oxidative phosphorylation and gluconeogenesis Flashcards
Describe the mechanisms that are responsible for the generation of the energy that is used to drive oxidative phosphorylation.
ATP synthesis is coupled to flow of electrons from NADH and FADH2 to O2 in electron transport chain. Complexes I, III and IV generate a proton gradient by pumping H ions from mitochondrial matrix to inter-membranous space. Then ATP formation is drived by this gradient (chemiosmotic coupling)
Describe the components of the electron transport chain and their location within the mitochondria.
4 multi protein complexes located in inner mitochondrial membrane.
How many ATP can 1 NADH and 1 FADH2 make
NADH: 2.5 ATP. FADH2: 1.5 ATP
what is respiratory control
Tight coupling of electron flow and ATP synthesis in mitochondria assures that O2 consumption depends on availability of ADP. If this didn’t occur, there would be excessive generation of free radicals which could injure the cell
low vs high ADP affect on electron transport
Low ADP (high ATP) decreases the flow of electrons, which decreases O2 consumption. High ADP (low ATP) increases the flow of electrons, which increases O2 consumption
shuttle for NADH
Shuttle mechanisms transport electrons from cytosolic NADH produced in the cytosol by glycolysis into mitochondria. Glycerol-phosphate shuttle: 2 cytosolic NADH produce 3 ATP. Malate-aspartate shuttle: 2 cytosolic NADH produce 5 ATP
Describe the consequences of defects in electron transport.
Errors in mitochondrial function can result in dysfunction of neural tissue or skeletal muscle which present as progressive retinal dysfunction, encephalopathy or myopathy. This is due to reliance on glycolysis for energy, increased lactic acid and elevated venous oxygen levels
Describe the roles of PGC1a and sirtuins
The peroxisome proliferater-activated receptor gamma co-activator 1alpha (PGC1a) appears to be one of the key molecular mediators of mitochondrial proliferation which occurs with exercise training. Sirtuins improve mitochondrial function and increase with underfeeding.
Resveratrol
compound found in red wine which activates sirtuins
inhibitors of electron transport system
cyanide, carbon monoxide
Where does gluconeogenesis occur
mostly in cytosol, although pyruvate carboxylase is in mitochondria. Liver is most important site and kidney has capacity for gluconeogenesis, particularly under prolonged starvation
when does gluconeogenesis occur
during fasting, vigorous exercise, a low carbohydrate/high protein diet (Atkins), under conditions of stress when counter-regulatory hormones are high and in states of insulin resistance and type 2 diabetes
which cells/organs require glucose as sole/major source of energy
brain, RBC, renal medulla, sperm and embryonic tissues
List the major gluconeogenic precursors and where they come from.
lactate from skeletal muscle and RBCs, amino acids (alamine and glutamine particularly) from protein breakdown, and glycerol generated from hydrolysis of triglycerides
function of fatty acids in gluconeogenesis
Fatty acids are NOT converted into glucose b/c the 2 carbons that enter the TCA cycle as Acetyl CoA leave the TCA cycle as CO2, leaving no net carbons to contribute to glucose synthesis. Thus, the role of fatty acids is to provide energy for gluconeogenesis in the form of ATP
What is the Cori cycle
in RBC or exercising muscle, glucose is converted to lactate via glycolysis pathway. Lactate then diffuses into the bloodstream, is taken up by the liver and reconverted to pyruvate which can then be used as a gluconeogenic precursor resulting in the production of glucose
3 irreversible steps of glycolysis
a. Pyruvate kinase/PEPCK (PEP + ADP—>pyruvate + ATP). b. Phosphofructokinase (F6P + ATP—-> F1,6BP). c. Hexokinase (Gluc + ATP —>G6P)
Identify the key enzymes in gluconeogenesis
Bypass rxns- bypass the irreversible steps of glycolysis. The enzymes are: pyruvate carboxylase, phosphoenol pyruvate carboxykinase (PEPCK), fructose 1,6 bisphosphatase, and glucose-6-phosphatase
function of pyruvate carboxylase
after pyruvate is transported into mitochondria (or gnerated from alanine) Pyruvate + HCO-3 + ATP —–> oxoaloacetate (OAA) + ADP + Pi. Requires biotin as coenzyme
Biotin deficiency
leads to build-up of pyruvate, which is converted to lactic acid and leads to lactic acidosis.
Malate dehydrogenase function
oxoaloacetate has to leave the mitochondria to be converted to glucose but in order to do this it must be converted to malate. This enzyme Catalyzes OAA + NADH +H+ ———> malate + NAD+ in the mitochondria. Then, in cytosol, the cytosolic form of this enzyme catalyzes the reverse rxn, regenerating OAA.
Function of Phosphoenol pyruvate carboxykinase
in cytosol, OAA + GTP phosphoenolpyruvate + CO2 + GDP.
Where does the ATP and GTP required for formation of PEP come from
oxidation of fat- glucose supplies are low
function of fructose 1,6 bisphosphatase
Conversion of fructose 1,6 Bisphosphate (F1,6BP) to fructose 6 phosphate. This enzyme is part of a bifunctional enzyme used in glycolysis.
key regulator of fructose 1,6 bisphosphate
fructose 2,6 bisphosphate and phosphorylation
Describe the mechanisms responsible for the coordinate regulation of glycolysis/gluconeogenesis.
regulation of phosphofructokinase-2 and fructose 2,6 bisphosphatase. High glucagon and low insulin causes increased activity of Protein Kinase A which phosphorylates PFK-2/FBP-2 complex. Phosphorylated PFK-2 becomes inactive and FBP-2 becomes active leading to decreased levels of fructose 2,6 bisphosphate, decreasing inhibition of FBP-1, leading to increased rate of gluconeogenesis.
function of glucose-6-phosphatase
Conversion of glucose-6-phosphate to glucose. Found in membrane of endoplasmic reticulum in hepatocytes and kidney cells. Not found in brain or muscle, thus the only tissues that can export glucose are liver and kidneys.
Von Gierkes disease
autosomal recessive (AR), deficiency of G-6-phosphatase in liver. Glycogen is normal but affected individuals have severe fasting hypoglycemia, ketosis, lactic acidosis, enlarged liver and kidneys
what compounds can be used for glucose synthesis
citrate, isocitrate, α-KG, succinyl coA, succinate, fumarate and malate-all can undergo oxidation to OAA. Amino acids can be catabolized to pyruvate and are said to be glucogenic. Glycerol released from adipose tissue during the breakdown of triglyceride, can enter the gluconeogenic pathway at the level of glyceraldehyde 3 phosphate.
List the unique roles of muscle, red blood cells, adipose tissue, liver, and kidney in the process of gluconeogenesis.
Muscle and RBC make lactate, used for gluconeogenesis. Liver and kidney make glucose. Triglycerides from adipose tissue used as precursor
