metabolismo lipídico II Flashcards
FA/TAG cycle ?
TAGs and obesity ?
What’s special about fat?
balance of FA esterification (for storage) and TAG lipolysis (for energy production and lipid synthesis) allows sufficient FA flux without toxic FA build-up
• More energy per unit weight from fat (9 vs 4 kcal/gm)
• Fat is more compactly stored than carbohydrate
• Glucose and glycogen are for short-term energy needs, quick delivery
• Fats are for long-term (months) energy needs, good storage, slow delivery
The Big Picture of Fat Metabolism ?
COMING LATER
Preparation and transport of FA’s prior to oxidation ?
Fatty acid trasnport proteins and Binding proteins get FA’s into the cytoplasm
source of carnitine ?
carnitine deficiency ?
Carnitine is acquired from diet (meat, dairy); also synthesized from lysine
strategy of beta oxidation ? The Four Steps of Beta Oxidation ?
Oxidation
why beta oxidation ?
the C-C bond between methylene groups in fatty acids is quite stable > the first three rxns of beta oxidation create a less stable bond by sequestering the alpha carbon between two carbonyls (beta ketoacyl coA) and then thiolase splits the 2-C fragment at fourth rxn.
palmitoyl coA — acyl coA dehydrogenase — trans enoyl coA
* Results in trans double bond, different from naturally occurring unsaturated FA’s
* e- pair from FADH2 into ETC –> ETF (electron transferring flavoprotein) –> ETF-Q oxidoreductase –> Q
* Acyl CoA dehydrogenase family; soluble matrix enzymes specific for long-, medium- or short-chain acyl CoAs por ejemplo: MCAD, Medium- Chain (C6-C12) Acyl Dehydrogenase, membrane-bound system for very long chain acyl coA’s
*Common genetic defect in FA catabolism due to recessive mutation in MCAD (1 in 10,000); treatment - carbohydrate-rich diet
• Infants are affected by MCAD deficiency since milk has mainly medium- chain fatty acids
trans enoyl coA – enoyl coA hydratase – beta hydroxy acyl coA
*Catalyzed by two isoforms of enoyl-CoA hydratase:
– Soluble short-chain hydratase
– Membrane-bound long- chain hydratase, part of trifunctional complex; Mitochondrial trifunctional protein (MTP) is a protein attached to the inner mitochondrial membrane which catalyzes three out of the four steps in beta oxidation; enoyl coA hydratase; beta hydroxy acyl coA dehydrogenase, and thiolase - note that palmitoyl coA dehydrogenase aint part of the complex
*the enoyl-CoA hydratase acts only on a trans double bond
beta hydroxy acyl coA – beta hydroxy acyl coA dehydrogenase – beto ketoacyl coA
*uses NAD as hydride acceptor
*NADH donates electrons to Complex I (NADH dehydrogenase) of ETC
beta ketoacyl coA — thiolase/ acyl coA acetyl transferase — acetyl coA + 14-C unit (myristoyl coA)
*beta carbonyl of beta ketoacyl coA is electrophilic while active site thiolate is nucleophilic
NOTE: Steps 2- 4 for FA >C12 are carried out by a multienzyme complex (trifunctional protein) in the mitochondria inner membrane; shorter fatty acids are processed by soluble matrix enzymes
Energy yield from palmitoyl oxidation ?
16 C’s –? 16/2 = 8 acetyl coA’s –> 7 cycles
1 FADH2 &1 NADH per cycle >
7 FADH2 and 7 NADH >
7(1.5) + 7(2.5) = 28
10 ATP’s per one TCA cyce –> 8*10 = 80 ATP
80+28 = 108
108-2 = 106 (activation cost)
oxidation of unsaturated fatty acids ?
energy yield ~less since unsaturated fatty acids are already partially oxidized
Two additional enzymes are required
– Isomerase: converts cis double bonds starting at carbon 3 to trans double bonds
why isomerase ? sine enoyl coA hydratase only functions with trans double bonds
– Reductase: reduces cis double bonds not at carbon 3
- Monounsaturated fatty acids require the isomerase
- Polyunsaturated fatty acids require both enzymes,
the isomerase and the reductase
*dienoyl coA reductase is NADPH dependent > NADPH expended to mend every double bond that counts after the first
oxidation of odd-chain fatty acids ?
propinoyl coA –> methylmalonyl coA – coenzyme B12 – succinyl coA (TCA cycle)
Note: conversion of propionyl-CoA to succinyl-CoA is also involved in the catabolism of certain glucogenic amino acids such as isoleucine and valine
Chain shortening of very long chained fatty acids (VLCFAs) ?
