Fat Metabolism Flashcards
What are the products of one turn of the TCA cycle?
2 CO2
3 NADH
1 GTP
1 FADH2
Why does TCA only operate under aerobic conditions?
The re-oxidation of of coenzymes is what generates the bulk of ATP in Oxidative phosphorylation
Why can Amino Acids also enter the TCA cycle?
Degradation removes amino group. Can be fed into Krebs cycle (or production of glucose)
seven molecules can be made from degradation of 20 amino acids:
pyruvate, acetyl CoA, acetoacetyl CoA, a-ketoglutarate, succunyl CoA, fumarate, oxaloacetate.
What occurs in transamination reactions?
An amine group is transferred from one amino acid to a keto acid to create a new pair of amino and keto acids.
Alanine metabolism example of transamination reaction?
Alanina + Alpha ketoglutarate –> [alanine aminotransferase] pyruvate + glutamate
(pyruvate can enter TCA cycle)
How does NADH/high energy electrons cross cytosol into mitochondrial matrix?
Glycerol phosphate shuttle ( skeletal muscle and brain )
Malate-Aspartate shuttle ( liver, kidney and heart )
Glycerol Phosphate shuttle:
Electrons from (a) are carried across via a shuttle. Cytosolic (b) transfers electrons from NADH to (c) to generate glycerol-3-phosphate.
A membrane bound form of the same (d) transfers electrons to (e). these get passed to coenzyme Q, part of the electron transport chain
a - NADH
b - glycerol - 3 - phosphate dehydrogenase
c - DHAP
d - enzyme
e - FAD
What reactions occur in the Malate-Aspartate shuttle?
Redox and transamination
How does the malate aspartate shuttle transfer electrons?
Malate is shuttled in through a porter and undergoes oxidation to oxaloacetate so NADH is reduced in the process.
The oxaloacetate is turned to aspartate through transamination and an antiporter take it back out.
Aspartate reverses back into malate and cycle continues.
How many ATP molecules are creates eventually from the oxidation of one acetyl CoA?
Krebs: 3 NADH ( 9 atp ) 1 FADH2 ( 2 atp ) 1 GTP ( 1 atp )
total = 12 ATP
What is the Warburg effect and why is it linked to cancer?
Preferential generation of lactate from glucose even under conditions of ample Oxygen
Mutations in TCA genes decrease TCA activity but enhance aerobic glycolysis which leads to a preference of lactate generation.
which enzymes in the TCA cycle can become mutated?
Isocitrate dehydrogenase
Succinate dehydrogenase
Fumerase
What are the five main classes of lipids?
- Free fatty acids
- Triacyglycerols = fatty acid storage ( linkages help keep caroboxylic groups neutral and pH normal )
- Phospholipids
- Glycolipids
- Steroids
What does fatty acid metabolism lead to?
Acetyl CoA production. Fats are broken down into fatty acids through beta oxidation.
How are Bile salts made and What do they do?
Generated by the Liver and stored in the gallbladder.
They pass from bile duct into the intestine. Emulsify fats aiding digestion and absorption of fats and fat soluble vitamins ADEK
Bile salts solubilize dietry fatty acids
What are examples of fat soluble vitamins?
A, D, E, K
What is Steatorrhea caused by?
Lack of bile salts results in majority of fats passing through gut undigested and unabsorbed leading to fatty stool
How is Orlistat used to treat obesity?
Inhibits gastric/pancreatic lipases
reduced fat absorption by 30%
side effects : abdominal pain, urgency to defecate, increased flatus and steatorrhea.
- tetrahydrolipstatin
- product of streptomyces toxytricini
- effective in treating obesity for 2 years
What types of Lipoproteins are there and what roles does each one have?
Chylomicrons : Made in intestine - used in dietary fat transport
Very LDL : made in Liver - Endogenous fat transport from liver
IDL : made by VLDL - LDL precursor
LDL : made by IDL - Cholesterol transport away from liver
HDL - made in Liver - Reverse cholesterol transport
How is a Chylomicron made?
Triglycerides are made by digested dietary products absorbed by enterocytes.
These are resynthesied by various enzymes and out into the chylomicron
The CM They get apoproteins from HDL when the CM are released from the lymphatics into bloodstream. So the outer shell is complete with apoproteins and phospholipids
How does Lipoprotein Lipase break down CMs?
CMs travel from lacteals of intestine to thoracic duct and to left subclavian vein, enter bloodstream
Lipoprotein Lipase in endothelial lining recognises apoproteins on CM
- found on adipose, heart, skeletal muscle endotheliam
Break down CM into fatty acids : Beta oxidation
Glycerol : liver for gluconeogenesis
What is the anatomy of a Lipoprotein like?
Phospholipid monolayer contains cholesterols and apoproteins. This surrounds the core made up of cholesterol esters and triglycerides.
- v similar to chylomicron as a CM is a type of LP
How and where are Cholesterol Esters synthesised? Which enzyme is involved?
In the plasma
From cholesterol and Acyl chain of phosphatidylcholine (Lectithin) via a reaction catalysed by lecthinin:cholesterol acyltransferase (LCAT)
- converting cholesterol to cholesteryl esters more cholesterol can be packaged into the interior of lipoproteins
What does LDL get uptaked by?
Macrophages
Liver
What role does HDL play in LDL synthesis?
IDL is a precursor to LDL, HDL transfers cholesterol esters for LDL to be made.
How do HDLs lower total serum cholesterol?
