Transcript L03_MitoOx
Overview of Fuel Oxidation II A/Prof Gareth Denyer [email protected] Beta-oxidation Swapping the CoA for carnitine allows the FA to get into the mitochondrial matrix Fatty acids Fatty acyl-CoA blood Fatty acyl-CoA Hydrogens removed by NAD Trapping involves attaching the FA to CoA cytoplasm NAD CoA matrix Acetyl-CoA Carnitine often sold as a ‘fat metaboliser’. Claim is that carnitine will help the transport of FA into matrix…. And that this will help burn fat. Sorry, unless you’re specifically deficient in carnitine, it doesn’t actually work.. NADH Fatty acyl-CoA (2 less carbons in FA) NAD • Nicotinamide adenine dinucleotide – Adenine nucleotide attached back-toback with a nucleotide that has nicotinamide as the “base” • Nicotinamide is made from nicotinic acid ribose PP – More commonly called NIACIN or Vitamin B3 – A supplement in our cereals! – Vital for fuel oxidation ribose • NAD not only rips hydrogens out of the fuels, it carries them around afterwards. – Actually rips out hydride ions – proton plus two electrons Nicotinamide Adenine base Beta-Oxidation • As the fatty acids lose hydrogens, they start to break up.. – – • • As a result, the FA becomes shorter by two carbons The process of H stripping and FA getting shorter happens sequentially – • They do so in a very regular way – by the loss of acetate groups These acetate groups are also carried around on CoA – so the acetate does not exist ‘by itself’ but rather as acetyl-CoA Until all the FA is converted into Acetyl CoA The scheme is often shown as a ‘sprial’ of degradation. – Fatty acyl-CoA NAD CoA FA(n-2)-CoA Acetyl-CoA NADH FA(n-4)-CoA Acetyl-CoA NADH FA(n-6)-CoA Acetyl-CoA NADH FA(n-8)-CoA Acetyl-CoA NADH NAD CoA NAD CoA NAD CoA With AcCoA and NADH coming off and NAD and CoA coming in. Acetyl-CoA Beta-Oxidation • Sequential cutting up of fatty acids – Into Acetyl CoA – With the release of NADH • And consumption of CoA and NAD, of course! • Occurs in the mitochondria • But what happens to the Acetyl CoA? Glucose Oxidation Glucose Transport into the cells requires GLUTs There are several forms of GLUT Glucose 6-phosphate More investment of ATP… and a bit of rearrangement Glucose blood Trapping involves phosphorylation Which uses a little ATP cytoplasm Fructose 1,6bisphosphate NAD matrix NAD rips out Hs, 6 carbon sugar breaks up into the 3-carbon pyruvate, and ATP is produced ADP NADH ATP Acetyl-CoA CO2 pyruvate pyruvate Hydrogens removed by NAD again… pyruvate breaks up Glucose Oxidation • First part happens in the cytoplasm – This section returns a very small amount of ATP – 2 ATPs per glucose • More energy will be extracted from pyruvate – Pyruvate transported into the mitochondria and further oxidised The Krebs Cycle Fuels Pyruvate and FA-CoA • Also called the Tricarboxylic acid (TCA) cycle or the Citric Acid cycle – DON’T PANIC… all you need to know is the POINT of the cycle Acetyl-CoA • It’s function is to rip out every last hydrogen and fully oxidise the carbons in acetyl CoA NAD NADH CO2 CO2 – So heaps of NADH is generated – And the carbon atoms in the fuels are made into carbon dioxide • So after all this, the fuels have been converted into carbon dioxide and Hs (which are carried around on NAD) • BUT WHAT’S THE POINT Energy in Hydrogen! • Hydrogen + Oxygen Water – Liberates a LOT of energy! – That’s how the Space Shuttle works! • We’re going to react the hydrogen in NADH with oxygen – But we’re going to do it in a controlled, stepwise manner in which the energy is harnessed as ATP e- Transport and H+ pumping • NADH passes H to a chain of electron transporting complexes in the inner mitochondrial membrane – • As the Hs move down the chain, protons are pumped from the matrix into the cytoplasm – – • This creates a PROTON GRADIENT Also called a pressure of protons H+ NADH H+ NAD H2O O2 The inner mitochondrial membrane is impermeable to protons – • The Hs are passed down the chain to oxygen This helps maintain the pressure! Note that NAD is regenerated by this H+ H+ Making ATP with H+ gradient • The protons flow (under pressure!) through the F0 channel in the inner mito membrane – – • H+ As they come in, they cause another protein (the banana shaped gamma-subunit!) to rotate The gamma subunit interacts with the subunits of the F1-ATPase to generate ATP from ADP and phosphate The ATP leaves the mitochondria – it does most of its work in the cytoplasm – – When ATP is used to do work, it turns back into ADP and phosphate The ADP and phosphate come back into the mitocondria to complete the cycle H+ ATP ADP ATP ADP H+ Fuels Acetyl-CoA H+ H+ ATP NAD H2O NADH CO2 O2 CO2 H+ H+ ADP