Chain-shortening is selective for very long chain fatty acids (24-26 carbons) that are transported into peroxisomes as acyl-CoA derivatives by an ATP-Binding Cassette (ABC) transporter
*step 1 - electrons go straight to O2, making peroxide that is cleaved by catalase; no ATP is ultimately produced by this step
*the NADH formed in the second oxidative step cannot be reoxidized in the peroxisome or glyoxysome, so reducing equivalents are exported to the cytosol, eventually entering mitochondria.
*The acetyl-CoA produced by peroxisomes and glyoxysomes is also exported;
the acetate from glyoxysomes (organelles found only in germinating seeds) serves as a biosynthetic precursor.
Acetyl-CoA produced in mitochondria is further oxidized in the citric acid cycle.
ADRENOLEUKODYSTROPHY (ALD) ?
ABC transporter defect (VLCFAs not transported into peroxisomes)
Monounsaturated fatty acids (C18:1 & C20:1) (Lorenzo’s oil) compete with saturated FAs for elongation, alleviating symptoms of VLCFA accumulation
carbon source of ketone bodies ?
ketone body synthesis ?
cytosolic Vs. mitochondrial HMG coA synthetase ?
statins?
Ketogenesis at starvation ?
fasting/diabetes –> TAGs mobilized –> beta oxidation –> replete acetyl coA –> inhibits PDH –> activates PC –> oxaloacetate produced used for gluconeogenesis rather than TCA cycle –> acetyl coA is spared for ketone body formation
*thiolase catalyzes the condensation of two acetyl-CoA molecules to acetoacetyl-CoA: the parent compound of the three ketone bodies.
*Acetoacetyl coA – MITOCHONDRIAL HMG-CoA synthase –> HMG-coA
^HMG-CoA is synthesized by parallel pathways in the mitochondrial matrix and in the cytosol;The matrix pool is used for ketone body production whereas the cytosolic pool is used for isoprenoid/ sterol biosynthesis
*HMG-CoA – HMG-coA lyase –> acetoacetate & hydroxybutyrate
*acetoacetate – acetoacetate decarboxylase –> acetone
Not to be confused with HMG-CoA reductase (!) which is needed for isoprenoid bioynthesis, inhibited by statins, and located in the ER of all cells
**Statins (or HMG-CoA reductase inhibitors) are a class of cholesterol lowering drugs that inhibit the enzyme HMG-CoA reductase which plays a central role in the production of cholesterol. High cholesterol levels have been associated with cardiovascular disease (CVD). Statins have been found to prevent cardiovascular disease and mortality in those who are at high risk.
When the rate of ketogenesis increases (during starvation/fasting or diabetes) the body is said to be in a state of ketosis (test for fruity odor of acetone in exhaled air); ketoacidosis (blood pH lowered because of increase in ketone bodies (which are really carboxylic acids)
*Ketone bodies are a source of energy for peripheral tissues; during fasting/starvation, the brain uses acetoacetate instead of glucose
* NOTE: Fatty acids cannot serve as a fuel for the brain possibly because they do not cross the blood- brain barrier
How are ketone bodies metabolized in extrahepatic tissue ?
acetoacetate is converted into acetoacetyl coA via thiophorase, and then into 2 acetyl coA molecules via thiolase.
MCAD deficiency Vs. ALD
ALD: defect in ABC transporter responsible for escorting VLCFA coA derivatives into peroxisomes for shortening > accumulation of saturated VLCFAs (C24:0 & C26:0; mainly biosynthetic in origin), in brain and adrenal glands; less so in other tissues
>Causes demyelination of the CNS & adrenal insufficiency
MCAD: the first step in beta oxidation requires an acyl coA dehydrogenase. Acyl CoA dehydrogenase family: soluble mito matrix enzymes specific for long-, medium- or short-chain acyl CoAs; #recessive mutation in MCAD: medium chain fatty acids not metabolized since they lack the dehydrogenase of the first step