Take Cholesterol from peripheral tissues back to the liver for use or disposal
Why are LDLs known as bad cholesterol?
Prolonged elevation of LDL levels leads to atherosclerosis ( hardening of arteries )
transports cholesterol made in liver to peripheral tissues
How are fatty acids converted into acyl-CoA species?
1st step of beta oxidation
fatty acid + ATP + HS-CoA [ Acyl CoA synthetase ] –>
Acyl CoA + CoA + AMP + PPi
AMP: monophosphate made by ATP, 2 high energy bonds used
How is Acyl CoA transported into matrix of mitochondria?
Carnitine shuttle:
In cytoplasm:
Carnitine –> Acyl Carnitine ( Acyl CoA becomes CoA through this)
Acyl Carnitine travels into matrix through translocase
Acyl Carnitine –> Carnitine ( CoA becomes Acyl CoA inside)
Carnitine shuttled out through translocase
Enzymes involved = carnitine acyltransferase I, carnitine acyltransferase II
What are the characteristics of Primary Carnitine deficiency?
What can ease symptoms?
Autosomal Recessive
Early symptoms : encephalopathies ( cardiomyopathies, muscle weakness, hypoglycaemia )
Mutations in SLC22A5 gene which encodes carnitine transporter = reduction in cells ability to take up carnitine needed for beta oxidation of fatty acids
Carnitor/ Levocarnitine used as supplement
- symptoms due to lack of energy made from fatty acids
How does Acyl CoA become Acetyl CoA?
Beta oxidation occurs involving a sequence of oxidation, hydration, oxidation and thiolysis reactions.
Resulting in Acetyl CoA which is 2 carbons shorter
Beta oxidation cycle
How many molecules does 16 carbon Palmitoyl CoA produce of Acetyl CoA?
8 Molecules. Each cycle of Beta oxidation also creates FADH2 and NADH. Overall are 7 cycles:
Acyl CoA + 7FAD + 7NAD+ +7H2O + 7 CoA –>
8 Acetyl CoA + 7 FADH2 + 7NADH
Why is fatty acid metabolism dependent on carbohydrate metabolism for entry into TCA cycle?
Acetyl CoA generated by Beta oxidation needs a balanced carbohydrate metabolism to provide oxaloacetate for entry into TCA.
Why do Ketone bodies form?
When fatty acid metabolism dominates over carb metabolism and Acetyl CoA generated by Beta oxidation cannot enter TCA cycle. e.g. fasting
Acetyl CoA forms Acetoacetate, D-3 hydroxybutyrate and acetone collectively known as ketone bodies
What is fatty acid biosynthesis?
How are the chains elongated?
Different to Beta Oxidation ( degradation of fatty acids )
Involves two enzymes
fatty acids are formed sequentially by decarboxylative condensation reactions involving acetyl-CoA and malonyl CoA
Following each round of elongation, fatty acid undergoes reduction and dehydration by sequental action of Ketoreductase (KR) and dehydratase (DH) and enol reductase (ER) activity
The growing fatty acyl group is linked to an acyl carrier protein - ACP
What enzymes are involved in Fatty acid synthesis?
Acetyl CoA carboxylase and fatty acid synthase
What are the differences between Fatty acid synthesis and degradation ( beta oxidation )
Carriers:
ACP - synthesis
CoA - degradation
Reducing Power:
NADPH - synthesis
FAD/NAD+
Location:
Cytoplasm - synthesis
Mitochondrial Matrix - degradation
What is the overall reaction of Lipogenesis?
(c2) Acetyl CoA + (c3) 7 Malonyl CoA + 14 NADPH + 14 H+
–>
Palmitate (c16) + 7 CO2 + 6H2O + 8 CoA-SH + 14 NADP+
How are fatty acids which are longer than 16 carbons synthesised?
How are fatty acids desaturised?
Elongation of the acyl group can make fatty acids longer.
Occurs separately from palmitate synthesis in the mitochondria and ER
Desaturation: fatty Acyl-CoA desaturases
Where does FA synthesis occur?
What about in cancer cells?
Liver, Adipose tissue, Lactating breast
- evidence shows reactivation of FA synthesis also occurs in some cancer cells. Maybe for energy source.
If FA synthetase is targeted in cancer by Cerulenin ( antifungal antibiotic ) tumour growth of ovarian cancer cells reduced.
disorders of beta OX
Various acyl CoA dehydrogenases can catalyze the first step in the Beta OX cycle.
This is because each enzyme can bind to an acyl CoA of various lengths
- –> can have a Medium chain acyl-coenzyme A dehydrogenase deficiency = MCADD
- screened through heel prick test
- px should never go without food for more than 10-12 hours
- take glucose atleast so body is not dependent on fatty acids for energy
What are the characteristics of Medium chain Acyl-Coenzyme A dehydrogenase deficiency? (MCADD)
Autosomal recessive
Undiagnosed can be fatal
Px cannot go without food 10-12 hours, Adhere to high carb diet
body should not be dependent on fatty acids for energy
heel prick test screening
Fatty acids can be either saturated or unsaturated, give examples?
oleic acid - unsaturated - has a double bond kink
stearic acid - saturated - no double bonds
Where does fatty acid metabolism take place?
Fats turn into fatty acids in the cytosol, fatty acids turn into acetyl choline in the mitochondria
Extra missed information ?
- Lipoproteins are categorized according to density
- Glucose makes 38 ATP, Palmitate metabolism makes 129 ( 35 from beta oxidation, 96 from 8 acetyl Coa = 131-2 = 129
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