + CoA-SH—-> Acetyl-ACP (uses acetyl-coA-ACP transferase)
Malonyl CoA —-ACP + CoA-SH—-> Malonyl-ACP (uses malonyl-coA-ACP transferase)
Acetyl-ACP + Malonyl-ACP —-> Acetoacetyl-ACP + ACP + CO2
This is a condensation and decarboxylation
What happens after the first step?
Steps 2 - 4, reduction (uses NADPH to form NADP+), dehydration (releases H2O), reduction (uses NADPH to form NADP+)
What is fatty acid synthase?
Big enzyme made up of seven smaller enzymes which catalyse all the reactions after the first step
How many times do these steps occur?
As many times it takes to get all the carbons that should be present in the fatty acid, e.g. for palmitate, the first step cycles round 7 times
Overall equation for lipogenesis if making palmitate acid:
AcetylCoA + 7 MalonylCoA + 14NADPH + 14H+ —-> palmitate + 7CO2 + 6H2O + 8CoA-SH + 14NADP+
Which enzyme carries out desaturation of fatty acids?
Fatty acyl-CoA desaturases
Key distinctions between lipogenesis and Beta Oxidation:
- ACP Vs CoA (as the carriers)
- NADPH (reduction) Vs NAD+/FAD (oxidation)
- Cytoplasm Vs Mitochondrial Matrix
In adults, where is de novo FA biosynthesis restricted to?
Liver, adipose tissue and lactating breasts
What occurs in certain cancer cells?
FA Synthesis is reactivated
What can drugs target to reduce cancerous tumour growth e.g. in ovarian cancer?
Inhibition of FA Synthetase by cerulenin (an antifungal antibiotic), to reduce FA synthesis, has been shown to reduce tumour growth of ovarian cancer cells
